Coordination Chemistry Reviews 409 (2020) 213212

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Coordination Chemistry Reviews

journal homepage: www.elsevier.com/locate/ccr

Heterogeneous surface architectured metal-organic frameworks for

cancer therapy, imaging, and biosensing: A state-of-the-art review
Abhijeet Pandey a, Namdev Dhas b, Prashant Deshmukh c, Carlos Caro d, Pravin Patil e,
Maria Luisa García-Martín d,f, Bharath Padya a, Ajinkya Nikam a, Tejal Mehta b, Srinivas Mutalik a,⇑
a
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
b
Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
c
Department of Pharmaceutics, H. R Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
d
BIONAND, Andalusian Centre for Nanomedicine and Biotechnology, C/Severo Ochoa, 35, Junta de Andalucía, Universidad de Málaga, 29590 Campanillas Málaga, Spain
e
Department of Pharmaceutical Chemistry, H. R Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
f
Biomedical Research Networking Center in Bioengineering, Biomaterials &Nanomedicine (CIBER-BBN), Spain

a r t i c l e i n f o a b s t r a c t

Article history: With recent progress in inorganic material based nanoplatforms for cancer therapy and imaging, multiple
Received 20 October 2019 nano vehicles have been developed and evaluated. These recent advancements in material science led to
Accepted 19 January 2020 the development of metal organic frameworks (MOFs) and nano MOFs (nMOFs) as the potential and ver-
satile delivery platforms for cancer theranostic. With a vast amount of ongoing research on MOFs, various
surface architectured MOFs for with variable properties have been developed and tested. The concept of
subcellular targeted therapy of cancer has also been employed using MOFs which demonstrated signifi-
cantly enhanced anticancer therapy. These MOFs have been developed in a way to provide them stimuli-
responsive drug release property which can be utilized for externally guided therapy of cancer. Apart
from cellular and subcellular targeted platforms and stimuli-responsive platforms, MOFs have also been
explored in the field of bioimaging and biosensing. Multiple types of biosensing platforms based on MOFs
and nMOFs have been proposed for biosensing of biomolecules related to cancer for sensing and early
detection. The bioimaging probes based on MOFs have been employed for multiple diagnostic platforms.
The review gives the recent updates for the abovementioned topics along with the toxicity aspects of
MOFs for human use. The review overall gives a detailed overview of research done to date in the field
of MOFs based nanoplatforms for cancer theranostics.
Ó 2020 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Synthesis of MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1. Conventional synthesis methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2. Microwave-assisted synthesis of MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.3. Electrochemical synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.4. Sonochemical synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.5. Mechanochemical synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3. Surface functionalization of MOF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.1. Coordination modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.2. Post synthetic surface functionalization of MOF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.2.1. Covalent bond based post-synthetic surface functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.2.2. Non-covalent bond based post-synthetic surface functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4. Mofs based therapeutic platform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1. MoFs for hyperthermia and photothermal therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

⇑ Corresponding author at: Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka
State, India.
E-mail address: ss.mutalik@manipal.edu (S. Mutalik).

https://doi.org/10.1016/j.ccr.2020.213212
0010-8545/Ó 2020 Elsevier B.V. All rights reserved.
2 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

4.2. Imaging-guided photothermia therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4.3. Mofs for photodynamic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.4. Combination therapy of cancer (Hyperthermia/Photothermia/Photodynamic Therapy). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
5. Stimuli-Responsive therapeutic platform based on MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5.1. pH-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.2. Temperature-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.3. Ion-responsive MOFs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.4. Magnetically-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.5. Pressure-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.6. ATP-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.7. Hydrogen sulfide-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.8. Redox-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.9. Light-responsive MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
6. Sub-cellular tumor target MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
6.1. Mofs based Sub-cellular compartment & organelles targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
6.2. Mitochondrial targeted MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6.3. MoFs based targeted cargo delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
7. MOF based biosensing platform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
7.1. MOFs-polymer/metal composite biosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
7.2. MoFs based luminescent sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
8. MoFs as imaging platform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
8.1. Magnetic resonance imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
8.2. Computed tomography (CT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8.3. Positron emission tomography (PET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
8.4. Multimodal imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
9. Toxicity aspects of MOFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
10. Recent advancement in MOFs based therapeutic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
10.1. Advancements in MOFs based radiotherapy and delivery of nucleic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
10.2. Advancements in MOFs based combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
10.3. Advancements in MOFs based biosensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Declatation of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

1. Introduction
Metal–Organic Frameworks (MOFs) or porous coordination sys-
tems are a class of cutting edge materials created by utilizing dif-
ferent metal ions and organic linkers. MOFs have been
developing as huge multifunctional crossover materials attributa-
ble to their characteristic advantages of natural linkers and inor-
ganic metal particles, tunable porosity, and differing usefulness.
They have risen as a broad class of crystalline materials with ultra-
high porosity (up to 90% free volume), considering numerous high-
lights, for example, warm security, ultra-low densities, discrete
arranged structure, enormous inner surface zone reaching out past
6000 m2/g, simplicity of union and with expansive range of prop-
erties appropriate for physical and substance applications [1].
From the last one and half decades, colossal research has been dis-
tributed on MOFs because of their more extensive relevance. MOFs
are unrivaled enthusiasm for potential applications in clean vital-
ity, most fundamentally as capacity media for gases, for example,
hydrogen and methane or detachment of gases, catalysis, and as
high-limit adsorbents to meet different division needs. Extra appli-
cations in layers, slender film gadgets, malignancy biomarker,
medicate conveyance, treatment and biomedical imaging are pro-
gressively picking up significance [2–5]. Anyway, there is more
prominent imperative to advance fundamental requirements for
the presentation of novel or streamlined functionalities of auxiliary
highlights and everlasting permeable conduct of MOFs to draw out
the chief applications towards ongoing regions of biomedicine,
attractive and electronic gadgets, proton conduction, supercapaci-
tors, battery-powered lithium-particle batteries and sensors [6–8].
Metal–natural structures are an adaptable and surprising class of
crystalline utilitarian materials with many intriguing properties
and incredible potential for various applications. Powerful fluores-
cence reaction in the vapor and additionally fluid stages can be
accomplished through the sound plan of tangible materials with
solid electron and vitality moves, appropriate porosity, and mole-
cule size, explicit utilitarian gatherings, and tunable electronic
structures. In the outline, both in the scholarly community and
industry, the transient diagram on structure and development of
MOFs and their applications prompted the fast progression,
improvement and common advancements in materials science.
Numerous manufactured plans accessible in writing could essen-
tially aid the structure and union of new materials of MOFs. The
unpretentious changes in the manufactured course could empower
the arranging of new MOFs with various system topologies. Albeit,
an assortment of MOF materials have been combined by a few ana-
lysts, there is an incredible need to have a complete comprehen-
sion of these materials. There is a lot of space for research to
investigate new materials and to abuse new domains for potential
applications. In the finish, the ache to explain a considerable lot of
the natural and cultural issues can be extinguished through the
improvement and planning of imaginative MOFs. Besides, there is
constantly a requirement for high affectability, specifically, worthy
security, the wide straight scope of the analyte focus, proposing
that MOFs can be filled in as a significant instrument for clinical
malignancy diagnostics. Different kinds of MOFs have been inves-
tigated and detailed having different compositions and shapes.
Based upon the technique for the union, the combination condi-
tion, and antecedent, the shape and size of the MOFs can be bal-
anced. Aside from the shape and size, the expansion of polluting
influence can help in a blend of doped MOFs with wanted proper-
ties. The combination of MOFs has been finished utilizing antece-
dent and chelating ligand which vary in physical and concoction
properties. Various kinds of MOFs have been orchestrated so far,
for example, heterogeneous composite MOFs, mesoporous MOFs,
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
blended metal MOFs, crystalline MOFs, MOFs nanosheets, Zirco-
nium based MOFs, Titanium-based MOFs, Iron-based MOF
cyclodextrin based MOFs, Silica based MOFs, Gallium based MOFs
and protein-based MOFs to name few. These MOFs have various
properties that can be investigated in treatment and indicative of
disease. Contingent upon size, the nano MOFs have been investi-
gated for subcell focused on the treatment of malignancy, such
as mitochondria focused treatment. The particular focusing of sub-
cell organelle has been finished by a reasonable surface change of
nano MOFs. Numerous surface adjusting gatherings have been
investigated, for example, polymer, polysaccharide, protein, apta-
mer, nucleic corrosive, DNA and so on for focused treatment of
tumor. The MOFs have the flexibility both as far as size, shape,
arrangement, and biodegradation. The ongoing headway in MOFs
based frameworks has given an adaptable stage to malignant
growth theranostic utilizing MOFs [9].
The present article portrays in insights concerning the adaptable
idea of MOFs as for treatment, imaging, and biosensing of malig-
nancy. The article gives a point by point audit about the different
restorative stages dependent on MOFs for malignant growth treat-
ment. The MOFs based remedial mediation incorporates the cell
and sub-cell focused on MOFs. Different surface alteration
approaches for MOFs have been likewise talked about. The article
likewise audits about the different MOFs based imaging and
biosensing modalities for disease. The article gives a brief review
of the ongoing headways in MOFs based on the theranostic applica-
tion regarding disease treatment. A different area has been included
in regards to the biodegradation and harmfulness parts of MOFs.
2. Synthesis of MOFs
Various method for synthesis of MOFs has been proposed to
achieve MOFs with desired size, surface topology, chemical content
and area of use. The MOFs are generally designed to tune the shape
and surface morphology of MOFs which in return depends on var-
ious other factors. We are going to discuss the various method of
MOFs synthesis along with alternative methods employed for
modulating and tuning the shape of MOFs. Fig. 1) gives an over-
view of different types of MOFs along with the synthesis methods
(Fig. 2).
2.1. Conventional synthesis methods
These synthesis methods are based on the application of heat
for designing MOFs. The temperature used to play a major role in
the type of MOFs being synthesized. These syntheses were termed
Fig. 1. Image depicting formation of MOFs using linker and metal ions.
3
as solvothermal or non solvothermal synthesis based on the type of
environment the synthesis is being done. Solvothermal synthesis
generally utilizes water as the solvent whereas non solvothermal
synthesis includes the use of solvents having boiling point more
than that of solvothermal synthesis. The non solvothermal method
is easy and is free of complex reaction setup. Various MOFs have
been synthesized using this method. In particular, mere mixing
of solutions without heating gave MOF-5, MOF-74, MOF-177,
HKUST-1, and ZIF-8. Solvothermal synthesis, on the other hand,
is useful when we need to synthesize crystalline MOFs. It gives
higher yields and better crystallinity of the product. The reaction
condition such as elevated pressure heats solvent which increases
the solubility of precursors leading to high yield and formation of
regularly spaced crystals. The non-solvothermal method has also
been used to synthesize MOF UiO-67 using ZrCl4 and terephthalic
acid as a linker with DMF as a solvent. It demonstrated a degrada-
tion temperature of 540 °C which is highest for MOFs [10–14]. The
conventional synthesis method is quite useful but in the case of
non-solvothermal synthesis methods, the selection of solvents
plays a vital role not only in deciding the shape and size of MOFs
but also the toxicity which has been discussed later in the article.
The advantage of high yield and formation of regularly spaced crys-
tals can be quite useful in designing MOFs for catalysis. The opti-
mization of solvent selection in non-solvothermal process will
help in keeping a balance between synthesis of MOFs with desired
quality attributes as well as toxicity.
2.2. Microwave-assisted synthesis of MOFs
The conventional techniques for synthesis of MOFs are gener-
ally time-consuming and the duration of the reaction is long. To
overcome this problem and synthesize MOFs in smaller durations,
this technique was developed. The one drawback of this technique
over conventional technique is the choice of solvent. In both
solvothermal and non-solvothermal techniques, the boiling point
of MOFs was considered before selection of solvent but in case of
microwave-assisted, the synthesis of MOFs, the choice of solvent
is done based on microwave absorption ability of solvent (Fig. 3).
The microwave absorption ability decides the efficiency of the sol-
vent to convert electromagnetic energy into heat to facilitate the
reaction. The second pre-requisite for initiating microwave-
assisted synthesis of MOFs is the reaction vessel as the penetration
depth depends on temperature. Therefore, for efficient heating in a
microwave oven, it is necessary either to use a container of appro-
priate volume or to stir the heated sample. In 2005, first MOFs
were synthesized using microwave radiation based synthesis.
4 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

Fig. 2. Various types of MOFs which can be synthesized.

Fig. 3. Microwave method for synthesis of MOFs.

The use of microwave radiation helped in reducing the reaction
time of MOFs such as MIL-100 from 96 h to 4 h using H3BTC as
the precursor and an aqueous solution of hydrofluoric acid. The
formation of MIL-100 was completed within 1 h but the complete
disappearance of chromium took place after 4 h [15].
Apart from MIL-100, MIL MIL-101 (Cr3F(H2O)2O[C6H4 (CO2)2]3)
was also synthesized using microwave radiation using terephtha-
late as a linker. The complete removal of impurity was observed
after irradiation for 60 min or more. It has been reported that the
irradiation time affects the particle size of MIL-101. Irradiation for
15 min led to the formation of MOFs with a size of 50 nm. In a sim-
ilar work involving the use of microwave radiation for MIL-101 syn-
thesis, amino-terephthalic acid was used as a linker in place of
terephthalate. Fe-MIL-101-NH2 MOFs with a crystal size of
200 nm was obtained within 5 min of microwave irradiation. The
published literature suggests a possible role of irradiation time,
type of linker used and irradiation power in deciding the particle
size of synthesized MOFs [16–22]. HKUST-1 was synthesized using
this method. From the above discussion, we can easily say that the
microwave synthesis method will helo reduce the time required for
the synthesis of MOFs but at the same time, this method might not
be useful for MOFs including proteins in their composition as core
or shell. The particle size can be modulated depending on irradia-
tion power and time. This can be used for the synthesis of core–shell
MOFs where the core can act as a seeding surface for MOFs to build
its structure. Although there has not been much report on the syn-
thesis of core-shell MOFs with a different core which is not MOF.
This method can be explored for the same.
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
2.3. Electrochemical synthesis
This method of MOF synthesis is based on the supply of metal
ions as the anode while the linker molecule is dissolved in reaction
mixture along with electrolyte. This method can be used for the
continuous production of MOFs. The deposition of metal ion from
anode onto cathode is suppressed by the use of protic solvents in
the reaction mixture (Fig. 4). In a similar work involving
hydrothermal method, non-solvothermal method and electro-
chemical method of synthesis, it was demonstrated that all three
methods give Cu3(BTC)2 phase having almost similar pore volumes
and surface area of HKUST-1 MOFs [23]. To exclude anions such as
chloride, perchlorate, and nitrate at the time to large-scale produc-
tion, the electrochemical synthesis route of MOFs was reported by
BASF. This method was utilized for the synthesis of multiple anode
combinations such as zinc, copper, magnesium, and cobalt with
linkers such a 1,3,5-H3BTC, 1,2,3-H3BTC, H2BDC, and H2BDC-
(OH)2]. Amongst these combinations, copper and zinc-based com-
pounds with high porosity were obtained [24]. Apart from MOFs
nanoparticles and porous nanoparticles, other MOFs structure
has also been tried. Patterned coating and film have been prepared
using HKUST-1. The growth of film was mediated by controlling
the reaction conditions carefully [25]. The galvanic replacement
method was also utilized as an alternative to the conventional
electrochemical method for the synthesis of MOFs. A film of small
octahedral crystallites with particle size between 100 and 200 nm
were synthesized using metallic Cu deposited on the glass slide.
H3BTC, DMSO, and AgNO3 were spin-coated on a copper-coated
glass slide where, silver ions oxidized copper leading to formation
of octahedral HKUST-1 crystallites [26]. Electrochemical synthesis
methods have been previously explored for the synthesis of porous
metal nanoparticles such as that of platinum and platinum bases
alloys. This method of MOFs synthesis can be combined with por-
ous metal nanoparticles to design a new class of porous core–shell
MOFs which can be further explored for catalysis or drug delivery.
2.4. Sonochemical synthesis
Sonochemical synthesis refers to the process of utilizing high-
energy ultrasound to a reaction mixture. The use of the Sonochem-
ical method of synthesis is quite limited and very few MOFs have
Fig. 4. Electrochemical method for synthesis of MOFs.
5
been synthesized using this method including MOF-5, MOF-177,
and HKUST-1 [27,28]. In an MOFs synthesis involving Zn carboxy-
lates, an aqueous solution of zinc acetate and metal and H3BTC as a
linker was mixed and in a mixture of ethanol and water and was
ultrasonicated at room temperature to obtain [Zn3(BTC)2] MOFs
[29]. The synthesis using this route was faster compared to the
solvothermal method of synthesis. Similarly, MOF-5 crystals were
obtained using NMP as solvent utilizing a horn-type reactor [30].
The duration of the reaction was 30 min. MOF-5 crystals have also
been reported to be synthesized using the same process but using
DMF in place of NMP as solvent [31]. In the case of HKUST-1, cop-
per acetate was mixed along with H3BTC in a mixed-solution of
DMF, ethyl alcohol and water. The reaction condition concerning
ultra-sonication time and strength, MOFs with different particle
sizes ranging from 10 nm to 40 nm were obtained. With an
increase in the reaction time, an increase in MOFs particle size
was observed leading to the formation of MOFs in size range of
50 nm to 200 nm. Apart from increase in particle size of MOFs,
degradation of MOFs was also observed with increase in duration
of reaction which was evident from blurred TEM images of
HKUST-1 showing irregular shape and morphology [31–33]. The
concentration of DMF affected the particle size as well as the
homogeneity of MOFs. In another synthesis of MOF-177, H3BTC
was mixed with NMP instead of DMF. The duration of the reaction
was 40 min and MOF-177 crystals having a particle size in the
range of 5–50 mm [34]. Two types of structures namely interpene-
trated and non-interpenetrated structures have been observed in
the case of PCN (PCN-6/PCN60) and IRMOF (IRMOF-9/IRMOF-10).
At low sonication power, non-interpenetrated structure dominates
while at higher sonication power interpenetrated structure domi-
nates. The intermediate sonication power leads to the formation
of a mixture of penetrated and non-penetrated structures.
2.5. Mechanochemical synthesis
Mechanochemical synthesis as the word suggest utilizes the
mechanical energy for the reaction. The mechanical breakage of
intramolecular bonds followed by a chemical transformation takes
place. The advantages of mechanochemical synthesis lie in the fact
that it can be carried out at room temperature and without using
solvent [35]. Apart from short reaction time, temperature and
6 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
solvent-free synthesis, this method also gives freedom to use metal
oxide salts as a precursor in place of metal salts which gives only
water as a byproduct. The metal oxide-based precursor is generally
not used due to their low solubility in solvents hence only
mechanochemical synthesis method is suitable in case of metal
oxides salt precursor such as in case of pillared-layered MOFs
and ZIFs involving zinc where zinc oxide was used as precursor
[36,37]. In a few cases, the addition of solvent in small quantity
helps in speeding up the mechanochemical reaction which is ter-
med as liquid assisted grinding (LAG) [38,39]. Along with speeding
up the reaction, LAG also exerts structure-directing properties.
Similar to LAG, ILAG (ion and liquid assisted grinding) was found
to be highly efficient for the selective construction of pillar-
Layered MOFs [40]. Many other MOFs such as HKUST-1 and Cu
(INA)2 have also been synthesized using this method.
3. Surface functionalization of MOF
MOFs owing to versatility in shape and size can be a potential
candidate for drug delivery. Porous MOFs with a large surface area
of pores is a convenient platform for designing functional materials
with tailored drug release. To make MOFs biocompatible and to
impart targeting ability and increase specificity, surface modifica-
tion needs to be employed. The metal sites of MOFs have no more
than one coordination vacancy (after removal of the solvent),
which limits the applicability of these materials (Table 1). Two
strategies have been used for surface modification of MOFs which
have been described briefly.
3.1. Coordination modulation
The coordination modulation strategy of surface modifications
just includes the incorporation of a monodentate ligand, which
has comparative chemical functionality to the existing multiden-
tate organic ligand, into the MOF synthesis reaction mixture. The
modulator, the incorporated ligand, competes with the bridging
ligands for the coordination to the metal ions; therefore a modula-
tor is responsible for inhibiting or inducing crystal growth [41]. On
account of the previous, the modulator controls nucleation to
accomplish MOF crystals of variable sizes relying upon concentra-
tion. In the last case, the modulator can be considered as a capping
agent, which terminates the network structure by coordinating to
the metal site where a polydentate ligand would typically be
found. The unavailability of additional binding sites on capping
agents terminates additional assembly of the network and thus
control over the surface chemistry and size of MOF crystal is
accomplished [41]. Guo et al. developed Ln-MOF (Ln(BTC)(H2O)
[where BTC = 1,3,5-benzenetricarboxylate and Ln = Tb3+,
Eu3 + or Dy3 + ] studied the use of sodium acetate as a capping
agent (has same chemical functionality as that of linker) for the
synthesis of bimetallic Eu1-xTbx-MOF nanocrystals by replacing
LnNO3
xH2O in the synthesis precursor with a mixture of Eu
(NO3)3
5H2O and Tb(NO3)3

5H2O The results demonstrated that
the obtained MOF nanocrystals have similar morphology and size
as that of single metallic Ln-MOFs and XRD diffraction patterns
are nearly similar demonstrating unchanged structure and mor-
phology. Additionally, sodium carboxylates such as sodium oxa-
late, sodium acetate or sodium formate were considered as
capping agents in synthesis of MOF to manipulate the morphology
and size of MOF crystal. Considering the same, Kitagawa et al
developed Ln-MOF without incorporating capping agent and
obtained Ln-MOF with a size of 60 mm. However, with the incorpo-
ration of capping agent, the significant changes have been obtained
in MOF size and shape. The results demonstrated that addition of
sodium acetate, the MOF with 90 nm in length and 75 nm in width
was obtained. Incorporation of sodium formate resulted in obtain-
ing uniform bean-like crystals with 125 nm long and 100 nm width
MOF crystals. Nevertheless, incorporation of sodium oxalate leads
to the formation of needle-shaped MOF crystals with a length of
30–60 mm. The drastic alteration in the size of MOF crystals due
to type of capping agents is due to 1) concerning sodium formate
and sodium acetate: their appropriate interactions with Ln cations
reduce the crystal growth resulting in uniform and smaller MOF.
Nevertheless, sodium oxalate fails to show a significant effect on
the MOF size. This is due to oxalic acid is dicarboxylic acid that
can be an organic linker for MOFs [42]. Furthermore, Carmona
et al developed [Al(OH)(SDC)]n, (H2SDC: 4,40 -stilbene dicarboxylic
acid) MOF and named it as CYCU-3, using coordination modulation
method to study the effect of the modulator on shape and size of
MOF. For the same, researchers screened various modulator/
ligands ratio (y = 5, 20 and 50) and reagent concentrations
(x = 20, 30, 40, 50 and 60) resulting into formation of twenty
CYCU-3 MOFs designated as CYCU-3 x_y. The effect of reagent con-
centration without the addition of modulator, PXRD study demon-
strated that higher reagent concentration (CYCU-3 60_0) when
utilized, more crystalline solids were recovered. However, less
amount of crystalline solids was obtained when diluted reagent
concentration is used i.e. (CYCU-3 20_0). Additionally, field emis-
sion scanning electron microscopy (FESEM) study demonstrated
that CYCU-3 30_0, CYCU-3 40_0, CYCU-3 50_0 and CYCU-3 60_0
were composed of particles in the micrometer range with bar-
like shape whereas CYCU-3 20_0 is composed particles in the range
of nanometer (100 nm) with pseudospherical in shape. The results
also showed that when higher reagent concentration used, more
heterogeneous materials involving agglomerated are obtained.
Moreover, the effect of modulator concentration with respect to
reagent concentration study resulted, that PXRD study revealed
that increase in the ratio of modulator did not show significant
changes in crystallinity of material. However, the utilization of
higher concentration of acetic acid (modulator) i.e. 50 times
greater than that of ligand constantly yielded low crystallinity
materials (CYCU-3 20_50, CYCU-3 30_50, CYCU-3 40_50, CYCU-3
50_50 and CYCU-3 60_50). Furthermore, the study revealed that
slight displacement of the most intense reflection to lower angle
(from 2h = 6.020 to 5.620), indicating the formation of a new phase.
Additionally, FESEM revealed that an increase in the modulator
ratio leads to the formation of longer needle-type material in all
cases. This fact can be explained considering the structure of
CYCU-3 in which the Al(III) ions are connected through OH bridges,
giving rise to 1D chains extended along the c-axis. Furthermore,
these secondary building units are linked through the SDC linkers,
leading to the formation of mono-dimensional channel structures
with triangular and hexagonal shapes. Therefore, the addition of
a modulator does not affect the Al-OH interactions and thus, does
not control the crystal growth along the c-axis. Besides, researchers
loaded the bioactive CO (carbon monoxide)-prodrug ALF794 in
selected three CYCU-3 materials (CYCU-3 20_0, CYCU-3 50_5 and
CYCU-3 50_50) and studied the effect of MOF features over the
properties of the resulting CORMAs (carbon monoxide releasing
materials). The results demonstrated that excluding CYCU-3
20_0, both hybrid materials retained the photoactive properties
of pristine CORM (carbon monoxide releasing molecule), with
CYCU-3 50_50@ALF794, demonstrated highest retention of metal
(molybdenum) fragments i.e. 75% of retention after 72 h, which
is the lowest value reported for the MOF based CORMA to date
[43]. The coordination modulation can regulate surface chemistry
and the size of MOF by reducing the size of the crystal and extraor-
dinary property enhancement. Additional research with certain
surface components, morphologies, and crystal facets could also
lead to the development of synthetic methods towards MOFs.
The method can also provide higher control over the self-
Table 1
MOF Table.

MOF Preparation Metal Surface Drug/ Cargo Size (nm) Route Loading (%) Cell line/s Animal Functions Refs.
method modification model
C18PMH-PEG-Hf-TCPP-MOF Hf C18PMHPEG – 130 Intravenous – 4 T1, HeLa, Balb/c TCPP as [56]
NIH3T3 mice photosensitizer for
photodynamic
therapy Hf4+ as
radio-sensitizer for
radiotherapy
RBC-ICG-UiO-66-O2-MOF Zr RBC – 50–60 Intravenous – RAW264.7, Balb/c nu Photodynamic [57]
membrane MCF-7 mice therapy against
hypoxic tumor
MIL-100(Fe)-OA-UCNPs Facile one-pot Fe MIL-100 DOX 32 Intravenous 72 L929, HeLa Female Chemotherapy, [58]
(NaGdF4:Yb,Tm@NaGdF4: liquid–solid- Kunming photothermal,
Yb,Nd) -DOX solution mouse photodynamic
method therapy
AuNRs/lipoic acid/ Solvothermal Zr MOF CPT Length: 53.8, Intravenous >25 4 T1 Female Combined [59]

A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

PEG@porphyrinic MOF- method Width: 25.2, Balb/c chemotherapy,
CPTWhere Porphyrinic is Zr6 Thickness of MOF mice photothermal and
(TCPP)1.5 shell: 8.1 (4 h) and photodynamic
13.2 (6 h) thrapy
Zr-fum MOFMIL-100 (Fe) MOF/- Zr, DOPC – 40–250 – – MLE12, MH- – Evaluation of [60]
DOPCMIL-101(Cr) MOF/- Fe, Cr S, HMEC, biosafety
DOPC Schwann concerning their
cells specific medical
application and
their interacting
primary cell types
UCNP (NaYF4:Yb,Er) /PVP@Fe- Fe PEG/FA – UCNP = 40; Intravenous – KB cells, Balb/c Luminescent/ [61]
MIL-101-NH2-PEG/-FA MOF = 120 with MCF-7 cells mice Magnetic dual
shell thicknesss 9 mode targeted
imaging
Fe3O4-NH2-CUR-Bio-MOF-5FU- Hydrothermal Zn CS-FA 5-FU Fe3O4-NH2 = 19– Intravenous 60 MDA-MB- Balb/c Targeted [62]
CS-FA method 50;Fe3O4-Bio- 231 (folate mice theranostic system
MOF = 42–80; receptor for cancer
Fe3O4-Bio-MOF- positive); treatment
CS-FA = 48–100 NIH-3 T3
(folate
receptor
negative)
Porphyrin-POPs (H2P-POP)– Zr Porphyrin- – 176 – – HepG2, HeLa – Photodynamic [63]
NH2-UiO-66-ICG POP cells therapy
UiO-66, TPP-SH, UiO-66-TPP- Solvothermal Zr TPP-SH – 140–142 – – HeLa cells – Photodynamic [64]
SH, and UiO-66-TCPP method therapy
FA-PDA-CPA-europium(III) ATRP strategy Eu FA – PDA-CPA = 176; FA- Intravenous – 4 T1 cells Balb/c Computer [65]
PDA-CPA-europium mice tomography/
(III) = 203 fluorescence dual
mode bioimaging
guided
photothermal
therapy
HA@ICG@MOF MIL-100 (Fe) NPs Fe HA ICG 100 and 106 Intravenous 40 MCF-7 cells Balb/c Targeted delivery [66]
and photothermal
therapy
Ce6@NH2-MIL-100 (Fe)-PEG- Fe FA Ce6,CPT 95 3.2%wt HeLa cells HeLa Chemotherapy and [67]
FACam@ Nh2-MIL-100 (Fe)- tumor photothermal and
PEG-FA bearing targeted therapy
mice

7
(continued on next page)
 8
Table 1 (continued)

MOF Preparation Metal Surface Drug/ Cargo Size (nm) Route Loading (%) Cell line/s Animal Functions Refs.
method modification model
MIL-53@cypate@PEG-Tf Fe Tf – 250 Intravenous – 293 T, A549, Male Multimodal [68]
MCF-7, HeLa Balb/c imaging and
cells nude guided
mice photothermal
therapy
Mn-IR825@PDA@PEG Mn PEG – 70 Intravenous – 4 T1, HeLa, Balb/c MRI guided [69]
A549 cells mice photothermal
therapy
GRGDS-NH2-/MTX@PNIPAM- Reverse Gd GRGDS MTX Length = 100–150 ; – 10–50 Canine – Theranostic and [70]
co-PNAOS-co-PFMA microemulsion Width = 20–25 endothelial targeted therapy
sarcoma cell
line
Cis-SiRNA (Bcl-2, P-glycoprotein Zr – Cis and SiRNAs 98, 103, 128 – Cis = 12.3SiRNA = 81.6 SKOV-3, – Co-delivery to [71]
[P-gp], and survivin)-UiO- A2780, PC-3, improve
NMOFs MCF-7, therapeutic

A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

H460, RAW efficacy in drug
264.7 cells resistant ovarian
cancer cells
FA-porphyrinic MOF (PCN-224); Zr FA – 90 – – HeLa, A549 – Targeted [72]
(PCN-224 monomer [Zr6 cells photodynamic
{TCPP}1.5]) therapy
BP@PDA-Ce6 and TPP nanosheet BP TPP Ce6 213.9 Intravenous – HeLa cells Mice Mitochondria [73]
MOF targeting,
synergistic
photothermal/
photodynamic
therapy
Zn-MOF-streptavidin-anti- Zn Anti-EpCAM DOX 5–40 mm – 45 MCF-7 cells – Targeted delivery [74]
EpCAM/ DOX system
DOX-ZIF-8@g-C3N4 Zn – DOX 60 – 35 A549 cells – Chemo- [75]
photothermal
therapy
F3-PEG-PGA-Py@DOX-UiO- Zr F3 DOX 250 Intravenous 1 mg DOX/ mg UiO-66 MDA-MB- Balb/c In vivo targeting [76]
66-89Zr 231, L929 mice and PET imaging
cells
[Ru(bpy)2+
3 -UiO-67 MOF Zr – – 92 – – A549 cells – Two photon [77]
fluorescence
imaging and
photodynamic
therapy
Se NPs and Ru NPs-Cysteine- Fe – SiRNA Se@MIL-101 = 160; Intravenous Se@MIL-101 = 6.92; MCF-7/T MCF-7/T SiRNA delivery [78]
MIL-101 (Fe)-SiRNA MOF Ru@MIL- 101 = 180 Ru@MIL- 101 = 8.13 cells cell platform
xenograft
mouse
model
5-FU/5-FAM-FA-NH2-Fe-MIL- Fe FA 5-FU 120 Intraperitoneal 23 MGC-803, Athymic MR/ Optical [79]
53 HASMC cells nude imaging and
mice targeted delivery
2I-BodipyPhNO2@ZIF-90 (1) Zr ZIF-90 – – – HepG2, – Mitochondria [80]
MCF-7 cells targeting
photodynamic
therapy
Table 1 (continued)

MOF Preparation Metal Surface Drug/ Cargo Size (nm) Route Loading (%) Cell line/s Animal Functions Refs.
method modification model
Rho/-BSA-Cu-NQ NPs MOF Cu – NQ (5-nitro-8- 70 Intravenous HPLC = 13.6;ICP- 4 T1, A549, Female Drug delivery [81]
hydroxyquinoline) MS = 62 HeLa cells ICR mice
and
female
Balb/c
mice
HA/-Polypyrrole (PPy)-MIL-53- Hydrothermal Fe HA DOX – Intravenous 90 4 T1 cells Balb/c Chemotherapy and [82]
DOX method mice photothermal
therapy
cRGD-@THA-NMOF-76@MB Rapid Eu cRGD MB 80–100 – 3 mg MB/ 1 mg THA- A549, HeLa – NIR-triggered and [83]
microwave- (III) NMOF-76 cells targeted two
assisted photon absorption
method photodynamic
therapy
IRMOF-3-CUR-FA Zn FA CUR 117 Intravenous DL = 52;EE = 98 MDA-MB- Balb/c Targeted delivery [84]

A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

231, 4 T1 mice platform for cancer
cells treatment
TPZ/-TCPP-Hf-DOPA-PIMA- Solvothermal Hf PEG TPZ 163 Intravenous 50 HeLa, 4 T1 Female Hypoxia-activated [85]
mPEG method cells Balb/c chemotherapy and
mice photodynamic
therapy
Porphyrinic-Zr-MOF (PCN-224)- Zr 140.5 DL = 32.9;EE = 98.3 4 T1, HUVEC, Balb/c Multifunctional [86]
apatinib@MnO2 Pan02, RAW nude nanoplatform for
264.7 cells mice tumor
DNA-NMOF (PCN-224)- Zr AS1411 DNA 144.7 Intravenous DNA = 6.1 nmol/mg MDA-MB- Mice DNA [87]
A30@T30-AuNPs/Aptamer particle 231, RAW functionalized
(AS1411) 264.7 platform for
biosensing,
nanomedicine,
bioimaging
DOX/Fe3O4@OCMC@IRMOF-3/ Fe FA DOX 250 – 163 mg/ 100 mg of L929, HeLa – pH sensitive [47]
FA-CDs NMOFs cells targeted delivery
platform
CTAB/MUA/-PEG-COOH-AuNPs- Fe CTAB – 89 Intravenous – MDA-MB- U87MG MRI, CT, PA [88]
MIL-88 (A) 231, MCF-7, tumor
U87MG, bearing
HepG2, mice
PANC-1
UiO-66@AgNCs@AS1411(Apt) Zr AS1411 DOX 200–400 – 46.7,98.0 MCF-7, L- – Targeted delivery [89]
@DOX (Apt) 929 cells system
Zr-NU-1000 MOF/calcein/ a- Zr – Calcein / a-CHC 150 nm,5 mm and – Calcein: NU-901 = 37.0 HeLa cells – Drug delivery [90]
CHCZr-NU-901 MOF/calcein/ 200 nm and 38.0;NU- platform
a-CHC 1000 = 41.6 and
19.7Α-CHC: 81
DOX-ZIF-8@GQDs MOF Zn – DOX 50–100 – 47 mg/ mg ZIF-8@GQDs 4 T1 cells – Synergistic photo- [91]
chemotherapy
UiO-66@polyaniline Zr Polyaniline – 100 Intravenous N content = 1.29 to CT26, Balb/c Photothermal [92]
3.12% and Zr HCT116 cells therapy for colon
content = 38.94 to cancer
35.30% after
introduction of
polyaniline on UiO-66

(continued on next page)

9
Table 1 (continued)

10
MOF Preparation Metal Surface Drug/ Cargo Size (nm) Route Loading (%) Cell line/s Animal Functions Refs.
method modification model
UiO-66@CyP (cyanine Zr CyP – 100 Intravenous, N content = 1.29 to HeLa, CT26, Balb/c Photothermal [93]
containing polymer) intratumor 3.84% andZr HCT116 cells mice therapy and
content = 38.94– fluorescence
32.65% after CyP imaging
introduction in UiO-66
Mn3[Co(CN)6]2@MIL-100(Fe)- Fe/ MIL-100(Fe) AS 170, 190, 200, 210 Intravenous 531 mg/ g of MOF HeLa, HTR8- Balb/c Multimodality [94]
AS (Artesunate) Mn SV neo cells mice imaging
PPy@UiO-66@WP6@PEI-FA NPs Zr FA 5-FU 150 Intravenous – L02, HeLa Femal Photothermal [95]
cells nude therapy and
mice chemotherapy
FA-IRMOF-3 Solvothermal Zn FA 5-FU 100 – 24 HeLa, A549, – Targeted delivery [48]
method KB cells platform
bezoporphyrin@MOF@PEG/ Zr PEG Benzoporphyrin 102.5 Intravenous – 4 T1 cells Balb/c Photothermal and [96]
FITC/aPD-1 mice immunotherapy
Texas red/CpG@MIL-100(Fe)-S- Fe CpG OVA, CpG 300 Subcutaneous 280 mg/ mg of MOF DC2.4, Female The reduction [97]

A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

S-OVA RAW264.7, C57BL/6 responsive co-
Splenocytes, mice delivery platform
E.G7 OVA for potent cellular
cells immune response
towards cancer
treatment
DOX HCL/verapamil HCL@ZIF- Zn FA DOX HCL, 185 Intravenous DOX = 8.9%; B16F10, Healthy Targeted delivery [98]
8@PEG-FA Verapamil HCL Verapamil = 32% MCF-7, MCF- Kunming platform and
7/A cells mice overcoming
multidrug
resistance
AuNS (nanostars)@MIL-101 Fe ZD2 – 255 Intravenous – MDA-MB- Female MRI and [99]
NH2 (Fe) MOF@PEG-ZD2 231, MDA- Balb/c photothermal
MB-435, mice therapy for triple
MDA-MB- negative breast
468, MCF-7 cancer
cells
Gd/Yb-BBDC-DOX@Glucose GD/ Glucose DOX 182 Oral 43.2% HeLa, Kunming Imaging guided [100]
Yb HUVEC cells mice precise-
chemotherapy
Cu(II)- Cu PEG – 207 (DLS),102 Intravenous Cu(II) = 12.18%; HepG2 cells SD mice Photoacaustic [101]
tetrahydroxyanthroquinone (TEM) THQ = 84.28% imaging guided
(THQ) i.e. [Cu(II)-THQ] photothermal and
n@PEG-NH2 chemotherapy
Zr/Mn-TCPP-MOF-DOX@SNO Zr/ SNO DOX 224.3; 265.5 Intravenous – MCF-7 cells Balb/c MRI guided nitric [102]
(S-nitrosothiol) Mn mice oxide and
photothermal
synergistic therapy
FITC-(Zr6 clusters and H2TCPP) Zr Pt – 90 Intratumor/ Pt content = 15.1% HeLa, 4 T1, Healthy Photothermal [103]
PCN-224@Pt MOF intravenous RAW264,7 female therapy
cells Kunming
mice
ZnO NPs-gated DOX@por Zr/ AS1411 DOX 161.7 Intravenous 72.90 HeLa, Female Targeted bimodal [104]
MOF@AS1411 Zn NIH3T3 cells Balb/c cancer therapy
nude platform
mice
Chlorin-TCPC@UiO-66 MOF Hf/ Zr UiO-66 – 183.7 Intravenous, Hf content = 59.7% HeLa, Mice Multi-modal [105]
intramuscularly HepG2, 4 T1, imaging guided
MCF-7 cells photothermal
therapy
Table 1 (continued)

MOF Preparation Metal Surface Drug/ Cargo Size (nm) Route Loading (%) Cell line/s Animal Functions Refs.
method modification model
Iron-TCPP MOF@BSA-SA Fe SA – 230 Intravenous – 4 T1 cells Female Targeting tumor [106]
(sulfonamide) Balb/c hypoxia by
mice carbonic
anhydrase IX
inhibition and T2/
T1 dual mode MRI
guided
photodynamic/
photothermal
therapy
AuNPs@PVP/CTAB@ZIF-8 Zn ZIF-8 DOX 140 Intravenous 0.358 mg/ mg of MOF 4 T1 cells Female Light and pH [107]
Balb/c stimuli responsive
mice drug release,
synergistic chemo-
photothermal

A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

therapy
DOX@HMONs@PDA@ICG@MOF Fe, MOF DOX, ICG 150–170 Intravenous DOX = 11.88%; 4 T1, MCF-7 Male ICR pH/NIR responsive [108]
(Fe and 1,3,5- PDA ICG = 19.52% cells mice and release and cancer
benzenetricarboxylic acid female theranostic
(H3BTC)) balb/c platform
mice
MIL-101(Fe)-SS-b-CD-RGD- Fe RGD DOX 100–200 Subcutaneous 13.4% HeLa, COS7 Female Multifunctional [51]
PEG@DOX MOF cells KM mice targeted delivery
platform
PMAABACy@(MOF)10@PDA Fe PDA DOX 224 – Loading = 0.9134 mg/ PC-3 cells – H2O2/GSH dual [109]
mg;EE = 91.34 responsive
delivery platform
CpG@MOF-OVA Eu CpG OVA 30 Subcutaneous 55 RAW264.7, C57BL/6j pH responsive [110]
B16-F10 mice release,
cells immunotherapy
MIL-100 (Fe) and MIL-101(Fe) Fe – CPT MIL-100 = 193MIL- – 18% HeLa, – pH responsive [111]
modification as follows– 101 = 117 fibroblast delivery platform
NH2, -Suc-CPT, click-CPT, 3 T3, SH-SY-
NH2 + CPT, RhB 5Y cells
PB@MIL-100(Fe)-ART Fe MIL-100 ART 190 Intravenous 0.8484 mg/ mg HeLa cells Female pH responsive [112]
(artemisinin) Balb/c drug delivery, dual
nude mode imaging
mice guided chemo/
photothermal
combinational
cancer therapy
ZIF-8ZnPc@ZIF-8ZnPc/ZIF- Zn CTAB ZnPc 99.1106.5225.083.5 – 0.295 mg/ mg HepG2 cells – pH controlled [113]
8ZnPc@ZIF-8/CTAB MOF delivery platform
and photodynamic
therapy
Fe3O4-MIL-100(Fe)-anti- Fe Anti-EpCAM – 110 – – MCF-7, – Self-release [114]
EpCAM HCT116, delivery platform
HeLa, HepG2 in the treatment of
cells cancer
CUR@MOF@M(DTBA)M = Al, Zr, Zr, – CUR 169.4 Intravenous Loading = 11.8% HeLa, MDA- Balb/c Redox responsive [115]
Fe Al, Fe EE = 78.8% MB-231 cells nude delivery platform
mice
DOX/Rhodamine-MOF@DNA- Zr PAA DOX 280–350Increases – 87.5 and 59.8 nmol/ MDA-MB- – Stimuli responsive [116]
PAA hydrogel to 400–450 mg;DOX = 72.6 nmol/ 231, MCF- delivery platform
mg 10A

(continued on next page)

11
 12
Table 1 (continued)

MOF Preparation Metal Surface Drug/ Cargo Size (nm) Route Loading (%) Cell line/s Animal Functions Refs.
method modification model
DOX/ZIF-8PDA-DOX-ZIF- Zr Aptamer DOX 118.8,123.1,129.9 Intravenous Loading = 9.12%; HeLa, MCF-7 Balb/c Stimuli responsive [117]
8Aptamer-PDA-DOX-ZIF-8 EE = 68.78% cells nude multifunctional
mice delivery platform
5-FU-MOF-808-FA5-FU-UiO-66- Zr FA 5-FU 100 – Loading inMOF- L929, HeLa – Active tumor [118]
NH2-FA 808 = 38.42%;UiO- cells targeting
66 = 30.26%
LA (lactobionic acid)–NH2-MIL- Fe LA DOX 40–50 – – HepG2, – Imaging and [119]
53(Al) HEK293 cells targeted delivery
platform
FA-CS@Bio-MOF@Fe3O4@CUR Hydrothermal Fe FA CUR/ 5-FU SEM = 48–100; Intravenous 60% MDA-MB- Balb/c Theranostic [62]
method DLS = 128.1 231, NIH- mice targeted delivery
3 T3 cells platform
NU-1000-TCPP@PEG-FA Zr FA – 160 Intravenous – HeLa cells Balb/c Photodynamic [120]
mice therapy
CS@Bio-MOF@DOX Co Cs DOX 200–400 – Loading = 40%; MCF-7, – pH responsive [121]

A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212

EE = 80.5% HUVEC cells delivery platform
for breast cancer
ZrMOF@PEG@TPP@DOX Zr TPP DOX 241.6 Intravenous Loading = 23.3%; – H22 TB Mitochondrial [122]
nanocubes EE = 26.4% mice targeting and
microwave
thermal therapy
against tumor
Fe3O4@IRMOF-3-FA Fe FA PTX 200 – 10% HeLa, NIH- – Delivery platform, [123]
3 T3 cells imaging and MRI
contrast agent
Hf-DBB-Ru-MOFHf-DBA-Ru- Hf Ru – 98.1 Intratumor – MC38, CT26 C57Bl/6 Mitochondrial [124]
MOF cells mice targeting,
radiotherapy and
radiodynamic
therapy
ZIF-8@CNPs-PEG MOF Zr PEG – 110 Intravenous – 293 T, A549 Balb/c Photoacoustic [125]
cells mice imaging guided
photothermal/
photodynamic
combined therapy
CUR-MIL-100(Fe)@PDA-HA Fe HA CUR 194.1 Intravenous Loading = 33.0%; HeLa, A549, Balb/c Photoacoustic [126]
EE = 94.3% MRC-5 cells nude imaging guided
mice chemo/
photothermal
tumor therapy
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
assembly of particles, as functionalization can be possible at the
surface of MOF [41]. From the above discussion, it is clear that
the coordination modulation depends on multiple factors such as
reagent concentration, temperature, and pH to name a few. Also,
depending on the reaction conditions and composition, the overall
structure of MOFs might change which can directly or indirectly
bring changes in properties of MOFs, one of which is crystallinity.
Although there are few limitations with this process, it is an effec-
tive method for surface modification of MOFs using dentate
ligands.
3.2. Post synthetic surface functionalization of MOF
3.2.1. Covalent bond based post-synthetic surface functionalization
There are just a few precedents where covalent alteration has
been restricted to the outside of a MOF, with two primary tech-
niques: (I) including usefulness that is too vast to even consider fit-
ting into the pores of the MOF, and (ii) specifically exposing
responsive moieties at the outside of the MOF just, with ensuing
surface-just adjustment. As far as possible the extent of surface
adjustment to either MOFs with little pores or surface design with
huge cumbersome units, thus a couple of models exist [41]. Cova-
lent surface modification is another type of post-synthetic method
to functionalize MOF and is entrenched, with various chemical
alterations equipped for encouraging bulk functionalization. The
covalent bond based post-synthetic functionalization of MOF
appears to be an efficient approach owing to their properties such
as imparting strength, chemical, and thermal stability to MOF as
compared to weaker coordination interactions [44–46]. Various
researchers have studied different kinds of covalent alterations
on the surface of MOF such as N-alkylation, click chemistry, amide
coupling, protonation, reduction, imine condensation, and bromi-
nation. It was explained, during a study of the covalent bond based
post-synthetic surface modification of IRMOF-3 with folic acid, that
reaction of the carboxylic group of folic acid with the amine group
of IRMOF-3. For the same free carboxylic groups of folic acid and
amine groups of IRMOF-3 were activated using carbodiimide cou-
pling agents to facilitate conjugation of CO-OH-H-NH groups. Fur-
thermore, larger molecules like proteins can also be conjugated
over the surface of MOF. Considering the same, another research
confirmed that the free carboxyl groups of linkers at the surface
of MOFs can be triggered using carbodiimide coupling agents to
facilitate bio-conjugation with various proteins. Three MOFs, the
three dimensional IRMOF-3, the two dimensional [Zn(bpydc)
(H2O)2]n [bpydc = 2,20 -bipyridine-5,50 -dicarboxylate] and the
one dimensional [In(1,4-pda)2(NEt2H2)]n [pda = phenylenediace
tate], were all triggered towards bio-conjugation with dicyclohexyl
carbodiimide (DCC) or 1-ethyl-3-(3-dimethyl aminopropyl) car-
bodiimide (EDC). Attachment to the protein surface was accom-
plished in aqueous buffer, was envisioned at first by utilizing
improved green fluorescent protein (EGFP), which was recognized
on the surfaces of the MOFs by CLSM [47]. As of late, Cohen and
colleagues started a precise examination of the covalent bond
based post-synthetic modification of porous MOFs. IRMOF-3,
which is the amino-substituted variant of IRMOF-1, was picked
as a model framework for the investigation of the covalent bond
based post-synthetic modification because of its presence of non-
coordinating NH2 groups on the 2-aminobenzenedicarboxylate
(NH2-BDC) linker, crystalline and exceptionally porous structure.
The underlying investigation concentrated on acetylation by
targeting acetic anhydride with amino groups of IRMOF-3. Under
ambient environment the activated IRMOF-3 crystals were treated
with dilute acetic anhydride solution in CDCl3. Within an hour, the
acetic acid byproduct was generated in the mother liquor as
dictated by 1H NMR, recommending that the MOF surface func-
tionalization is in process. The IRMOF-3 structural integrity was
13
confirmed as no obvious quantity of NH2-BDC ligand was recog-
nized in the bulk solvent. 1H NMR demonstrated that MOF crystals
after surface functionalization and digestion revealed that the pro-
duct, IRMOF-3-AM1, was composed of >85% acetylated NH2-BDC
ligand [48]. Furthermore, Zimpel et al. developed a MIL-100(Fe)
MOF platform which consists of iron clusters acting as nodes and
trimesic acid serving as linker molecules, which offers aromatic
carboxylic groups at the MOF surface. Furthermore, researchers
considered two distinct types of polymers 1) Stpio-C- oligoamino
amide based bi-functional linking polymer, offering thiol group
for additional functionalization or fluorescent labeling and a pri-
mary amine for conjugation with the surface of MOF; 2)
amino-PEG-5000-used to mediate surface shielding of MOF and
enhance colloidal stability. Both polymers were covalently bound
to the surface of MOF utilizing carbodiimide chemistry [49].
Gadzikwa et al. demonstrated for covalent bond based surface
functionalization of MOF utilizing CuI- catalyzed Huisgen
cycloaddition (CuAAC). The MOF synthesis involves 2,6-
naphthalenedicarboxylic acid (NDC), dimeric Zn(II) and bis(pyri-
dyl) ligand, 3-[(trimethylsilyl)ethynyl]-4-[2-(4-pyridinyl)ethenyl]
pyridine (L1). In the initial step, the MOF surface was desilylate
(deprotected) when treated with tetrabutylammonium fluoride
(THF). The process of deprotection was assured using matrix-
assisted laser desorption ionization time-of-flight mass spectrom-
etry (MALDI-TOF). Additionally, Ethidium bromide monoazide was
selected as azide conjugated with surface terminal alkynes owing
to its fluorescence which can be used to detect attachment, utiliz-
ing CuAAC. The fluorescence of the azide allowed for direct visual-
ization of the modification. Indeed, the depth profiling/confocal
microscopy imaging confirmed that the functionalization occurred
exclusively on the MOF surface [50]. Additionally, Wang et al. syn-
thesized DOX-MIL-101(Fe) MOF without the involvement of toxic
reagents and organic solvents using one-pot synthesis. The surface
functionalization of MOF was carried out by bicyclononyne func-
tionalized b-cyclodextrin (b-CD) derivatives (b-CD-SS-BCN) using
strain-promoted (3 + 2) azide-alkyne cycloaddition (SPAAC).
SPAAC is considered an efficient reaction in aqueous solution with-
out the use of Cu as a catalyst and has been used to modify MOFs in
bulk with high efficiency. The completion of SPAAC reaction
resulted in the formation of DOX-MIL-101(Fe)-SS-b-CD, making
them a versatile system that can be easily further functionalized
by taking advantage of the host–guest interaction between
hydrophobic molecules such as adamantane and b-CD. Addition-
ally, the supramolecular structures for a variety of applications
can be constructed through strong host–guest interaction between
adamantine and b-CD owing to their high association constant in
water (104–105/ M) [51]. The use of DCC for surface functionaliza-
tion of MOFs using this process might not go hand in hand with
aqueous solvents as DCC won’t work efficiently in tht case. But
with the growing interest in use of cyclodextrins (CDs) for surface
modification of MOFs will surely new avenue for multidrug loading
on MOFs utilizing host–guest interaction. This stragety can be
explored in cases where out of two drugs, one drug is hydrophobic
while another is hydrophilic. The hydrophilic drug can be incorpo-
rated in MOFs while hydrophobic drug can be incorporated inside
the CDs providing the formulator opportunity for simultaneous
delivery of two drugs having different chemical properties.
3.2.2. Non-covalent bond based post-synthetic surface
functionalization
Non-covalent is the most widely recognized type of post-
synthetic surface functionalization of MOFs incorporates the
exchange of ions, guest exchange, and guest removal. Though the
activity of exchange of ions is essentially confined to charged struc-
tures, guest exchange and guest removal are all the more by and
large appropriate. Removal of guest species that consume the free
14 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
space of the lattice was inconvenient to numerous earlier genera-
tion MOFs, and lead to frameworks breakdown Evacuating visitor
species that consume the free space of the cross-section was incon-
venient to numerous before age MOFs, and caused breakdown of
the frameworks [52]; notwithstanding, a few frameworks were
appeared to keep up their crystallinity upon simultaneous
exchange with other guests [53]. Ensuing advancements in MOF
development prompted an age of increasingly powerful materials
that considered the free movement of neutral guest molecules
without compromising the integrity of frameworks. Lee et al.
revealed that a 2D MOF based on tritopic 1,3,5-tris(3-ethynylbenzo
nitrile) benzene ligand and 3 coordinated Ag(I) could undergo a
single-crystal-to-single-crystal transformation by partially releas-
ing benzene guests upon heating at 1100 °C for 10 min. The process
was reversible and the material could reabsorb the same amount of
benzene rather rapidly, indicating zeolite like behavior [54]. Simi-
lar properties were also observed by Yaghi and co-workers [55] in a
2D Co(II) BTC (BTC = 1,3,5-benzenetricarboxylate) based MOF,
which was stable upon loss of pyridine guests.
4. Mofs based therapeutic platform
MOFs owing to their versatile nature found multiple uses in var-
ious fields including the biomedical field. They have been doped,
surface modified using polymer and peptides and studied for their
ability and applicability in the field of cancer therapy. The potential
of MOFs based therapeutic platform in cancer therapy has been
described along with alternative therapeutic approaches other
than chemotherapy such as hyperthermia, photothermal therapy,
and photodynamic therapy to name a few.
4.1. MoFs for hyperthermia and photothermal therapy
Hyperthermia recently gained a lot of attention in the area of
cancer therapy. Multiple metal-based nanoparticles including iron,
gold, silver, etc., have been explored in the field of hyperthermia
based cancer therapy. As of late, useful nano-vectors having com-
binational properties of microwave dynamic treatment (MDT)
and microwave warm treatment (MTT) have been created as it
has the upside of improving the helpful impact on tumors along-
Fig. 5. MIL-100 shells coated on the PPy NPs acted as Doxorubicin reservoirs with pH-responsive drug-release.
side limiting the reactions. Considering this, Fu et al., created man-
ganese (Mn) doped zirconium metal-natural system (Mn-ZrMOF)
nanocubes (NCs) utilizing a one-pot aqueous strategy. The got
MOFs were having a normal size of around 60 nm. The solid inelas-
tic crash of particles bound in an enormous number of micropores
affirmed that the readied MOFs can go about as a successful
microwave-delicate specialist having high warm change effective-
ness up to 28.7%. The Mn-ZrMOF NCs saw as increasingly produc-
tive in the concealment of the tumor cell development under low-
force microwave illumination for the synergic impact of MTT and
MDT [127]. Working on a similar line, nanoscale MOFs (nMOFs)
was developed which demonstrated efficient photothermal ability
[131]. Polypyrrole based nanoparticles (PPy-NPs) were prepared
using a facile microemulsion method, which was further, trans-
ferred into a MOF system using a mesoporous MIL-100 structure.
Doxorubicin (DOX) was loaded efficiently on the developed system
owing to the mesoporous nature of the MOF structure. Besides, the
MIL-100 shells coated on the PPy NPs acted as drug reservoirs and
demonstrated pH-responsive drug-release (Fig. 5). The PPy core
has been reported as an organic photothermal agent and helps to
diminish cancer cells and improve the efficacy of chemotherapy
beneath NIR irradiation. The fabricated system proved to be an effi-
cient platform for synergistic PTT and chemotherapy of cancer
[128]. Another MOF system based on UiO was developed by Wang
and co-workers. They explored a novel UiO-66@CyP based uni-
formed size MOFs system with controllable morphology and
superb aqueous dispersibility. The developed system was suitable
for traditional dyes such as indocyanine green (ICG), which suffers
from the drawback of poor stability, aqueous solubility and low
tumor specificity with quick blood clearance. UiO-66@CyP was
prepared using a simple multi-component passerine reaction in
the presence of Zr-based (UiO-66-MOFs) adding cyanine contain-
ing polymer (CyP). It was the best example of a template-
mediated synthesis of the MOF nanoparticles via a multi-
component reaction. UiO-66@CyP demonstrated excellent cancer
cell growth suppression owing to NIR triggered PTT [93]. Graphene
quantum dots (GQDs) were incorporated in MOFs to develop a
novel MOF/GQDs nanoparticles ZIF-8. The researchers for the first
time fabricated GQDs incorporated MOFs. GQDs with multiple
active functionalities inculcate photothermal effect in the MOF sys-
tem. Benefitting antitumor property to the MOF, DOX was added as
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
an anticancer agent. The weak interaction between DOX and zinc
ions establishes a stable network for firm fixation of DOX itself in
the MOF. The drug release behavior showed that ZIF-8/GQD not
only improve delivery efficiency but also reduce the side effect of
toxic drugs to normal organs and tissues. The photothermal effect
of the MOF system had a direct proportional relationship to the
temperature. The synergistic chemo/photothermal effect of DOX-
ZIF-8/GQD was investigated on 4 T1 mammary carcinoma cells.
The obtained results showed desired synergistic effect on cancer
cells, in addition, pH-controlled DOX release also obtained [91].
ZIF-8 was also coated on gold nanorods (AuNRs@ZIF-8) to enhance
the stability, plasmonic resonance as well as photothermal
response. It was observed that coating not only decreases the cyto-
toxicity of CTAB-stabilized Au-nanorods but also enhances the
photothermal efficiency. This ultimately reduces the required con-
centration of Au Nanorods and laser power density respectively.
More notably, the in vitro PTT studies showed that ZIF-8 coated
Au Nanorods were capable of photothermal devastation of the can-
cer cells. This excellent biocompatibility and photothermal behav-
ior of AuNRs@ZIF-8 promotes its applications in the combination of
chemotherapy and PTT in cancer [129]. Apart from photothermal
therapy, MOF can effectively apply as drug delivery vehicles
[130]. A novel ZIF-8 adopted for the co-delivery of the quercetin
overcoming its potential drawbacks. Quercetin is a multifunctional
natural compound possessing poor bioavailability due to the low-
est water solubility. The significance behind the use of Bovine
serum albumin (BSA) is its good adhesiveness; quercetin can firmly
bind with BSA through hydrophobic interaction and hydrogen
bonding. Herein, folate used as targeting ligand with folic acid.
Copper nanoparticles were incorporated in the system as PTT
agent, which further adds a dual property to the MOF system.
The fabricated FA-BSA/CuS@ZIF-8-QT NPs were examined for
Hemolysis assay, in-vitro Cytotoxicity, cellular uptake, and in-
vivo NIR imaging. The overall study gives promising results from
which researchers can conclude that the prepared MOF NPs can
effectively be used as pH-responsive anticancer chemo-
photothermal therapy.
A center shell-type nanostructures including MOFs were manu-
factured by a combination of center shell nanostructures covered
onto single gold nanorod (AuNR) center for synergistic photother-
mal and chemotherapy activated by close infrared (NIR) light. The
got MOFs framework had high medication stacking limit, pH and
light double upgrades responsive medication discharge. In a nut-
shell, ZIF-8 was covered onto the center of a solitary gold nanorod
(AuNR) having extra solid longitude surface plasmon reverberation
(LSPR) adsorption trademark in the NIR locale. This property com-
mits profound tissue entrance. It was noticed that both pH and NIR
light indicated the effect on the controlled arrival of DOX. The
structured MOF nanostructure reasonable in an acidic condition
of tumor cells and NIR-light-changed over warmth dissemination
incredibly impact for setting off the breakage of coordination
bringing about better biodegradation. The mix of AuNPs and ZIF-
8 into center shell nanostructures goes about as nanoplatforms
for improved multimodal malignancy treatment and even in vivo
bio-applications [107]. Multifunctional theranostic nanostructures
were built utilizing ultrathin copper-tetrakis (4-carboxyphenyl)
porphyrin (Cu-TCPP) with attractive reverberation/close infrared
warm imaging potential for phototherapy of malignancies. The
MOF nanosheet was set up by a solvothermal course with
Polyvinylpyrrolidone (PVP) as the surfactant. The readied ultrathin
Cu-TCPP MOF nanosheets show solid NIR retention because of the
d-d vitality band progress of Cu2+. The inalienable normal for TCPP
produces singlet oxygen and the ability for MR imaging as a result
of the unpaired 3d electrons of copper supplied extra favorable cir-
cumstances to the MOF framework. Infrared warm imaging of
tumor-bearing mice after the intratumoral infusion of PBS or
15
nanosheets and introduction to 808 nm laser illumination exhib-
ited for the antitumor action of the MOF framework. The general
examination affirmed that the Cu-TCPP MOF nanosheets are a
promising phototherapy nanoplatform with the synergistic capac-
ity for PTT and PDT for malignant growth treatment [132].
For synthesizing nanoparticles with enhanced photothermal
conversion ability, polydopamine (PDA) was self-polymerized on
MnCo to get stronger NIR absorbance than single-component
NPs. The dopamine monomer was effectively incorporated due to
the p-p stacking interaction among organic linkers and monomer
leads to the formation of a hierarchical MnCo–dopamine interme-
diate. Moreover, to enhance the therapeutic efficiency PTT agent
and MCP NPs were further modified with functional polyethylene
glycol (PEG) and thiol terminal cyclic arginine-glycine-aspartic
acid peptide. Further, they evaluated the independently in vitro
cell toxicities of MnCo, MCP, and MCP-PEG NPs. The resultant
MCP and MCP-PEG NPs demonstrate nontoxic behavior to HeLa
and 4 T1 cells for 24 h. the hemolytic test showed no significant
hemolysis [133]. Multifunctional MOF based theranostic systems
for Raman imaging and chemo-photothermal therapy for cancer
were fabricated using a step-by-step approach based on the con-
trollable growth of a Cu3(BTC)2 on a Raman reported molecules
4-mercaptobenzoic acid (4-MBA). The in vivo antitumor activity
was demonstrated using A549 tumor-bearing mice showing the
potential applicability of the MOF system as an antitumor agent
[134].
Building up well-structured upgrades responsive MOFs frame-
work is a tough task. Conquering this, Feng and colleagues devel-
oped a robust responsive MOFs. They demonstrated that the mix
of PDA as a flexible covering material with MOFs empowers an
easy mix of assorted productive remedial applications. They got
boosts responsive multifunctional MOFs with broad photothermal
proficiency and awesome ability to treat tumors by chemo-
photothermal treatment. They investigated various kinds of MOFs
including ZIF-8, MIL-101 and UiO-66 functionalized with PDA were
viably conjugated with focusing on particles, for example, aptamer
and folic acid (FA). Moreover, they amassed nanocarriers with
upgrades responsive nature for controlled malignant growth treat-
ment having great solidness under various physiological condi-
tions. The topping layer of PDA granted a multifunctional
interface going about as a restorative segment giving a photother-
mal transduction impact. Besides, the readied aptamer-PDA-DOX/
MOFs and FAPDA-DOX/MOFs get deteriorated at lower pH and dis-
charge DOX in the tumor condition which connotes the utilization
of PDA. Additionally, the general assessment utilizing cell take-up,
cell cytotoxicity, and antitumor productivity demonstrate that the
planned MOF framework can be productively utilized as a clinically
powerful antitumor application [117].
From the above discussion, it is clear that MOFs have a pivotal
role in the development of inorganic materials for hyperthermia
treatment. Although the ongoing research suggests the superiority
of MOFs over existing inorganic nanoparticles still a lot of research
has to be done to enhance the observed efficacy of these carriers.
The MOFs have been shown to exert a good hyperthermic effect
in presence of magnetic field or NIR, but an amalgam of other
molecules such as photosensitizers or radiosensitizers may further
enhance the efficacy of cancer treatment using MOFs. It is well
reported that the use of hyperthermia does sensitize tumor cells
towards chemotherapy but at the same time, it enhances the
release of heat shock protein which resists the cell apoptosis due
to hyperthermia. The MOFs can be modified in a way it can tackle
this problem and should attack tumor in more than one way. The
concept of singlet oxygen generation has been explored using
MOFs also but the generation of singlet oxygen or reactive oxygen
species does not take place in tumor cells which lack vasculature
and in the hypoxic region of cells. The MOFs can be modified in a
16 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
way that MOFs can target the hypoxic region of tumor cells and
exert hyperthermia and singlet oxygen generation to suppress
the viability of those cells. It is very important to target the hypoxic
region of tumor cells as these are the most appropriate region for
the growth of cancer stem cells which lead to cancer relapse and
migration.
4.2. Imaging-guided photothermia therapy
Imaging-guided phototherapy with MOFs intervenes in various
strategies for the treatment of cancer. As we review the past and
upcoming literature it was obvious that the scientific fraternity
was widely used dyes like Prussian blue [135], heptamethine
[69], cyanine dye [136], in the fabrication of the MOFs system.
Since imaging-guided therapy systems (IGTSs) revolutionized,
MOFs effectively practiced in photodynamic therapy in combina-
tion. A nanoscale zirconium-porphyrin metal–organic framework
(NPMOF) based IGTS was developed by Wei L. et al., to identify
and treat cancer with PDT co-therapy. A simple one-pot
microemulsion method employed admixing porphyrin MOFs
(NPMOFs) were built with Zr ions and meso-tetrakis(4-carboxyl)-
21H,23H-porphine (TCPP). They also emphasized the ADME pro-
cess of NPMOFs in mice revealing its selective accumulation at
the cancer location. In combination with selective laser irradiation,
the drug shows an ideal release pattern and the tumor tissue was
efficiently treated with fewer side effects [137]. In the case of dyes,
Indocyanine green (ICG) has been utilized as NIR imaging colors
however it suffers from the limitation of low water solubility. To
overcome this, Cai et al., proposed a multifunctional hyaluronic
acid (HA) conjugated nanoplatform with ICG-built MOFs (MIL-
100(Fe)) nanoparticles (MOF@HA@ICG NPs) which were effectively
produced for imaging-guided, hostile to malignant growth pho-
tothermal treatment (PTT). The blended NPs demonstrated a high
stacking substance of ICG with solid NIR absorbance and great pho-
tostability. Also, the in-vitro and in-vivo imaging study demon-
strated that the MOF@HA@ICG NPs displayed more prominent
cell take-up in CD44-positive MCF-7 cells. What’s more, it indi-
cated upgraded tumor aggregation in xenograft tumors because
of their focus on ability, contrasted with MOF@ICG NPs (non-HA-
focused on) and free ICG. The in-vitro photothermal cytotoxic
activity and in-vivo PTT medications uncovered that MOF@-
HA@ICG NPs could successfully restrain the development of MCF-
7 cells/xenograft tumors. Condensing, MOF@HA@ICG NPs could
be utilized as another promising theranostic nanoplatforms for
improved therapy of disease PTT all through malignancy explicit
and picture guided medication conveyance [66]. Double activity
imaging-guided combinational MOF framework was investigated
by Wang D. et al., this framework had pH-responsive medication
discharge property alongside MRI and optical imaging capacity.
This epic center shell PB@MIL-100 (Fe) MOFs examined for the
in-vivo and in-vitro contemplates. Artemisinin stacked in the
framework with a high stacking limit up to 848.4 mg/g. In summa-
rizing, the manufactured framework indicated great outcomes
with gathering all ideal viewpoint guaranteed by agents and will
clear another pathway for the imaging-guided therapy [112]. A
nanoscale MOF (Mn-IR825@PDA–PEG NMOPs) system with rapid
body clearance was designed by Yang and coworkers [69]. Wang
and co-investigators contributed to the MOFs system in imaging-
guided therapy. They fabricated surfactant modified Prussian blue
(PB) score was coted using ZIF-8 shell (core–shell dual-MOFs, CSD-
MOFs). The significance of using Prussian blue as the core in CSD-
MOFs is that it serves as both magnetic resonance imaging (MRI)
and fluorescence optical imaging (FOI) agents. They also demon-
strated the loading of DOX on CSD-MOFs crystals leading to the
formation of efficient pH and Near-Infrared (NIR) dual-stimuli
responsive drug delivery vehicles. The interesting mechanism
behind this is that the ZIF-8 starts to degrade concurrent NIR irra-
diation to the inner PB MOFs continuously generate heat which
starts to kill cancer cells [135]. A nanoscale mixed-component
metal–organic frameworks comprising a photosensitizer with spa-
tial arrangement-dependent photochemistry was formulated for
multi-modal imaging-guided photothermal therapy. Tetratomic
chlorin (TCPC) ligands was directly incorporated into Hf-UiO-66.
The significance of using TCPC that, it had improved photo-
thermal properties than its counterpart porphyrin. Moreover, its
strong X-rays attenuating capability for CT imaging and the high-
Z element of Hf atom can effectively enhance intersystem crossing
(ISC) of singlet-to-triplet by weakening spin prohibition. Hence, in
conclusion, researchers anticipated the use of the fabricated poten-
tial MOFs system in cancer therapy [105].
A combinational approach employing (MOF) MIL-100 loaded
with curcumin for photoacoustic imaging-guided chemo/pho-
tothermal tumor therapy was investigated. Polydopamine-
modified hyaluronic acid (HA-PDA) was coated on the MIL-100
surface to design MOF nanoparticles. It was observed that the coat-
ing of the HA-PDA improved the dispersibility and stability of the
system and also imparts tumor-targeting potential. Researchers
also investigated the effect of particle size of the starting material.
MIL-100 used in the preparation of MCHNPs, which will further
important for the bio-distribution of the MOFs nanoparticles in
the bloodstream. The drug-loaded MC NPs exhibited notable NIR
absorption due to the interaction between curcumin and ferric
ion in MIL-100. The cellular imaging results reveal that the CD44
receptor-targeting ability of the MCH NPs had better targeting abil-
ity. Overall results indicate that the engineering MCH NPs are
promising candidates for imaging-guided combinational chemo/
photothermal therapy for cancer treatment [126].
First time report claiming the construction of the Mn-porphyrin
NMOFs platform for MR imaging-guided nitric oxide (NO) and pho-
tothermal synergetic therapy of cancer was reported by Zhang and
co-investigators. They established the MOFs system with entrap-
ment of Mn ions in the porphyrin rings offering strong T1-
weighted MR contrast ability, high molar extinction coefficient,
and effective photothermal stability. S-nitrosothiol having the con-
trollable NO producing ability was effectively used as the source of
NO by integrating on the NMOF as the triggered release of NO.
They have used doxorubicin (DOX) as a comparative study, the
NMOF-SNO composites exhibited high tumor suppression activity
compared to chemotherapy with DOX for a simple drug-
resistance model. It is noteworthy that this research is its infancy
furthermore research should be carried out on the robust NO pro-
ducing MOF system [102].
4.3. Mofs for photodynamic therapy
Photodynamic therapy has been practiced ranging from topical
therapy to cancer-treating applications (Fig. 6) [138,139]. A porous
DBP-UiO nMOF was investigated for highly effective PDT of can-
cers. The interesting mechanism in the fabricating MOF involves
three critical steps, the PS molecules were dispersed uniformly in
the framework without aggregation. In the second step, porphyrin
ligands were conjugated to heavy Hf centers using carboxylate
groups which assisted the inefficient generation of ROS. The porous
nMOF structure provided a trail for the diffusion of ROS (1O2) from
NMOF which are cytotoxic for cancer cells. The NMOF works as an
efficient PDT photo-sensitizer. In-vivo PDT efficacy studies demon-
strate 50 times enhancement in tumor reduction efficiency [140].
In further investigations, chlorine-based nano-metal organic
framework (NMOF), DBC-UiO, with exceptionally high photosensi-
tizer (PS) loading, crystallinity, framework stability, porosity, nano-
plate morphology, and the improved intersystem crossing was
developed. In-vivo anticancer efficacy experiments on subcuta-
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
Fig. 6. MOFs based Photodynamic therapy of cancer cells.
neous flank tumor mouse models of CT26 and HT29 were per-
formed to assess the in vivo efficacy of the developed system.
[141]. The formulated chlorin-based nanoscale metal  organic
framework (nMOF), TBC-Hf, along with a small-molecule
immunotherapy agent-induced systemic antitumor immunity.
[142]. Working on a similar line Zhou et al., established a Zn(II)-
porphyrinic dicarboxylic species (ZnDTPP-I2) doped UiO-66-type
NMOF ZnDTPP-I2-UiO-66 via one-pot synthetic approach. They
successfully converted conventional Photosensitizer PS of metallo-
porphyrin with heavy iodine atoms in nanosized utilizing NMOF
supports. The comparative study shows the second assembly gives
a better photodynamic effect. The fabricated NMOF evaluated for
anticancer activity against liver cancer cell lines with effective out-
comes [143].
Strong oxygen dependence and limited penetration are the
major concerns with photodynamic therapy while lack of effective
energy accumulation in the tumor region is the major challenge
faced in radiotherapy. Lots of research has been done and still
going on to tackle this problem using surface modification and
conjugations. Taking in the consideration Zhang et al., executed
the amalgamation of a scintillator and a semiconductor as an
ionizing-radiation-induced PDT agent, achieving synchronous
radiotherapy and depth-insensitive PDT with diminished oxygen
dependence. The scintillator has the characteristic property that
high-energy electromagnetic radiation can be down transformed
giving rise to luminescence in the UV–visible region of the spec-
trum. Moreover, the photo-destruction could be largely prevented
by the employment of highly photostable inorganic semiconduc-
tors instead of organic photo-sensitizers. In summing up, this
new technique employing synchronous radiotherapy and PDT with
a single excitation source would be of great clinical interest. This
method demonstrates diminished dependence on intracellular
oxygen levels by integrating a scintillator and a semiconductor as
a photo-sensitizer activated by ionizing radiation [144].
A novel MOF-based multifunctional nanoprobe was fabricated
for the cancer cell imaging and chemo-photodynamic therapy.
Cathepsin B (CaB) is a lysosomal cysteine protease of the papain
family that shows increased expression in many types of cancer
which can be a significant principle to trigger cancer theranostics.
A post-synthetic method with entrapping functional molecules in
the MOF framework for CaB-activatable fluorescence imaging and
dual therapeutics of target-controlled photodynamic therapy and
chemotherapy were utilized for the same. Moreover, this inte-
grated treatment platform reduces side effects, retards multidrug
resistance of the drugs, and overcomes the low efficiency of the
PDT in the hypoxic cells, which ultimately benefits significant
enhancement in the therapeutic efficacy. For this, to investigate
whether the specific response obtained with Ce6@MOF or not an
in vitro test by fluorescence spectrophotometer was done. Further,
17
MOF modified with Ce6-peptide on the surface the fluorescence
intensity of Ce6-peptide was quenched due to the electron transfer
from the excited Ce6 to MOF-NH2. It was observed that the fluores-
cence intensity increases with the enhancement in the cleavage
reaction with an optimal dependence in the pH range of 4.5 to
6.0. Thus, pH 5.0 was used for the subsequent experiments. Inter-
estingly, the unique inner porosity and post-synthetic clemency
enable the MOF nanoprobe with target-cell-specify delivery, in-
situ imaging and synergistic therapy for promising application in
specific medicine [67]. Park and coworkers hypothesized Zr(IV)-
based porphyrinic metal–organic framework (MOF) nanoparticles
for photodynamic therapy. Also, they proved it by extrapolating
the different characterization and cellular imaging studies. The
photosensitizing ability and the emissive nature of the porphyrinic
linker enable the theranostic modality of MOF contributing to its
multifunctional properties. They constructed a novel MOF system
using a bottom-up approach, tuning the size of nanoparticles in a
broad range with a designed functional motif. Size-dependent cel-
lular uptake expected in the PDT, hence nanoparticle formulation
of the photo-sensitizer showed enhanced PDT efficacy than that
of its small molecule. Additionally, Zr6 clusters in the MOF enabled
an active targeting modality through post-synthetic modification.
They also observed the size-dependent cellular response to inves-
tigate this, a five size fractions, ranging from 30 to 190 nm, taken
based on transmission electron microscopy (TEM) results, were
applied to HeLa cells. Interestingly they got a good result on the
size 90 nm- PCN224. On the other hand, saying about active target-
ing, folate modification on the PCN224 was done. They foreseeing
that MOFs can be a hopeful nanoplatform by adopting advanced
small-molecule systems into the tunable framework [72]. Chen R.
et. al., and the team claimed the first application of enhanced
two-photon absorption and luminescence in fluorophores
entrapped in MOF. They had successfully fabricated Ruthenium
(II) tris(bipyridyl) cationic complex (Ru(bpy)3 2+) incorporated into
UiO-67 nanoscale metal–organic frameworks (NMOFs) based
nanoplatform for in vitro two-photon fluorescence imaging and
photodynamic therapy. The synthesis mechanism was quite inter-
esting. Briefly, they followed step by step assembling of the mole-
cules of ruthenium(II) tris(bipyridyl) with cationic complex (Ru
(bpy)2+3 ) it is then incorporated into the NMOF by soaking the
UiO-67 NPs in a bath of the tris(2,2- bipyridine) ruthenium(II) hex-
afluorophosphate solution at 90 °C. Wonderful results were
obtained after incorporation into the NMOF, which is fluorescent
quantum yield, two-photon luminescence intensity, two-photon
absorption cross-section, singlet oxygen generation capability sub-
stantially increased. While tremendous advancement in photosta-
bility and water dispersibility of the Ru complex observed. The
MTT assay was carried out using the A549 cell line for the evalua-
tion of cytotoxicity of NPs. It is found that cytotoxicity much
18 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
increased when irradiation power is elevated the thermal effect
imparted by light can also be examined. This can pave a pathway
for the explore and develop NMOF-based theranostics for future
applications [77].
Epitaxy has known as the deposition of a crystalline overlayer on
a crystalline substrate [145]. Using this principle Zheng and the
group developed a metal–organic framework based on porous
organic polymer without losing the crystallization, pore structure,
and size distribution. The traditional ROS indicators had been used
for UNM using confocal laser scanning microscopy on the HeLa cell.
The fabricated light-activated system exhibits an efficient ability to
generate singlet oxygen under various investigational conditions
and PDT efficacy by photo-induced apoptosis of cancer cells [63].
Meng et al., claimed earlier report on the aptamer functionalized
MOFs by using the simple solvothermal reaction between ZrCl4
and H2BDC in N, N-dimethylformamide (DMF). They have synthe-
sized the desired TMPyP4-G4-aptamer-NMOFs nanosystem by
reacting Zr-NMOFs with phosphate-functionalized G4-aptamer to
fabricate the G4-aptamer-NMOFs. They also highlighted the singlet
oxygen generated by TMPyP4-NMOFs, which was achieved by
directly loading MPyP4 into the pores of MOFs. Furthermore, the
cytotoxicity study was done using MTS assay on both target HeLa
and CEM cells and non-target Ramos cells. The selective phototox-
icity of the TMPyP4-G4-sgc8-NMOFs nanosystem also studied
using the same cell lines. They choose TMPyP4 as photosensitizer
aiming PDT, due to its unique symmetrical aromatic structure and
cationic properties, TMPyP4 can bind to and stabilize the G-
quadruplex structure. The feasibility of in vivo PDT using TMPyP4-
G4-sgc8-NMOFs was then confirmed by investigating the fate of
TMPyP4 using fluorescence imaging assay on a HeLa subcutaneous
xenograft tumor mouse model [146].
It is necessary to maintain the supply of O2 and improve the cir-
culation lifetime of photosensitizers for efficient elimination of
cancer tumors using PDT. Elaborating the concept, Gao and the
team fabricated a biomimetic O2-evolving PDT nanoplatform with
extended circulating properties. Zirconium (IV)-based MOF (UiO-
66) was adopted as a novel vehicle for O2 storing which was then
conjugated with indocyanine green (ICG) by coordinating with red
blood cell (RBC) membranes. They choose UiO-66 was as O2 carrier
as it had high absorption capacity and biocompatibility. Indocya-
nine green (ICG) was capped on the surface of the UiO-66 by the
coordination reaction of a sulfonic acid group with Zr6 clusters.
The fabricated O2@UiO-66@ICG@RBC MOF system was invisible
to immune systems in vivo which could be beneficial to enhance
the Enhanced Permeability and Retention (EPR) effect and attain
passive targeting in vivo for tumor. The intended nanotherapeutic
agent can advance the efficiency of treatment against hypoxic
tumor cells through PDT. The present study opens up a new arche-
type for the co-delivery of O2 and photosensitizers [57].
Benzoporphyrin-based metal–organic framework (TBP-MOF), with
10-connected Zr6 cluster with improved photophysical character-
istics, was introduced by Zheng et. al., to overcome the problems
associated with traditional porphyrin-based MOFs. The experimen-
tal findings showed that TBP-MOF exhibited red-shifted absorption
bands and strong near-infrared luminescence. Moreover, the p-
extended benzoporphyrin-based linkers of TBP-MOF facilitated
1
O2 generation, which will benefit the photodynamic therapy
(PDT). They also focused on preserving the stoichiometric concen-
tration of reactant species for the fabrication of the MOF system as
a result of this smaller particle size was obtained which is con-
firmed by TEM analysis. UV–visible findings proved that TBP-
nMOF not only showed a relatively shorter fluorescence lifetime
of 2.12 ns but also enhanced intersystem crossing (ISC) to Zr4+ ions
through the carboxylate groups. Hence, TBP-nMOF can be used as
an efficient PDT photosensitizer and a strong NIR imaging agent
too [96].
Yet another aspect regarding the surface decorated porphyrinic
photosensitizers (PS) reported for the PDT tumor therapy. The
comparative investigation on the interior loaded porphyrinic
NMOF to the UiO-66-TPP-SH shows significantly higher photody-
namic activity. The fabrication involved using UiO-66 NMOF and
S-ethylthiol ester monosubstituted metal-free porphyrin (TPP-
SH) via a simplistic post-synthetic approach under normal reaction
conditions. S-ethylthiol ester proved for its good chelating ligand
and binding property to different metal ions forming a stable
five-member ring. This new surface decorated NMOF with PSs
assembly will be useful as PDT therapy in cancer [64]. An earlier
report on the copper-gallic acid-based nanoscale MOF was
explored for photodynamic therapy and drug delivery purpose. In
brief, a complex of copper-bioactive frameworks was employed
as the carrier of two anticancer agents. Gallic acid and methylene
blue loaded as a guest molecule within the amphiphilic pores of
the framework. However, Gallic acid proved for its use in combina-
tion with metal ions showing good coordination chemistry [147].
In vitro cytotoxicity and in vivo tumor regression assays showed
enhanced cytotoxicity of dual drug nano-framework when com-
pared with the equivalent dosages of free drugs in the presence
of light [148]. Boron-dipyrromethene (BODIPY) member of family
Organoboron compounds fluorescent dye, now gained interest in
the construction of a nanoscaled MOF system. Earlier claim for
introducing the NCOF based MOFs was made by Guan and co-
workers. Covalent organic frameworks (COFs) are firstly reported
for tumor photodynamic therapy. BODIPY-decorated COFs was
synthesized using bonding defects functionalization. BODIPY-
decorated COFs demonstrated with better anti-tumor efficacy as
investigated in vitro and in vivo. Highlighting some drawbacks, this
study only focused on the free end –CHO on LZU-1 by BDF, thus no
further chemical modification on the free –NH2 of LZU-1NP was
investigated. However, the fabricated system will be an example
of the biomedical treatment of cancer using PDT [149].
With recent advancements in PDT, MOFs have the advantage of
the inherent ability to provide PDT owing to the presence of metal
ions. Although many metal ions that possess the ability to provide
PDT have been used such as zinc, iron, copper to name few, still
many metals have not been explored. Metals such as platinum
which can intercalate with DNA can b explored for this purpose.
Heavy metals such as zirconium and gallium have been reported
but such metal may not be suitable for human consumption. The
selection of metal ions can be done keeping in mind the safety as
well as PDT efficiency. In a few cases, metal ions can be used in
combination with other metal ions in the form of doping. This
strategy will enhance the overall PDT efficiency due to synergistic
action but at the same time, this might affect the crystallinity as
well as morphological features of MOFs. A balance between doping
and PDT efficiency needs to be balanced. Another strategy for
enhancing the PDT is the use of porous MOFs. The porous MOFs
will help in loading of drug which can also demonstrate PDT or
photosensitizers which will sensitize tumor cells towards PDT.
Many unexplored strategies can be utilized to enhance MOFs based
PDT of tumor cells.
4.4. Combination therapy of cancer (Hyperthermia/Photothermia/
Photodynamic Therapy)
A combinational approach for the targeted tumor therapy had
been employed since the last few decades, since singular
approaches showed some diminishing properties, a combination
of the conditions results in better performance. Altering the pyrol-
ysis temperatures and sizes of ZIF-8 derived carbon nanoparticles
(ZCNs) were designed by direct pyrolysis of ZIF-8 nanoparticles.
The more emphasize had been added on the photothermal effect
and PA imaging capability of ZCNs, it was observed that an increase
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
in size exerts more anticancer effect. It was confirmed by in-vivo
and in-vitro experiments the PA imaging-guided ZCNs can com-
pletely inhibit tumor growth with a minimal side effect, even at
the minimal NIR laser power. Hence, it was proved that the ZIF-8
derived carbon nanoparticles are expected to have wide applica-
tions in the phototherapy of cancer. Likewise, they can be utilized
photothermal operators and photosensitizers to deliver heat and
receptive oxygen species at the same time upon NIR laser light
[124]. A tale multifunctional zirconium-ferriporphyrin metal-
natural structure Zr-FeP-MOF (Nanoshuttle) by an effortless one-
pot aqueous strategy. Furthermore, the PEG functionalization came
about because of the siRNA/Zr-FeP MOF nanoshuttles with great
solidness uncovered by the irrelevant difference in the hydrody-
namic size during 7 days of consistent estimations. The readied
nanoshuttles were been analyzed for ROS age and saw as true to
form to create rich ROS under a NIR laser illumination. It addition-
ally showed great photothermal changeability. The siRNA/Zr-FeP
MOF nanoshuttles under a solitary NIR laser illumination produc-
tively stifled the tumor development both in vitro and in vivo attri-
butable to PDT and low-temperature PTT synergistic treatment. It
opened another road for tri-mode tumor-explicit imaging were
likewise shown for tumor exact finding [150].
To date, plenty of researchers explored the use of porphyrins to
construct structures in MOFs, as discussed in the above kinds of lit-
erature. These systems take advantage of the Lewis acidity of the
metal, typically much better with zinc. Novel porphyrinic metal–
organic frameworks coated gold nanorods as versatile nanoplat-
forms for combined photodynamic/photothermal/chemotherapy
of tumors were investigated with NIR triggered drug release prop-
erty. This unique platform was also demonstrated for the antitu-
mor performance at the cellular level which was confirmed by
histological analysis of the tumor tissues in mice using hema-
toxylin and eosin (H&E) staining. In short, the majority of tumor
tissue cells became apoptotic and necrotic and were killed after
the mice treated with AuNR@MOFs@CPT under 660 and 808 nm
laser irradiation (Fig. 7). This unique feature imparts triple proper-
ties to the system becoming the most impotent tool for cancer
treatment [59]. An account added on the nanoscaled multifunc-
tional Zn-porphyrin nanoscaled metal–organic framework (Zn-
TCPP nMOF) fabricated through a facile one-pot hydrothermal
method for dual tumor therapy. The fabricated nMOF system pro-
duces plenty of singlet oxygen species when irradiated under NIR
radiations with a fine photothermal conversion. The present
attempt provides new insight to devise facile functionalized
nanoagents for both PDT and PTT [151].
Inorganic-organic Fe3O4/ZIF-8-Au25 nanocomposite has been
successfully designed by a facile route for multimodal cancer ther-
apy. Upon 808 nm NIR light irradiation, fabricated MOF clusters
Fig. 7. AuNR@MOFs@CPT for multimodal therapy of cancer.
19
can generate hyperthermia with efficient singlet oxygen that can
also be produced for PDT. Besides, the entangled Fe3O4 nanocrys-
tals can also be acts as a PTT agent. To investigate the tumor inhi-
bition efficacy of the fabricated MOF system and the in vitro
cytotoxicity to HeLa cells was evaluated employing an MTT assay
by altering two variables of concentration and external condition
[152]. Similarly, Gold-based MOFs were developed for trimodal
therapy of tumors (Fig. 8). The obtained results demonstrated the
efficient suppression of tumors owing to the trimodal therapy
strategy [153]. A novel method was explored using functional
ligand namely tetrakis(4-carboxyphenyl) porphyrin (TCPP) was
introduced into NU-1000 via post-synthetic ligand exchange
method. Resultant mixed ligand MOF possesses an excellent pho-
todynamic effect. In-vitro and in-vivo assessment about the antitu-
mor efficacy was investigated for the first time. It is demonstrated
that the feasibility of TCPP substituted NU-1000 to be used for pho-
todynamic therapy, and provides an alternative approach to enrich
the function of MOF for various applications via the post-synthetic
method [120]. A near-infrared dye (cypate) knowing its interaction
with Fe3+ and carboxyl group yang et al., 2019; was constructed a
multifunctional MOF. Furthermore, this system can achieve multi-
modal imaging-guided phototherapy. Subsequently, the precise
cancer phototherapy was investigated in vivo, and the tumors are
eliminated without obvious side effects, demonstrating the high
efficacy and safety of this multifunctional platform. Hence, it was
expected that not only this system is simple, safe and high effective
but also our method of the defect structure of MOFs will open a
new way to develop multifunctional nanoplatforms for bioapplica-
tions [68].
5. Stimuli-Responsive therapeutic platform based on MOFs
Stimuli-responsive based MOF delivery platforms, which speak
to a standout amongst the most encouraging and intelligent
nanocarrier systems, have pulled in a lot of enthusiasm for
biomedical applications since they encapsulate cancer therapeutic
moieties and diagnostic agents into the carrier for cancer theranos-
tic applications and activated to release payloads because of
changes in the environment [153–155]. As a result, multifunctional
stimuli-responsive ligands have broadly been developed and
attached to fabricate a wide range of MOF-based delivery platform
and steer their effective amassing at tumor locales, and thusly
accomplish on-request release of therapeutic moieties or MOFs in
the desired pathological areas. The stimuli-responsive MOF-based
delivery platform is extensively classified into two classes: frame-
works that react to exogenous stimuli (light, temperature, mag-
netic field, etc.) and frameworks that respond to endogenous
20 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
Fig. 8. Gold based MOFs were developed for trimodal therapy of tumor.
Fig. 9. Schematic reresentatiom of Endogeneous and Exogeneous stimuli respon-
sive MOFs.
stimuli (redox, enzyme, pH) for controlled release of therapeutic
moieties and targeted delivery (Fig. 9) and imaging [156].
5.1. pH-responsive MOFs
pH-responsive MOFs are the most extensively researched of all
stimuli-responsive MOF, particularly for tumor therapy, as a result
of the acidic tumor microenvironment and the sensitivity of coor-
dination bonds to external pH (Fig. 6). To date, numerous examina-
tions have included the pH-responsive properties of CpG@OVA-
MOFs for therapeutic delivery and treatment of cancer. Duan
et al. developed MOF by utilizing Eu as a lanthanide ion and gua-
nine monophosphate (GMP). The OVA or OVA-FITC was encapsu-
lated simply by adding OVA or OVA-FITC and GMP into pure
water, followed by the addition of the EuCl3 solution into it,
whereas CpG was attached to GMP-Eu-MOF surface via Watson-
crick base pairing, which is convenient for co-delivery of
immune-stimulator and antigen. Undoubtedly, the coordination
of GMP and Eu dissociates under pH 5, which facilitates protein
vaccines escape from endosomes/lysosomes (pH 4–5) into the
cytosol, optimal for enhancing antigen cross-presentation [110].
Cabrera-Garcia et al. developed CPT-MOFs with various types of
incorporation of CPT in MOF i.e. NH2-M1 (Nano-MIL-101(Fe)),
CPT-S-M1, CPT-C-M1, CPT-A-M1, RhB-M1, NH2-M2 (Nano-MIL-
100(Fe)), CPT-S-M2, CPT-C-M2, CPT-A-M2, RhB-M2. The results
demonstrated that CPT-C-M1 and CPT-S-M1 samples release at
pH 7.4 respectively, 12% and 8% total CPT in an hour, however sub-
sequently, till 48 h, there was no additional release. The aforemen-
tioned release pattern obtained resembled typically to physically
adsorbed CPT prodrug, due to the high surface area and highly
ordered porosity of NH2-M1 material. The unwanted CPT adsorp-
tion over the surface of NH2-M1, the CPT-C-M1, and CPT-S-M1
samples were washed with tween-20 and SDS surfactants. How-
ever, the XRD results showed the structure of functionalized MOF
was severely altered. On the contrary, covalently bound CPT was
found to be physiologically stable. The initial burst release of CPT
was not recorded over the CPT-C-M2 sample, owing to its lower
crystallinity and BET area avoid strong physical adsorption of CPT
derivatives which was retarded to 2%. Due to lower CPT content,
CPT-S-M2 was not considered for further study. Nevertheless, it
was found that CPT nanocarriers obtained via physical adsorption
demonstrated instability in the cell culture medium, for example,
50% of the therapeutic load in CPT-A-M1 was released within 6 h
and completed the process in 24 h [111]. The pH-responsive bond-
ing will not only help the release of drugs in the suitable area
inside tumor cells but this pH-responsive feature can also be
explored for synthesizing MOFs which degrade in particular pH
giving instant drug release.
5.2. Temperature-responsive MOFs
The delivery platform obtained from the materials which are
thermosensitively resulting in the release of therapeutic moiety/
is at the site of action in the treatment of cancer. These are the
thermosensitive material based platforms that alter through slight
changes at the physiological temperature of 37 °C [157]. In
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
addition to this, Lin et al. developed two Zn based porous
Zn16(ad)8(TP)8O2(H2O)8.4HTP.36DMF
16H2O MOF (ZJU-64-CH3
(20 50 -dimethyl-[1,10 :40 10 ’-terphenyl]-4,40 ’-dicarboxylic acid) and
ZJU-64 (H2TP = 1,10 :40 10 ’-terphenyl]-4,40 ’-dicarboxylic acid) and
ad = adenine)), which comprised of adenine as a bio-molecular lin-
ker, Zn ions and carboxylate based ligands. The impregnated
method was utilized to load MTX into ZJU-64-CH3 and ZJU-64
where the payload was found to be 10.63% and 13.45%
respectively. The release study demonstrated that ZJU-64-CH3
and ZJU-64 released an equal quantity of MTX at 37 °C for 72 h,
however, at 60 °C, the drug released within a short period i.e.
1.5– 6 h. The results concluded that ZJU-64-CH3 and ZJU-64 MOF
perhaps can be utilized as an efficient temperature-responsive
delivery platform [158]. Furthermore, another thermo-sensitive
material i.e. poly(N-isopropyl acrylamide) (PNIPAM) acquires
lower critical solution temperature and acts as a building block
of MOF. PNIPAM displays hydrophilicity when the temperature is
lowered below its cloud point (Tc nearly 32 °C), nevertheless it per-
haps forms a aggregates above cloud point. Considering the same,
Nagata et al. developed PNIPAM-UiO-66 MOF that showed ON-OFF
(ON (open) = lower temperature due to coil conformation, OFF
(closed) = higher temperature due to collapse globules) controlled
release of three loaded guest molecules (Procainamide, Caffeine,
Resorufin) [159]. The release study demonstrated that, at 40 °C
where PNIPAM showed globular conformation, the release ratio
was of guest molecules were held less 20% even after 7 days.
However, at 25 °C where PNIPAM showed coil conformation, all
the guest molecules were rapidly released from PNIPAM-UiO-66
and the release ratio was saturated within 4 days. Thus it can be
concluded that the release of guest molecules turned upon
variation in temperature.
5.3. Ion-responsive MOFs
Ion-responsive MOFs have found to be one of the emerging and
effective stimuli-responsive delivery platforms. It works on the
principle that frameworks and therapeutic moieties are attached
with strong electrostatic interactions that control the diffusion
and release of therapeutic moieties. Subsequently, the ionic frame-
works and ionic therapeutic moieties possessing strong electro-
static interactions have pulled specifically intrigue because the
release of ionic therapeutic moieties is a chemical stimuli-
responsive process occurring through ion exchange [157]. For
example, Hu et al synthesized positively charged MOF-74-Fe (III)
through oxidation of neutral crystals of MOF-74-Fe (II), because
it cannot be formulated directly utilizing ferric salts. The Ibuprofen
anions were loaded in MOF with the loading efficiency of 15.9 wt%
via ion exchange and salt penetration method. Surprisingly, the
MOF synthesis method was able to generate hydroxide, which
resulted in the availability of two distinctive Ibuprofen anions in
MOF channels, therefore MOF demonstrated two distinct release
behaviors. Initially, the present coordinated free anions and
sodium Ibuprofen was release owing to diffusion and ion exchange
between PBS solution and MOF encapsulated with the drug. The
later release of drug was actuated by phosphate anions through
competitive adsorption [160]. Furthermore, An et al. developed
anionic Zn based bioMOF-1 (Zn8(ad)4(BPDC)6O.2Me2NH2.8-
DMF
11H2O) by incorporating biphenyldicarboxylic acid to the
mixture of Zn acetate dehydrate and adenine. The study demon-
strated that procainamide HCl was loading in bioMOF-1 with a
loading efficiency of 0.22 mg /mg owing to the electrostatic inter-
actions between cations and anions. It was further found that the
release of procainamide was actuated owing to the presence of
cations in the biological fluids. Moreover, Du et al. synthesized
5-FU loaded MOF-In1 comprised of tris(para-carboxylphenyl)
phosphine oxide and In3+. The results demonstrated that the
21
5-FU loading (34.32 wt%) was simply dependent on size and charge
selective ion exchange. The release study revealed that the release
of 5-FU from MOF-In1 was dependent on the Zn2+ ions. For the
same, PBS with different concentrations of Zn2+ ions (500* 10-9 to
10* 10-3 M) was considered and further added with 5-FU loaded
MOF-In1. The results revealed that as the Zn2+ ion concentration
increases the 5-FU release was also increasing subsequently [161].
5.4. Magnetically-responsive MOFs
Magnetically-responsive based delivery platform is another
critical stimuli-responsive delivery system. Here, a magnetic field
plays a significant role as a non-invasive energy source and exoge-
nous stimulatory signal that has been energetically advanced after
the development of a magnetically-responsive delivery platform
for the controlled release of loaded therapeutic moiety/ies. For
instance, Sharma et al. synthesized DOX/ and MB loaded magnetic
nanoscale MOF (M-NMOFs). The fluorescent measurement con-
firmed the loading of MB (4.3 wt%) and DOX (0.69 wt%). The release
study demonstrated that both the therapeutic moieties shown a
differential release pattern, specifically at the initial stage of
release. On day one, DOX showed enhanced release whereas MB
showed poor release, perhaps due to the stifling of MB release of
DOX release. However subsequently, the MB showed a higher rate
of release whereas DOX release was lessened as compared to the
previous day. Nevertheless, MB and DOX were released within
4 days, signifying the complete degradation of MOF. The compara-
tive release study between co-loaded drugs and mono-
encapsulated MOFs demonstrated that DOX (68%) and MB (41%)
release was far less than when co-encapsulated (DOX = 95% and
MB = 72%). The M-NMOFs with superparamagnetic property owing
to the presence of Fe3O4 allowed the cell toxicity effect of DOX and
MB loaded M-NMOFs to be further enhanced with an external
magnetic force. This integration of light-triggered therapy and
magnetic field guidance therapy would increase the efficiency of
the treatment of cancer [162]. Furthermore, Wu et al. developed
c-Fe2O3@MIL-53(Al) MOF and c-Fe2O3@ZIF-8 MOF using a one-
step in situ pyrolysis method. The results revealed that MOF
showed controlled release behavior in physiological saline at
37 °C. The release study further showed that the complete release
of Ibuprofen was accomplished after 7 days. In addition to this, ini-
tially within 3 h, 30% of Ibuprofen was released by the physical-
desorption of Ibuprofen to the solution. Later, 50% of the drug
was released during the next two days, owing to the steady release
of therapeutic moiety from the 1-D framework channels to the
solution. The release followed by 20% of remained amount got
release as long as 5 days, which can be attributed to the strong
interaction between the aromatic frameworks and therapeutic
moiety and coordinatively unsaturated metal nodes of the MOF-
based nanocarrier [163].
5.5. Pressure-responsive MOFs
It is the type of stimuli-responsive delivery platform which per-
haps shows high therapeutic efficiency owing to sustained release
time. Besides pressure can be applied for controlled release of the
the therapeutic moiety. Thus, the the platform can neglect the pre-
mature release of the therapeutic moiety, unless it reaches site of
action. Lately, Jiang et al developed diclofenac sodium loaded Zr
based MOF comprised of Zr clusters and (2E,2E’)-3,30 -(2-fluoro-1,
4-phenylene) diacrylic acid (F-H2PDA). The results showed that a
better loading capacity of diclofenac sodium in MOF was found
to be 58.80% owing to its extended organic spacer and its increased
polarity. The release study demonstrated that the release of
diclofenac sodium can be altered through changing pressure,
which leads to prolonged-release time between 2 and 8 days [164].
22 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
5.6. ATP-responsive MOFs
A multifunctional nucleotide, ATP (adenosine triphosphate) that
gives energy to every biological process by hydrolyzing phospho-
anhydride bonds. Presently there is developing proof demonstrat-
ing that numerous pathological processes such as neuronal
synaptic transmission tumor growth, chemoresistance are con-
nected with the upregulation of ATP levels, which makes them a
critical marker that recognizes normal cells and cancer cells. Many
researchers got motivated owing to the upregulation of ATP levels
and fabricated numerous ATP-responsive delivery platforms that
explicitly perceive ATP just as the competitive binding of ATP apta-
mers. Additionally, Chen et al fabricated DOX loaded ATP-AS1411-
NMOFs comprised of amino-triphenyldicarboxylic acid capped
with complementary nucleic acid and Zr4+ ions. In the presence
of ATP, these NMOFs were unlocked through the formation of
ATP-aptamer complexes, resulting in loaded therapeutic moiety
being released. As the nucleolin receptor sites on the cell mem-
brane were recognized by AS1411 aptamer and ATP is overex-
pressed in cancer cells, the cytotoxicity was enhanced by
targeting and effective permeation of ATP-responsive NMOFs into
the cancer cells [165].
5.7. Hydrogen sulfide-responsive MOFs
Hydrogen sulfide-responsive MOFs are another type of stimuli-
responsive delivery platform. This platform came to existence
based on the importantly high content of hydrogen sulfide in
human colon adenocarcinoma cells [166]. MA et al. fabricated
bimetallic Zn-Cu based mixed MOF (Cu2(ZnTcpp).H2O)n comprised
of Cu(NO3)2
3H2O and 5,10,15,20-tetrakis (4-methoxycarbonyl-
phenyl) porphyrin (ZnTcpp). The Cu2+ ions, an important hydrogen
sulfide-responding site in hydrogen sulfide fluorescence probes,
were selected for the metal nodes of this, Zn-Cu mixed MOFs.
The paramagnetic Cu2+ ions are responsible for both, considerably
reduce the ROS production efficiency of the photosensitive ligands
and quenched the ligand-based fluorescence. When hydrogen sul-
fide appeared, the Cu2+ ions were removed from the MOF nodes,
and thus a luminophore photosensitive ligand was simultaneously
obtained [167].
5.8. Redox-responsive MOFs
The redox-responsive delivery platform is based on the sub-
stantial varying redox concentration in normal cells and cancer
cells. GSH, an endogenous reducing agent, present more abun-
dantly in human cancer tissues. GSH is responsible for the cleavage
of a disulfide bond (redox-responsive group), thus makes GSH an
attractive receptor site in the fabrication of a redox-responsive
delivery platform in the treatment of cancer [168,169]. In addition
to the aforementioned statement, Lei et al fabricated redox-
responsive CUR loaded MOF i.e. CUR-MOF-M(DTBA) platform for
the treatment of cancer. This platform comprised of GSH sensitive
organic ligand i.e. M(DTBA) where, M = Zr, Al and Fe (metal node)
and 4,40 -dithiobisbenzoic acid (4,40 -DTBA). Here, disulfide bond
present in 4,40 -DTBA is cleaved by GSH present at the tumor
microenvironment. The release study demonstrated that CUR
release from CUR@MOF-Zr(DTBA) in the presence of GSH
(concentration = 10 mM) was found to be 87.4% after 22 h of incu-
bation in PBS (pH 7.4). However, in the absence of GSH, the release
of CUR was found to be 50% only, within the same amount of time.
Subsequently, considering the tumor microenvironment pH, the
same experiment was performed in pH 5.5, and the result demon-
strated that in the presence of GSH, the cumulative release of CUR
was found to be 85% just within 5 h. Furthermore, another type of
receptor site i.e. hydrogen peroxide (H2O2), a ROS molecule gener-
ated during reperfusion or ischemia, usually induces inflammation
and actuates apoptosis, leading in oxidative damage to tissues
[115]. Considering the same, Liu et al. synthesized H2O2-
responsive delivery platform based on nanoscale coordination
polymers (NCP), which comprised of NCP as shell material (consist
of cisplatin prodrug and Hf ions) which encapsulates core consist
of MnO2 stabilized with BSA, overall forms NCP(Cisplatin)-PEG
NPs MOF. The results revealed that MnO2 is responsible for the
generation of O2, from the decomposition of endogenous H2O2 pro-
duced in the cancer cells. Furthermore, the study also revealed that
the absence of MnO2 in the core MOF was not able to induce O2
generation. This O2 generation through MnO2 would help over-
come hypoxia-associated radio-resistance. Furthermore, the
decomposition of MnO2 could result in improve T1 contrast for
in vivo tumor MRI [170]. Moreover, Duan et al. studied the
glucose-responsive delivery platform based on the ZIF-8 MOF
based on the self-regulated insulin release dependent on the glu-
cose concentration. This MOF comprised of insulin and glucose oxi-
dase and was incorporated in ZIF-8 MOF (2-methylimidazole and
Zn2+). The principle behind this responsive platform is: the higher
concentration of glucose is sensed, it enters the pores of the MOF
and makes contact with glucose oxidase, leading to glucose oxida-
tion to H2O2 and gluconic acid. The reduced pH in the MOF results
in its decomposition and hence insulin release [171]. These, MOF
can be used for glucose-sensitive and self-controlling insulin deliv-
ery platform
5.9. Light-responsive MOFs
Light-responsive delivery platform based treatment has been
appeared to be extraordinarily unrivaled in accomplishing on-
request diagnostic and therapeutic at the site of action both
in vivo and in vitro because of its spatiotemporal precision by irra-
diation with a particular wavelength of light and non-invasiveness
[172]. With the on-going improvements in nanotechnology, vari-
ous nanomaterials, including NMOFs, have been used to develop
a light-responsive delivery platform. Additionally, light-
responsive MOF can be fabricated utilizing photosensitizer as an
organic linker [173]. For instance, the combination of MOF and
NCPs, like structures, comprised of Hf ions and bis-(alkylthio)
alkene (BATA, a singlet oxygen-responsive linker) were used as a
carrier for the light-responsive delivery platform under red-light
660 nm with a low power density (5 mW/ cm2). The DOX and
Ce6 were co-loaded in NCPs and coated with lipid bilayer which
was followed by PEG coating to form DOX-Ce6-NCP-PEG NPs with
good colloidal stability. When DOX-Ce6-NCP-PEG NPs exposed to
light, the singlet oxygen generated from these MOFs could be
employed for both, to stimulate cleavage of the BATA linker and
therefore decomposition of MOF structure, thereby releasing the
therapeutic moieties and photodynamic therapy [174]. Recently,
During et al. fabricated CO loaded Zn(IV) based MOF comprised
of manganese carbonyl complex, MnBr(bpydc)(CO)3 (bpydc = 5,50
-dicarboxylate-2,20 -bipyridine). The results demonstrated that
when low visible light (460 nm) was exposed MOF the release of
CO was is inefficient and controllable manner. However, as soon
as the light was switched off, the release of CO was immediately
stopped. Therefore, the light-responsive delivery platform can
serve for efficient and controlled manner release of therapeutic
moiety and can be explored for further investigation for the treat-
ment of cancer [175]. Furthermore, Zhu et al. developed DOX
loaded PPy@MIL-100(Fe). The release study demonstrated both
with and without NIR irradiation and photothermal effect. It was
found that with NIR irradiation, DOX release up to 70.4% (pH 5.0)
and 53.2% (pH 7.4) was obtained after 2 h, owing to the increased
local temperature caused by the photothermal effect of PPy under
NIR irradiation. However, without NIR irradiation, the DOX release
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
was found comparatively very low i.e. 49.1% (pH 5.0) and 31.9%
(pH 7.4) [128].
6. Sub-cellular tumor target MOFs
Since the progress in the application of MOFs in cancer treat-
ment started it branched in many aspects such as targeting, sens-
ing and various guided therapy (PDT, PTT, etc). Nanoscale metal–
organic frameworks (nMOFs) are budding as an imperative class
of biomedically applicable nanomaterials due to their multifunc-
tionality, high porosity, and biocompatible nature. A Fraternity of
researchers working on the strategies to improve drug specificity
and subcellular targeting by increasing its concentration in the cel-
lular compartment by which the drug can elicit its action using
MOFs respectively. Ongoing studies on MOFs systems trying to uti-
lize cellular assemblies for specific delivery [176,177]. The funda-
mental of the targeting strategies for the MOFs nanoparticles is
given as; Targeting to the cytosol [178] Drug targeting to mito-
chondria [80,179], Intracellular membrane trafficking [180,181],
and Targeting DNA, RNA and lipids [182–184].
6.1. Mofs based Sub-cellular compartment & organelles targeting
It would be quite interesting to assess the effects of the MOFs
system for investigating the cellular challenges, which can be fur-
ther beneficial for rational therapy. The effective On-site delivery
of the therapeutic agents with the help of MOFs will be a challeng-
ing task. Also, the fundamental basis for intracellular transporta-
Fig. 10. Various subcellular targeted TCPP, ZIF-8, MIL-88A and PCN224 MOFs.
23
tion with MOFs systems has been rarely discussed. Fig. 10
represents various subcellular targeted MOFs. On the other hand,
reliability as a vector for cargo delivery, high porous nature and
biocompatibility make MOFs suitable to be used in cancer nano
therapy Hence, to evaluate this Fang and co-workers elucidated
the porous coordination cages (PCCs) of 1–10 nm-sized nanoscopic
structures assembled by metal clusters and organic linkers. These
three types of PCCs namely, PCC-1, PCC-2, and PCC-3 were synthe-
sized by using respective ligands and linker molecules. In brief,
PCC-1 prepared by the solvothermal reaction of the H4V1 and panel
ligand (H3L1) with ZnCl2. PCC-2 was prepared by reacting Na4H4V2
and panel ligand (H3L2) with CoCl2. Lastly, PCC-3 was created by
the reaction of the metal complex [Pd(V3) (NO3)2] and the panel
ligand (L3). In context to fluorescence study, PCC-1 had its intrinsic
fluorescence and PCC-2 and PCC-3 because of internal cavities does
not possess fluorescence, but can encapsulate fluorescent dye. The
demonstration of the cellular distribution and transportation for
PCCs showed fair results. They exhibit differential cellular uptake
trail and distribution in comparison with AuNPs. These well-
suited properties of PCCs proposed that it could be a powerful tool
for the exploitation of cellular transportation and targeted delivery
of the guest molecules [185]. According to Wang et. al., and team,
for localized drug synthesis was been a challenging and mysterious
task for artificial determination of the location where copper-
catalyzed azide-alkyne cycloaddition CuAAC reaction occurred in
living cells. However, the copper catalyst shows some drawbacks
related to the CUAAC reaction about the living system. To over-
come these problems they designed an assorted copper-catalyzed
MOFs system that could specifically accrue in mitochondria of
24 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
living cells and served as localized drug synthesis under subcellu-
lar organelles for in-vivo tumor therapy. Triphenylphosphonium
(TPP) lipophilic cation used as a vector for selectively accumulation
of catalysts. Further, localized drug synthesis in subcellular orga-
nelles demonstrated with modified MOF-Cu with TPP. The in-situ
synthesis of an active therapeutic agent by inert prodrugs in sub-
cellular organelles was proved with minimizing the toxic side
effects. The biocompatibility of the prepared systems evaluated
using C. elegans and in vivo tumor therapy point out that the local-
ized synthesized resveratrol derived drug showed improved anti-
cancer activity [186].
Constructing the MOFs system with an intracellular environ-
ment responsive properties still a challenging task. Because of
the nanoparticulate system have to escape from lysosomal and
endosomal pathways. Considering this, Dong and Co-workers
designed a novel MOFs system which can successfully escape from
endo/lysosomal pathways and will exert antitumor property inher-
ently. The nMOFs system (DOX@ZIF-8), fabricated using a simple
method. In brief, organic linkers (2-methylimidazole) gathered
with Zn2+ to form ZIF-8. The chelation with Zn2+ and p-p
interaction with 2-methylimidazole, DOX get encapsulated into
the ZIF-8 Then, the targeted aptamer AS1411 was linked with the
anticancer drug@ZIF-8 by the electrostatic interaction. The nMOF
firstly targeted to the cancer cells and then it was entrapped in
endo/lysosomes it results in pH-responsive breakdown and
released profused Zn ions. Moreover, The pH-responsive nature
of the nMOFs could facilitate the release of the drug into the
cytosol and entrance into the nucleus [187].
The subcellular and organelle targeting is the latest concept
being explored for the complete eradication of tumor cells. The
MOFs can be used as nanoshuttle in which active moieties can be
loaded and sent for subcellular organelle targeting. The presence
of metal ions such as Zn gives MOFs an upper hand for interacting
with biomolecules or surface receptors which have an affinity for
metals such as Zn. Like in the case of multiple myeloma, there
are zinc finger proteins such as IKZF1 and IKZF3 which promote
the proliferation of Multiple myeloma. There are chances that the
zinc ions present in MOFs might interact with these proteins and
render them inactive to suppress the proliferation of cancer cells.
Similarly, in a few cancers, the tumor cells crave for metals such
as iron for their survival and proliferation. In such cancers, MOFs
with iron (MIL) can be used as a cargo delivery vehicle. The tumor
cell will engulf MIL as an iron source and will indirectly help tumor
localization of drugs and MOFs.
6.2. Mitochondrial targeted MOFs
A lot of research is being done on mitochondria-targeted
nanoparticles for tumor therapy. Similar to other nanoparticles,
using appropriate modifications MOFs have been targeted to mito-
chondria for efficient cancer therapy. Deng J. and co-investigators
for the first time reported the nanoscale ZIF-90 self-assembled
from Zn2+ and imidazole-2-carboxyaldehyde (2-ICA) for the speci-
fic mitochondrial targeting in the live cells. The key finding
observed that ZIF-90 responsive for adenosine triphosphate
(ATP), exerting ATP-triggered action for ZIF-90 decomposition.
Assuming this, they prepared a fluorescent nanoprobe by encapsu-
lating Rhodamine B (RhB) into ZIF-90 to form RhB/ZIF-90 complex.
The confirmation of the ATP detection ability of the formulated
RhB/ZIF-90 complex RhB/ZIF-90, firstly they found out AT concen-
tration in cell lysate with RhB/ZIF-90 nanocrystals using HeLa cell
lysates spiked samples. DOX used as fluorophore as well as drug,
incubation of Dox/ZIF-90 nanocrystals with cells for 4 h of incuba-
tion showed a partial accumulation of Dox in the cell. Summing up,
the agreeable response of RhB/ZIF-90 nanocrystals toward intracel-
lular ATP and targeted imaging of mitochondrial ATP ultimately
facilitates the study of ATP metabolism dynamic in live cells
[179]. Site-specific delivery is a crucial need for a targeted delivery
system. The proliferation, invasion, and metastasis of the cancer-
ous cell wholly depend upon mitochondria. Generating 1O2 inside
mitochondria can damage them at the very initial stage of PDT
treatment and thus maximize the cytotoxic effect. Cationic ruthe-
nium (Ru)-based PSs can be used as a direct targeting without
any extrinsic compound. Based on the concept Ni et. al., developed
a Hf-DBB-Ru nanoscaled MOF assembly for mitochondrial-targeted
Radiotherapy (RT) and radio dynamic therapy (RDT). The overall
mechanism involved integrating Ru(bpy)2+ 3 PSs mounted on the
into the framework Hf-DBB-Ru possessing a cationic UiO topology.
Additionally, they investigated the singlet oxygen generation using
a singlet oxygen sensor green (SOSG) assay by Hf-DBB-Ru. The
mitochondrial targeting capability of Hf-DBBRu evaluated by com-
paring it with neutral nMOF Hf-DBA. We first used inductively cou-
pled plasma-mass spectrometry (ICP-MS) to determine time-
dependent cellular uptake of Hf-DBA and Hf-DBB-Ru on MC38
( murine colon adenocarcinoma cells) cells. Mitochondria localiza-
tion of Hf-DBA and Hf-DBB-Ru in mitochondria envisaged by con-
focal laser scanning microscopic (CLSM) imaging appeared as
strong red phosphorescence. The investigational key findings con-
clude that the given nMOF enables mitochondria-targeted RT-RDT
in the future [124]. Zeolitic imidazolate framework (ZIF-90)
explored as much interestingly Due to their robust porosity, resis-
tance to thermal changes and chemical stability for the construc-
tion of different kinds of nanoscaled MOF systems. An earlier
report on a new class of NMOF-based host–guest photosensitive
system 2I-BodipyPh-NO2@ZIF-90 synthesized with a simplistic
one-pot in situ method for the pH-responsive and mitochondrial-
targeted photodynamic therapy. The pH-responsive mechanism
revolves around the concept that the positively charged nano spe-
cies after accumulation in an acidic tumor cellular microenviron-
ment shows cellular uptake due to their high affinity to the
negatively charged cell membranes. Hence, the evidence presented
the targeting capability of the MOF host–guest framework for sub-
cellular organelles provides a substitute to extend the designing of
a new type of NMOF-based PDT agents [80].
A broader perspective was adopted by Liu and the group in con-
text to fabricating mitochondria-targeting visible light photosensi-
tizers generating Rhodamine triplet state as for efficient
photodynamic therapy. Tumor cells with increased activity shoes
elevated mitochondrial movement and higher net negative charge
than healthy cells. The cationic rhodamine can be fascinated and
amassed onto the mitochondria showing migration towards the
organelle. The short lifetime of singlet oxygen and rapid subcellu-
lar diffusion creates some problems for localization of the photo-
sensitizer for its PDT performance. For the triplet state formation,
rhodamine molecule needs to get incorporated by a heavy atom
(such as attaching Br or I on the xanthene framework) or replacing
O atom by S, Se or Te atom. These results strongly suggest that the
incorporation of various transition metal systems into the rho-
damine unit can remarkably enhance the ability of 1O2 generation
with exception of Rh-Rho, mainly originated from the formation of
triplet state (T1) from rhodamine. This was confirmed by Nanosec-
ond transient absorption (TA) difference spectroscopy in MeCN.
Compared to another photosensitizer, rose Bengal, it is remarkable
that M-Rho is much more photostable as revealed from their neg-
ligible absorption spectral change during irradiation. These results
demonstrate their high resistance to photobleaching and excellent
photostability. On the other hand, in vitro photocytotoxicity, and
in vivo antitumor activity also demonstrated which makes the sys-
tem as a versatile tool for potential PDT application of M-Rho (tran-
sition metal systems) [188].
Mitochondria have been a centre for attraction not only in case
of cancer but several other diseases including several neurodegen-
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
erative diseases and aging, MOFs can be explored also in such dis-
ease as its use for subcellular targeted therapy has been more con-
fined to tumor cells only although the same concept can be applied
for efficient therapy of several diseases involving mitochondria.
Another area that is very less explored is the use of the MOFs for
the delivery of mitochondrial RNAs (mRNA) and proteins via mito-
chondria targeting strategy. It has been reported that the delivery
of mRNAs to mitochondria can efficiently treat cancer such as mul-
tiple myeloma, mantle cell lymphoma, and other hematological
malignancies. Combining mRNA with subcellular targeted MOFs
will be quite beneficial for the efficient therapy of multiple cancers.
6.3. MoFs based targeted cargo delivery
In contrast to earlier findings, it is an overtime point of debate
whether the MOFs nanomaterials have to take part in the drug
delivery with all ideal outcomes. From the past decade, nMOFs
had been used as potential bioimaging and anticancer drug deliv-
ery vectors [189]. The targeted application of the nMOFs can be
elaborated under the subheadings namely Stimuli-Responsive
MOFs for Drug Delivery, which includes Single-Stimulus-
Responsive MOFs for Drug Delivery [157], pH-Responsive MOFs
[47], Magnetically-Responsive MOFs [152] and Temperature-
Responsive MOFs [90,150]. MOF based multifunctional and
biocompatible drug delivery system with responding to tumor-
specific biosignals and targeting potential introduced by Wang
and group. The MOFs were fabricated using a one-pot
post-synthetic method initially from azide functionalized MOF
MIL-101-N3(Fe) without any organic solvents or toxic reagents.
Followed by the doxorubicin (DOX) was loaded into the porous
cages MIL-101-N3(Fe) by impregnation of nanoparticles. The
drug-loaded MIL-101-N3(Fe) was further modified by a bicy-
clononyne functionalized b-cyclodextrin (b-CD) derivative through
the azide-alkyne cycloaddition (SPAAC) reaction. To investigate the
in vivo antitumor efficacy of DOX-loaded TTMOF, four groups of
hepatoma H22 tumor-bearing mice with different treatments were
studied. The investigational findings denote that, both DOX loaded
TTMOF and free DOX showed significant tumor growth inhibition
compared to the PBS control group, whereas bare TTMOF without
DOX loading showed nearly no tumor inhibition. It can be con-
cluded that the formulated MOFs system will be a powerful tool
for the drug delivery antitumor agent [51].
Another aspect regarding the zeolitic imidazolate framework
involving a one-pot synthesis strategy had been employed for the
variety of metal–organic frameworks with encapsulated with
tumor-targeting molecules and its applications for controlled drug
delivery. Also, the process was used for both ZIF-8 and ZIF-67, and
with four types of a molecule with dissimilar functional groups.
The versatility of this one-pot encapsulation expanded by using
it with other organic dyes, such as rhodamine B, methyl orange
and methylene blue, etc. the weak coordination bonding between
these dyes and Zn2+ gives stability to the system. The cellular
uptake was examined using breast cancer cell lines. The uptake
of ZIF-8 particles into the cells measured with the relative cellular
Zn2+ level of fluorescence was compared. The relative fluorescence
intensities from cells treated with DOX@ZIF-8, ZIF-8, or ZIF-
8 + DOX were appreciably higher. The ZIF-8 crystals loaded with
DOX will be used as an efficient pH-responsive drug-delivery sys-
tem. Under physiological condition drug not released and at low
pH (5.0–6.5) drug released in a controlled pattern. From this, it
can be concluded that the fabricated MOFs system can be used
for targeted tumor therapy in the future [190]. A well-
constructed tumor-targeted zinc nanoscale MOFs encapsulating
chemotherapeutic agent explored by using a post-synthetic
approach. Folate-targeted IRMOF-3 drug carrier with conjugation
via the amide linking between the carboxylic groups of folate
25
and the amino groups of IRMOF-3 results in a stable MOFs system.
Moreover, the existence of amino groups on IRMOF-3 allows for
covalent attachment of folate as the targeting agent through
post-synthetic modification [191]. Autophagy is a self-
degradative route that is significant for balancing sources of energy
at critical times in development and in response to nutrient stress
[192]. ZIF-8 nanoparticles were continuously involved in the con-
struction of MOFs. Cancer cells, in turn, showed lowered autophagy
response. Conversely, introducing autophagy inhibitor 3-
methyladenine (3-MA) can significantly inhibit the class III PI3K
(Vps34)/Beclin-1 complex and thus can interfere with the forma-
tion of autophagosomes and thus resulted in improved autophagic
response towards cancer cells. The 3MA loaded MOFs with drug
the effects on autophagy inhibition and the antitumor efficiency
of 3-MA encapsulated ZIF-8 NPs (3-MA@ ZIF-8 NPs) was investi-
gated by [193]. The formulated MOFs system showed high drug
loading capacity as well as good biocompatibility. The work pro-
vides a novel platform by utilizing the self-destructive ability of
the cells to treat cancer itself with a mediator agent.
Although it was tried to minimize the overall pitfalls regarding
the MOFs system, multidrug resistance which is a recurring issue
for the effective treatment of cancer which is resulted due to over-
expressed active efflux transporters such as P-glycoprotein often
decreases the efficiency of MOFs in cancer therapy. To overcome
the limitation of multidrug resistance, ZIF-8 MOFs were explored
as the multidrug carrier to recognize the efficient co-delivery of
verapamil hydrochloride (VER) as the P-glycoprotein (P-gp) inhibi-
tor along with doxorubicin hydrochloride (DOX). The practical
investigation supports the hypothesized concepts, uniform ZIF-8
nanoparticles encapsulating DOX and VER are Methoxy-poly (ethy-
lene glycol)-folate (PEG-FA) obtained, used to stabilize the
(DOX + VER)@ZIF-8 to maintained extended circulations and an
active targeting drug delivery. The MOFs showed greater drug
loading and pH-responsive release performance. In conclusion,
the prepared PEG-FA/(DOX + VER)@ZIF-8 showed improved thera-
peutic activity that can be used for the in vivo applications [194].
7. MOF based biosensing platform
Owing to the versatility of MOFs concerning shape and compo-
sition, various biosensing platforms have been developed and
explored for cancer biosensing. Luminescent as well as normal
biosensors have been developed and have proved successful in
biosensing of cancer. The different biosensors have utilized metal,
polymers, proteins and nucleic acid for the development of effi-
cient and sensitive sensor development. The different biosensors
based on MOFs developed so far have been described briefly
(Fig. 11).
7.1. MOFs-polymer/metal composite biosensors
Polymers have been used for long in biomedical applications.
They have found extensive use in drug delivery, stents, grafts,
and scaffold to name a few. These polymers have also been
explored in the development of biosensors. Recently, polymer-
MOFs composites have demonstrated excellent biosensing ability.
Gu, et al. and co-workers prepared carbon dot (CD) based zirco-
nium (Zr) and hafnium (Hf) metal–organic framework (CD@ZrHf-
MOF) aptasensor for the determination of human epidermal
growth factor receptor-2 (HER-2) and MCF-7 cells. Due to the CD
doping in MOF, it offers high binding and detection ability. Also,
it has been reported that the amorphous nature of MOF provides
the high adsorption of biomolecules. This method provides a low
detection limit for HER-2 (19 fg∙mL1) and MCF-7 cells (23-
cell∙mL1) [195]. Recently, polystyrene/metal–organic
26 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
Fig. 11. Surface modified MOFs as biosensing platforms.
frameworks-199 (PS/MOF-199) based electrospun nanofiber film
for aldehyde (lung cancer biomarker) detection in human urine
of cancer patient using new thin-film micro-extraction technique.
It offers more superior extraction as compared to other reported
methods with a low limit of detection (4.2–17.3 nmol L-1). This
scheme holds much attention for cancer biomarker detection due
to non-invasive, determination of complex aldehyde [196]. Qiu,
et al. investigated the cationic Copper-based dicarboxylate ligand
containing a pyridinium one-dimensional metal–organic frame-
work, which exhibits the hybridization and interaction with fluo-
rophores probe DNA (fluorescence quencher) via pi staking,
electrostatic force, and hydrogen bonding. This hybrid probe DNA
offers the potential for the detection of target gastric cancer-
related biomarkers mainly five miRNA (miR-185, miR-20a, miR-
92b, miR-25 and miR-210) detection. furthermore, authors were
claimed miRNA complementary target detection limit from 91 to
559 pM [197]. The chain hybridization technique based electrode
was prepared for the detection of cancer biomolecules, this glass
electrode was associated with gold nanoparticle (AuNPs) and
coupled with the copper metal–organic framework (Cu-MOFs).
Furthermore, the author immobilized the DNA(S1) on MOF. Thus,
prepared biosensor (S1-AuNPs@Cu-MOFs) was used for miRNA-
155 detection in the serum sample of a cancer patient along with
the healthy population. Briefly, for the detection of miRNA, the
AuNPs tailored into Cu-MOFs (AuNPs@Cu-MOFs) provides the
immobilization platform for DNA strand, it acts signal reporting
material and catalyst for glucose oxidize (Fig. 12). Being there glu-
cose, the AuNPs and Cu-MOFs catalyzed the glucose oxidation
which gives the detection limit of 0.35fM. Hence this sensor pro-
vides the new potential for the detection of miRNA in clinical appli-
cation [198]. Yet another prostate and breast cancer biomarker,
Prostate-specific antigen (PSA) determination was carried out by
label-free electroluminescence (ECL) process. In that the b-
cyclodextrin (b-CD) base silver nanoparticle (AgNPs) doped with
lead [Pb(II)] metal–organic framework (Ag-MOF) sensor (Ag@Pb
(II)-b-CD). The antibody of PSA was immobilized with a sensor
and this final material was used as a substrate in the glass elec-
trode for ECL detection. It demonstrates the ECL behavior because
of AgNPs increase the Pb(II)-b-CD ECL intensity, although it fur-
nishes 0.34pgmL-1 detection limit. The author claimed, Because
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212 27

Fig. 12. Schematic illustration of (A) S1-AuNPs@Cu-MOFs based biosensor for the detection principle for glucose and the strategy of signal amplification (B); structure of H1,
target, and H2 (C) (taken with permission from wang et al. Ultrasensitive electrochemical paper-based biosensor for microRNA via strand displacement reaction and metal–
organic frameworks, Sensors and Actuator B: Chemical, 257 (2018), 561–569.

of the presence of AgNPs in pb(II)-b-CD (Ag@Pb(II)-b-CD), the PSA
antibody was easily immobilized and it enhanced the specific PAS
interaction towards the electrode consequently the initiation of
PSA electrode specificity reduced the ECL [199].
Apart from the use of metal such as silver and gold for biosens-
ing, several dyes have been explored for the development of MOFs
based biosensors. An electrochemical dye-based biosensor was
developed for the concurrent detection of tumor biomarkers let-
7a and miRNA-21 by the assembly of UIO-66-NH2 (nanocontainer)
and dsDNA (gatekeeper) based MOFs. These MOFs were further
modified using methylene blue (MB) and 3,30 ,5,50 -Tetramethylben
zidine (TMB) (MB@UIO and TMB@UIO) and used for the biomarker
simultaneous detection. Briefly, UIO-66-NH2 offered the high sen-
sitivity because of its porous nature entrapped the more quantity
of dyes, moreover small amount of analyte was detected, because
of the dsDNA to ssDNA superior gating effect. It furnishes the
detection limit for let-7a and miRNA-21 3.6fM and 8.2fM. As a
result, the author reported that the dye-based MOF could provide
more excellent potential for target detection and overcome the
drawback of dye-based simultaneous conventional sensing of
biomarkers [200]. Jiang and co-authors explored the area for the
biosensor to the detection of mucin1 on MCF-7 cancer cells with
H2O2 free approach via an ultrasensitive assay using of lumino-
phore N-(aminobutyl)-N-(ethylisoluminol) [ABEI] and Fe-MIL-101
functionalized MOF (ABEI@Fe-MIL-101) based biosensor. Due to
the conversion of dissolved oxygen into superoxide ions increases
the ECL behavior of MOF. Hence, Investigator claimed this biosen-
sor provides a safe environment to the cell and used for the early
detection of cancer [201]. Another study detected mucin 1
(MUC1) cancer biomarker using polyvinyl pyrrolidone (PVP)
assisted 2D zirconium (Zr)-based metal–organic framework (Zr-
MOF) nanosheets (521-MOF) [(6.0–7.5 nm)]. Because of the two
dimensional Zr-MOF, it provides enormous intact interaction and
it gives the affinity towards the analyte. MOF nanosheets have pro-
vides versatile properties including the high surface area, strong
affinity, in addition to oligonucleotides as well as good electro-
chemical activity. therefore, thew present biosensor furnishes the
0.12 and 0.65 pg
ml1 detection limit was observed from electro-
chemical impedance spectroscopy and SPR, in that order [202].
The highly sensitive biosensor was developed for the detection of
28 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
telomerase activity which is a biomarker in the malignant tumor
cells. in brief, for the telomerase detection, the Nobel Pd nanopar-
ticle (PdNPs) fixed on amine-functionalized chromium metal–or-
ganic framework (Cr-MOF) [(Pd/MIL101-NH2)] and used as a
redox mediator and it proved that the prepared MOF gives electro-
catalysis mechanism (Fig. 13). This functionalized MOF gives the
platform for the detection of the analyte via hydrogen bonding
and the transformation of an electron from MOF to an analyte. It
offered 11.25 HeLa cells mL1, detection limit. The hybridized
form[Pd/MIL101-NH2-Cd] conjugated to glass electrode attached
telomerase primer and capture probe DNA with (Pd/MIL101-NH2)
provided the amplification towards the acetaminophen. And this
same strategy was used for the detection of telomerase activity.
Herein, the enzyme and PCR free detection of biomarker although
it would be used in the bioassay [203].
Ling, P., and co-workers investigated the Platinum nanoparticle
(PtNPs) encapsulated MOF sensor demonstrates a rapid and sensi-
tive detection of telomerase activity by electro-catalysis. This plat-
inum encapsulated MOF was synthesized by using UiO-66-NH2, in
detail by using one pot encapsulation the PtNPs were encapsulated
into MOF and final prepared Pt@UiO-66-NH2 complex confirmed
the high electrocatalysis intended for NaBH4 oxidation and due
to that, it provides the detection of telomerase. The cDNA attached
MOF (Pt@UiO-66-NH2-cDNA) were hybridized with telomerase
primer loaded glass electrode, hence it improved the detection of
the analyte. So, the present report claimed that the detection level
of telomerase sensitivity down to 100cell mL1. In conclusion, for
the elucidation of telomerase functionality, the Pt@MOFs can be
tremendous importance and this approach was given the platform
for identification telomerase activity in a single cell [204]. The
highly selective and sensitive Ni-hemin MOF based folic acid (li-
gand) sensor for human breast cancer cells (MCF-7) and Human
Caucasian gastric adenocarcinoma detection was proposed by
Alizadeh, N. et al. This novel MOF nanocomposite gives the
catalyze oxidation in the existence of H2O2 on 3, 3, 5,
50 -tetramethylbenzidine (TMB) along with it behave like intrinsic
peroxidase activity. The investigator reported that it gives the
simple enzyme mimic approach based on the Ni-hemin MOF. An
MCF-7 cell has a surface folate receptor which offered the interac-
tion between the MOF and target. Hence, via this strategy sensor
was worked for cancer cell detection and for detection purpose
Fig. 13. Schematic representation Pd/MIL101-NH2 based biosensor for the electrochemical detection of telomerase activity (taken with permission from wang et.al.,
Fabrication of amine-functionalized metal–organic frameworks with embedded palladium nanoparticles for highly sensitive electrochemical detection of telomerase activity,
Sensors and Actuator B: Chemical, 278 (2019), 133–139.
the colorimetric assay was developed with a detection limit of 10
cells/mL. The prepared Ni-hemin MOFs provided the specificity
towards the cancer cell and damaged the MCF-7 cells and the neg-
ligible killing effect towards the normal cell [205]. The modified
glassy carbon electrode (GCE) labeled with Pb(II) or Cd(II) and 2-
aminoterephthalic acid (BDC-NH2) based MOF (Pb-BDCNH2and
Cd-BDC-NH2) labeled with antibody (Ab2) as signal amplifier and
target the simultaneous detection of cancer biomarker primarily,
carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP). The
BDC-NH2 contains an amino group that gives the linking of Ab2
for anchor signal amplification and hydrophobicity for MOF. Zhang
et al., GCE was tailored using chemically synthesized polyaniline
(electron-rich site) nanofiber along with mercaptosuccinic acid
for complexing purposes. Prepared Pb(II) or Cd(II) and 2-
aminoterephthalic acid-based MOF were used in the sandwich
assay as electrochemical labels for anti-FAP and CEA secondary
antibody moreover it showed detection limit was 0.03 pg
mL1
and 0.1 pg
mL1 for CEA and AFP respectively. hence the author
reported this MOF Provide the potential for immunoassays [206].
Ling, et al, Investigated the electrochemical finding of telom-
erase activity via using material iron porphyrin as a linker along
with zirconium ion as node-based nano porphyrinic–MO (Por-
MOF). It based on MOF electrocatalysis towards the oxygen reduc-
tion approach and telomerase generates the conformation signal.
In favor of the detection of telomerase, the water stable tracer
was prepared by using reorganization element streptavidin (SA)
functionalization with Por-MOF. SA based Por-MOF enhanced the
current of electrocatalytic reduction towards the O2 also reported
the strong signal with the detection limit 30 Hela cells mL-1. The
hybridization of assistant DNA2 (aDNA2) with capture DNA was
happed after the release of aDNA2 from the hairpin structure,
based on the assistant DNA 1 (aDNA1)-assistant DNA2 (aDNA2)
duplex. This duplex was switch into the hairpin structure while
the telomerase trigger extension. Therefore the newly developed
SA based Por-MOF gives the platform for enzyme-free and PCR free
detection as well as bioassay [207]. Another work reported the
highly sensitive detection of prostate cancer marker was carried
out by using the gold screen-printed electrodes which based on
the high electron affinities containing multidentate ligand tetra-
cyanoquinodimethane (TCNQ)-doped thin films of Cu3(BTC)2 Cu-
MOF. Furthermore, taking into the benefit of hydrophobicity of
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
MOF the antibody of PSA was modified on the above conducting
platform via physical adsorption method and this new anti-PSA -
TCNQ-Cu3 (BTC)2 conjugate provide the 0.06 ng/mL PSA specific
detection limit. Even though, TCNQ-Cu3 (BTC)2 was facilitated
PSA detection with robust physical immobilization of Anti-PSA
[208]. The self-calibrating florescent based indicator used for the
detection of ovarian cancer lysophosphatidic acid, by using mixed
Crystal Lanthanide (Eu-Tb) Zeolite based MOF (MZMOFs). The host
gust chemistry of Ln-MOF offers the detection of lysophosphatidic
acid (LPA). The Ln-ZMOFs assembly of Eu/Tb was prepared by
4-lanthanide molecular building block along with a bipyridine-
dicarboxylate used as a ligand. Although they have reported the
MOF offered the fluorescence in the presence of LPA via energy
transfer mechanism from Tb3+ to Eu3+. In conclusion, the author
claimed that MZMOF-3 approach was used for the early detection
of cancer via its lysophosphatidic acid detection [209].
The luminescent-based sensor was used Ln-MOFs (Ln = Eu)
using carboxy rich ligand for quantitative detection of carcinoid
tumor biomarkers namely Serotonin (HT) and its metabolite
5-hydroxy indole-3-acetic acid (HIAA). It has been reported the
high selectivity towards the biomarker even though the presence
of another neurotransmitter, also excellent sensitivity along with
fast response within 1 min. two different MOFs were prepared
and checked for the biomarker detection. Moreover, it has been
reported this MOF offered the sensitive luminance for biomole-
cules with bright emission, consequently, it provides the high
luminance quenching towards the carcinoid tumor biomarkers
mainly HT, HIAA along with low detection limit 0.66 and
0.54  106 m respectively. Hence it concludes that this could pro-
vide the new arena for the detection of cancer biomarkers [210].
The core–shell gold nano rod-MOF nanoprobes for glioma detec-
tion was reported by Wenting Shang et al. they have offered new
approach and prepared Au@MIL-88(Fe) on the surface of gold
nano-rod via controlling the MOF shell layer growth and the
11-mercaptoundecanoic acid (MUA) were used for the exchanging
the nano-rod surface ligand and reduce the cytotoxicity as well as
increase the COOH. This nanoscale framework contains metal
enhance optical and magnetic properties, although, it offered the
high X-ray attenuating, so it can be served as an imaging agent
in cancer detection. Also, the prepared nanoparticle was used as
a triple modifier in magnetic resonance imaging (MRI), computed
tomography (CT), and photoacoustic imaging (PAI)). It provides a
less level of radiation exposure as compared to CT in a stroke
patient, so this investigation provided the new platform for various
diagnosis methods for in vitro and in vivo. Thus this Au@MIL-88
(Fe) nanoparticle could be useful for glioma diagnosis and it might
be used as tripe-modality molecular imaging for examination [88].
Wu and co-workers reported that the multiplexed mRNA biomar-
ker of cancer cells detection via nano MOF (UiO-66) (NMOF) based
approach. Briefly, the peptide nucleic acid (PNA) was labeled with
fluorophores as well as a conjugate with NMOF (PNAMOF), which
gives the miRNA detection. Due to the bonding of the PNA probe to
MOF, the dye-labeled PNA contains fluoresces get sharply quench-
ing. In the presence of miRNA, the dye-based PNA was free from
NMOF and it offers the hybridization with the analyte of cancer
cells, which gives the recovery of PNA probes. Yafeng Wu, et al
claimed that this technique was more superior for the detection
and monitoring of the level of miRNA in living cancer cell than
the conventional reported techniques mainly PCR, northern blot
and microarrays. Also, this method offered more advantages over
the recently developed graphene oxide, single-walled carbon nan-
otubes and carbon nanoparticle-based fluorescence biosensor.
Hence, they concluded that the reported NMOF based platform
was highly sensitive, useful for quantitative detection in multi-
plexed miRNAs in living cancer cells also, monitored the in situ
spatiotemporal miRNA expression and its changes [211].
29
The non-invasive quantitative detection of lung cancer bio-
marker mainly volatile organic compounds and gaseous aldehyde
detection was carried out by using Superparticle@MOF Structure
via selective surface-enhanced Raman scattering technique
(SERS), which offered a low detection limit of 10 ppb. For MOF
preparation they were used gold super-particles (GSPs) although
it acts as SERS hotspots. This new approach provides proper time
for gad adsorption via gas rate flow. For aldehyde detection, the
biomarker was capped ion GSP using Raman-active probe mole-
cule p-amino thiophenol (4-ATP) and it gives the Schiff base reac-
tion. The gas adsorption rate was modified by using ZIF-8 coated
gold nanoparticle (GSP). Thus, it tailored the high adsorption rate
and slow gas flow rate consequently lower the GSP electromag-
netic field exponential decay and provide tremendous opportuni-
ties in the detection of cancer biomarkers [212]. A newly tailored
gold and copper MOF (Au/Cu-MOF) nanocomposite of dual
response (electrochemical and glucometer) was used for Dam
MTase biosensing, along with detection limit 0.001UmL1. This
nanocomposite offers the redox probe attributing to the coordi-
nated Cu2+, also it gives the platform for invertase immobiliza-
tion. Furthermore, it catalyzes the sucrose to glucose, which
recognizes the EC with glucometer responses for DNA MTase
finding. The MOF containing metal sites present the high density
along with abundant invertase on nanocomposite by high effi-
ciency; ultimately catalysis recognized the signal amplification.
Although, Author reported that the signal intensities of the detec-
tor are directly proportional to the analyte (DNA MTase). Also, the
efficacy of the prepared model was checked via using the anti-
cancer 5-fluorouracil. Consequently, a prepared dual response
biosensor showed good selectivity and potentially used for inhibi-
tors testing. Due to that, this biosensor assures for early cancer
detection [213].
The cancer biomarker MUC1 detection was carried out by using
coupled luminescent N-(4-aminobutyl)-N-(ethylisoluminol) [ABEI]
with 2-aminoterephhalic acid [MIL] (ligand) functionalized Fe
based MOF [ABEI/MIL-101(Fe)]. Moreover, the prepared composite
showed the improved electrochemoluminance (ECL) intensity
owing to the inherent mimic peroxidase action of MIL-101(Fe).
Thus, synthesized ABEI/MIL-101(Fe) was used for the mucin1
(MUC1) detection. Due to the presence of intrinsic mimic peroxi-
dase activity of ABEI/MIL-101(Fe), gives the notable ECL signals.
Although, as a result, the decomposition rate of hydrogen peroxide
gets enhanced. Moreover, this process produced the reactive oxy-
gen radicals which participated in the ECL. The authors reported
the ECL sensor gives the low detection limit for MUC1 (1.6fgmL1),
hence, it could effective probe used for the early diagnosis of
biomarkers [214]. Wang and other authors developed functional-
ized magnetic graphene (MagM) composite coated-magnesium
(Mg) MOF (MagG@Mg-MOFs-1C) for the arrest of glycopeptides,
which provided the low detection limit (0.1fmol/lL). Herein, the
MagG based composite offered the more selective detection of gly-
copeptides due to its porous nature and hydrophobicity. Although
it has more affinity towards the analytes due to the delocalized pi-
pi electron structure of the composite and magnetic property.
Moreover, it increases the adsorption forces of MOF also; it pro-
vided the proper separation of analytes. Magnesium was worked
on a molecular level and avoids the larger size molecules. It shows
a high recovery of glycopeptides due to strong magnetic property,
excellent hydrophobicity, the planet of affinity site. Hence,
prepared composite has been selectively applied for the bladder
cancer biomarker detection mainly glycopeptides
(406 N-glycosylation peptides) in urine as well as it also applied
for the other glycoprotein based biomarker detection like
a-2-macroglobulin, complement C4-B, and a-1-antitrypsin. Inves-
tigator concludes that this composite gives the new platform for
the rapid and convenient diagnosis because it showed tremendous
30 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
potential towards the detection of low abundance molecule in the
urine [215].
The first time porphyrin-based covalent organic framework (de-
noted as p-COF) was used for the detection of trace epidermal
growth factor receptor EGFR and living Michigan cancer
foundation-7 (MCF-7) cells by using oil bath method. This two-
dimensional nature of prepared MOF provides more binding sites
for respective biomolecules or analytes/ aptamer. Also, it improved
the electrochemical activity in analytes, its porosity offered the
platform for immobilization of aptamer, and besides, it enhances
the absorption of the probe, consequently the increase the detec-
tion sensitivity. Besides this, P-COF based MCF-7 detection showed
the LOD of 61cell∙mL1. It concluded that this sensor offers good
stability, recyclability, applicability and high selectivity towards
the human serum cancer biomarker also it could use in the disease
diagnosis [216].
7.2. MoFs based luminescent sensor
Lan and coauthor developed the highly luminescent MOF
([Zn2(bpdc)2-(bpee)] sensor for detection of explosives in the vapor
through redox quenching mechanism using ligand (bpdc: 4,40 -bip
henyldicarboxylate and bpee = 1,2-bipyridylethene), furthermore,
this both ligands provided the luminance property, analyte detec-
tion capability and high conjugated pi systems. The [Zn2(bpdc)2-
(bpee)]
2DMF was prepared via a solvothermal method, Due to
the 3D structure and porosity of MOF provides the highly sensitive
detection of nitro explosives reported by authors. Consequently,
the nitroaromatic explosive, plastic explosive, 2,4-Dinitrotoluene
(DNT), as well as 2,3-dimethyl-2,3-dinitrobutane (DMNB) detec-
tion, was finished using this novel sensor. Also, it exhibited a rever-
sible detection process, therefore it explored the platform for
explosive sensing highly sensitive and selective sensor for explo-
sives based on luminescent MOFs [217]. Lewis basic pyridyl sites
for the sensing of metal ions reported by Chen. The detection was
carried out using Eu based MOF {[Eu(pdc)1.5(DMF)]
(DMF)0.5(H2-
O)0.5}, (pdc: pyridine-3,5-dicarboxylate) a luminescent based sen-
sor. This MOF contains Eu free sites that were engaged with
carboxylate ions and it stabilized the Eu sites and pores, and
because of its one-dimensional channels recognized the new guest
analytes or molecules. Due to the presence of free Lewis basic pyr-
idyl sites within the pores, it enhanced the detection capacity
towards the metal ions, and acidic molecules along with it
enhanced the sensing function of MOF. Also, they have claimed
that porous MOF based the Lewis basic sites expected to play the
main role for the detection of small Lewis acidic molecules as well
as metal ions. Besides, it finds functionalities in chemical transfor-
mation with sensing [218].
Self-assembled Europium (III)-MOF [ITQMOF-3-Eu],
(ITQMOF = Instituto de Tecnologia Quimica Metal-Organic Frame-
work) based highly photo-luminescent linear pH sensor was devel-
oped using 1, 10-phenanthroline-2, 9-dicarboxylic acid as the
ligand. This prepared MOF provided an excellent balance among
emission rate, energy transfer, and absorption. Owing to these
advantages, it offered the sensing property at the physiological
pH range. Moreover, for a self-calibrating sensor, MOF material
was used with optical fiber, which offered the signal within the
given pH range. By using lanthanide ions or mixture, the
ITQMOF-3 composite could be obtained and it offered a new arena
for bimodal imaging nanoprobe for biomedical application [219].
The Luminescent Cu2+ based metal–organic framework Cu-TCA
(H3TCA = tricarboxytriphenyl amine) MOF for detection of Nitric
Oxide (NO) in an Aqueous Solution as well as in Living Cells.
Herein, the TCA was used as an emitter. Briefly, Due to the Cu2+ions
paramagnetic nature would quench the ligand-based fluorescence.
Whereas the NO and metal ions coordination occurred on the MOF
surface and it reduced the Cu2+ to Cu+, and it improved the lumi-
nescence of MOF. Herein, two NO MOF-sensor was reported based
on the triphenylamine (TCA) moiety, mainly Cu-TCA and Eu-TCA.
In that, the presence of NO the Cu2+ gets reduced and it showed
luminescence in aqueous solution which provides the high selec-
tivity and sensitivity towards the bio imagining application in
the living cells. Furthermore, MOF explored the NO sensing appli-
cation as a ratiometric luminescent chemosensor. Also, the investi-
gator developed the MOF based luminescent nanoparticles for the
detection of NO using the optical fluorescent technology [220]. The
nanoscale luminescent Tb-MOF-76 for molecular Sensing reported
by Weiting Yang et al. the MOF was prepared by using microwave-
assisted methods with amino acids (proline) as capping agents
which contains only one carboxylic group as compared to the other
organic linker 1,3,5-benzenetricarboxylic acid (H3BTC). Authors
were reported that the increase proline concentration reduced
the crystal size of composites and after a certain concentration;
there is no chance like the composite. They conclude that the pro-
line offered the reduction in crystal size; because of it shows a
modulating effect among lanthanide as well linkers. Although, as
compared to the glycine, proline more suitable capping agent got
this MOF sensor because of its solubility, and size reduction capa-
bility. Furthermore, nanoscale MOF exhibited photoluminescence
in solution and which explored the platform for solvent sensing
like acetone. So, they concluded that this property of MOF towards
the terminal solvent and pore structures explored the new arena in
luminescent microporous small molecular sensors [221]. For
detection DMF vapor the lanthanide (Ln) based MOF sensor was
successfully developed by Yu Li et al. It has been reported that sift-
ing of the excited state energy level of ligand because of the DMF
vapor-ligand interaction, thus it showed the luminescence. The
reported turn on mechanism discovered the new strategy for the
lanthanide-MOF sensor by proper ligand design and targeting ana-
lyte through ligand– analyte interactions. So, it provided the new
potential for DMF vapor detection by using the Ln-MOF sensor
[222].
A targeted self-referencing Eu3+-doped into an isostructural
3+
Tb based metal–organic framework was fabricated which gave
Eu0.0069*Tb0.9931-DMBDC (DMBDC: 2,5-dimethoxy-1,4-benzenedi
carboxylate) MOF for a luminescent thermometer for wide temper-
ature. The DMBDC acts as an organic linker in the prepared MOF
and it offered the effective sensation to lanthanide MOF for detec-
tion of temperature. It worked on the energy transfer mechanism,
they reported the energy transfer considerably enhance when the
temperature was increased. The linear correlation among temper-
ature and luminescence intensity ratio from 50 to 200 K thus, lumi-
nescent MOF thermometer provides the new step for cryogenic
temperature sensors. It has been reported that these newly pre-
pared luminescent thermometers can be used in intracellular sens-
ing as a nano-thermometer also, thermal mapping with nano-
special resolution [223]. Furthermore, the mixed-ligand Zn-MOFs
for highly luminescent sensors developed for nitro compounds
using rigid carboxylic acid ligand and compared with the semirigid
ligand. Briefly, they have been prepared the three Zn based MOF
via dual-ligand approach using N-donor ligand 1, 3, 5-tris (1-
imidazolyl)-benzene (tib) and above reported carboxylate ligand
by hydrothermal process. This MOF provides the solvent depen-
dant photo-luminance phenomenon, although, it provides the high
sensitive nitroaromatic detection via fluorescence quenching, even
though they have reported that the fluorescence quenching prop-
erty was based on the e- transfer from electron-donating MOF
towards the e- withdrawing nitro group within the nitro com-
pound. It concluded that this electron-rich MOF can be used for
the detection of nitro-substituted compounds [224].
In a similar work, the 1D, honeycomb type channels based,
microporous lanthanide-MOF {[Tb(FDA)1.5(DMF)*DMF}n (1
nDMF
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
and DMF: N, N-dimethylformamide). It demonstrated exceptional
separation and adsorption capabilities towards the hydrogen,
nitrogen, and carbon dioxide, although it provided the selective
significant sorption of CO2 over nitrogen and CH4. Authors were
reported that the separation and detection of gases molecules were
occurred due to MOF offers the hydrogen bonding, Vander Val
forces, etc towards the gases. Ultimately, it enhanced the adsorp-
tion and detection of small molecules due to the open metal sites
in porous lanthanide MOF. It has been reported that the emulsion
luminescent studies provide the guest-dependent luminescent
emissions, because of this potential it could be used for benzene
and acetone or small molecule pollutant detection [225].
The very rare azobenzoic acid-functionalized graphene oxide
(GO) nano-composites with luminescent MOF (A-GO/L–Zn2+) sen-
sor developed for detection of high explosives. For this MOF, due
to its photo-luminescent properties stilbene derivative was
selected as a ligand. In that, they have been reported that the
GO-based MOF offered the small molecules retention because of
its dispersive forces. This nanocomposite showed the typical p–
p* transition and due to this transition provided the high fluores-
cence property. Owing to the functionalization graphene-based
MOF; the nanocomposite was offered the prominent and long term
fluorescent enhancement as compared to the ligand. Also, this
nanocomposite can be used as chemosensor in the detection of
DNT molecules, moreover, it offered a new approach for the arena
of molecularly designed materials of biology, medicine, and mate-
rial science [226]. Using mixed ligand approach the isostructural
lanthanide MOF (Ln-MOFs), [Ln2(BPDC)-(BDC)2(H2O)2]n [Ln: Eu
(1) and Tb(2)], was prepared by Zhou, et al, via hydrothermal cir-
cumstances. These ligand containing aromatic-carboxylic groups
like phenyl and pyridyl (luminescent chromopore) play a role as
an antenna for energy transformation to a luminescent component
center. Due to the Van der Waal radius, explosive organic mole-
cules could arrest on MOF and it influences the energy transfer
from ligand to luminescent Center of MOF. This luminescent
MOF showed the selectivity towards the fluoride anion and small
molecules including acetone, acetonitrile as well as formaldehyde.
And it could use for the detection of poisonous small molecules as
well as anions [227].
The terbium-MOF, [Tb(1,3,5-BTC)]n (1,3,5-
benzenetricarboxylate,) was designed for picric acid detection
and Synthesis of MOF carried out via the combined ultrasound-
vapor phase diffusion technique. Due to this technique, nanoscale
MOF crystals were prepared with high yield as compared to the
conventional method. Although they have mentioned that
nitroaromatic having a capacity to accept electron and substitution
of e- withdrawing nitro groups on the aromatic ring which affects
the energy of orbital, means it reduces the energy of p*orbital. And
because of this electron transfer (donor and acceptor), mechanism
quenching occurred. Ultimately, this prepared MOF provided more
selectivity to the picric acid and used as a luminescence sensor for
picric acid [228].
The novel lanthanide luminescent MOF composed on Eu3+ ion
and a tricarboxylate ligand, for cation sensing Eu(BTPCA)(H2O)]

2DMF
3H2O [H3BTPCA: 1,10 ,100 -(benzene-1,3,5-triyl)tripiperidine-4
- carboxylic acid;18 DMF: dimethylformamide]. In that, the Lewis
basic triazinyl nitrogen atoms showed complexation with present
metal ions, also this interaction has been determined quantita-
tively. Although they have reported that the ligand for, coordinates
six lanthanide ions via carboxylate group exclusively, moreover
out of these two are chelating and another is bridging. The nature
of interaction and ligand electronic structure affected the quench-
ing and detection capacity of MOF towards the analytes. In conclu-
sion, the author has been reported it could use for the sensing of
metal ions [229]. Nagarkar and authors reported that the detection
of nitro-explosive 2, 4, 6-trinitrophenol (TNP) was carried out by
31
using 3D fluorescent MOF [Cd(NDC)0.5(PCA)]Gx (1G = guest mole-
cules) using NDC (2,6-naphthalene dicarboxylic acid) and PCA (4-
pyridine carboxylic acid) as a ligand. The author has been claimed
the selective detection of TNP due to the electrostatic interaction
among TNP highly acidic hydroxyl group and fluorophores, also
the electron and its energy transfer mechanism involved in it.
Along with TNP detection was carried out without inference of
another nitro compound in aqueous as well as organic solvents.
As concluded that MOF was more stable with water, enormous
electrostatic interaction with TNP might be offered the potential
of other analytes detection [230].
Kim, et al, prepared the luminescent Li-based MOF [{Li3[Li
(DMF)2](CPMA)2}
4DMF
H2O] modified form using the solvother-
mal process for explosive nitroaromatic compounds selective
detection, also, direct examination of the interaction site. A ditopic
H2CPMA: bis (4-carboxyphenyl)-N-methylamine] used as ligand
and it affords the luminescence properties to MOF. Although, this
ligand molecule was offering good luminance towards the analyte
detection; because of the charges transformation from N-methyl
amino (donor) to the carboxylate(acceptor). Due to the strong
interaction of MOF and nitroaromatic explosive compounds alter
the electronic structure of MOF, thus it exhibited a suitable MOF
based sensor for the detection of electron-deficient (nitroaromatic
compound example like nitrobenzene [231]. Moreover the another
study was demonstrated the 3D, cationic MOF [Ag2-(btr)2]
2ClO4-

3H2O (ABT
2ClO4;[btr:4,40 -bis(1,2,4-triazole)] consisting of nanos-
cale cages for detection of Cr2O72- via single-crystal to single-
crystal (sc-sc) process. Although they have been reported that
the exchange of analyte was achieved by the ligand contains 4
nitrogen atoms. Moreover, ligand (btr) molecules act as a tetraden-
tate ligand to bridge four Ag; consequently, it constructed the 1D
MOF which provides the detection of anion analytes ions. As a
result, this MOF proved that an effective, easy and fast process
for pollutant detection [232]. The NU-1000, pyrene-based lumines-
cent microcrystalline MOF Zr(IV) ions were newly investigated
using tetraethyl 4,40 ,400 ,4000 -(pyrene-1,3,6,8-tetrayl) tetrabenzoic
acid (TBAPy) as a ligand for detection and screening of human uri-
nary 1-Hyroxypyrene (1-HP). The ligand structural arrangement, in
MOF, provides the detection of 1-HP via strong intermolecular pi-
pi interaction. Although in presence of analyte MOF provides the
quenching and give the low detection limit of 48 nm as well as
high sensitivity and selectivity for the urinary metabolite of poly-
cyclic aromatic hydrocarbons (PAHs) 1-HP. Consequently, this sen-
sor showed good feasibility for practical application besides this it
demonstrated that good recovery of human urine contains 1-HP
[233].
Tian and coauthors prepared the 3D, Cd-MOF, [NH2(CH3)2]2*
[Cd17(L)12(m3-H2O)4(DMF)2(H2O)2]*solvent. It has been assembled
with a pi electron-rich aromatic H3L as a ligand (2,4,6-tris[1-(3-car
boxylphenoxy)yl methyl]mesitylene) and d10 configuration
Cd2+(metal ion) using solvothermal conditions. Furthermore,
C3-symmetrical multicarboxylate as a ligand-based this MOF used
for the detection of nitroaromatic explosives compound in the
vapor state. Although it has been reported that the nitroaromatic
containing the nitro group provides the electron-withdrawing sub-
stituent, additionally, as a result, it enhanced the oxidative stability
of the aromatic ring. Thus, due to the electron transfer quenching
mechanism, the MOF shows fluorescence at the present of nitro
explosives (nitrobenzene). Although it showed the high sensitivity
and selectivity, it investigated a new method for the detection of
nitrobenzene and its derivative in solution or vapor state [234]. A
double-paned, extended, 2D network-based terbium metal–or-
ganic framework [Tb(Hbtca)(H2O)2]*H2O (Tb-MOF–COOH) was
developed by Sun, et al, using uncoordinated carboxyl-rich 1,10-b
iphenyl-2,3,30,50-tetracarboxylic acid (H4btca) as a ligand.
The author has been claimed, the carboxyl group pointing to the
32 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
interior pores of MOF furnish luminescent-based sensor and it
offers the selectivity and specificity towards the metal ions
(Fe3+), although the concentration of Fe3+ based luminescence of
MOF [235]. Another study reported the SC-SC transformation
mechanism-based Eu-MOF luminescent sensor using bpydbH2
(4,40 -(4,40 -bipyridine-2,6-diyl) dibenzoic acid) as a ligand.
Although this ligand provides the intense rigidity which furnishes
the porous structure, also it has gives the high capacity to conquer
the low absorption coefficient of single lanthanide ions via the
antenna effect, although ligand conjugated rings with available
Lewis-base sites may improve the sensitivity through a variety of
host–guest interactions. They were reported that the sensing and
detection of analyte mechanisms are not clear. The hydrothermally
robust and luminescent microporous MOF was served host mate-
rial based multi-responsive luminescent sensor by Song, et al, This
sensor was capable of the detection of acetone, highly explosive
TNP and selective for aliphatic alcohols. So, it concludes that this
sensor can serve as multi responsive for pollutant detection
[236]. The present work reported the novel anionic, 3D metal
MOF for the detection of nitrobenzene. Briefly, the preparation of
MOF [(CH3)2NH2] + [Cd3+(H2L)], was prepared via the solvothermal
method, for this a multidentate organic carboxylic acid used as a
ligand (H12L) was used. The Cd3+ oxidation and reduction are the
task and this ligand 12 carboxyl groups could provide adequate
oxygen atoms to assemble the coordination requirements of metal
ions (Cd3+). As a result, MOF provides a novel cage to cage the con-
nection between 3D MOF and 1D channels. Thus, it furnishes the
tremendous luminescent property with the respective analyte.
Furthermore, it was tested for nitrobenzene detection and it
offered sensitivity and selectivity towards nitrobenzene [237].
Dou, et al, reported that luminescent MOF films offered fast and
reversible detection of oxygen. This highly porous MIL-100
(In)  Tb3+ MOF was prepared by using indium organic CPM-
5  Tb3+ and MIL-100(In)  Tb3+ respectively. The author has been
reported that the CPM-5, every single one carboxylate acids of
H3BTC ligand are deprotonated in addition to (CH3)2NH2+ provide
as the variable charge-balancing cation in pores. Although, the
additional trimesic acid which has strong interaction with the
In3O trimer by way of the CO  In mono-dentate coordination plus
serves as one of the terminal molecules of the In3O trimer in for
MIL-100(In). Besides, the deactivation of on triplet state organic
ligand by oxygen demonstrates the oxygen quenching as well this
offered some interaction with excited state of lanthanide atoms.
The author has been concluding that the Also the MIL-100
(In)  Tb3+ illustrated the more energy transfer efficiency as com-
pared to CPM-5  Tb3+, and as a result MIL-100(In)  Tb3+ provide
the high luminescent properties. It has been reported that intra-
molecular energy transfer luminescent Ln-centered MOFs demon-
strate higher oxygen sensitivities as compared to the MOFs with
intermolecular energy transfer while the Ln ion is sensitized by
the identical organic ligand. Consequently, this MOF showed great
potential to the oxygen sensitivity (KSV = 7.59) as well as short
response or recovery time (6 s/53 s) [238]. The new luminescence
LnMOF [Eu*L(OH)2](NO3)*x (solvent) were used for the detection of
Fe3+ ions and nitrobenzene (NB). These targets were achieved by
using the tripodal flexible zwitterions (H3LBr3) 1,10 ,100 -(2,4,6-trime
thyl benzene-1,3,5-triyl)tris(methylene)-tris(4-carboxy-pyridi
nium)tribromide as a ligand which offers the bowl-shaped config-
uration. Resulting MOF shows the chair shape configuration with
carboxylate groups orientate to two sides of the basic phenyl
group. Also, it has been reported that the luminescent intensity
of Ln depends upon the energy transfer efficiency of respective
ligand to Ln. Consequently, it showed high selectivity as well as
sensing for Fe3+ ions and NB. Based on the ability it concluded that
this MOF offers the new platform for the detection of metal ions
and small molecules [239]. The detection of picric acid and palla-
dium was carried out by using zinc metal-based MOF. Briefly, the
novel dual sensor Zn based MOF {[Zn (C34H18O8)0.5(C20N2H16)0.5]
∙0.5(C20N2H16).2H2O]}n along with Zn(NO3)2*6H2O. for the detec-
tion of picric acid and palladium. They have selected bpeb {1,4-
bis [2-(4-pyridyl)ethenyl]}benzene)as a linker for the synthesis of
MOF with H4tcpb [1,2,4,5,-Tetrakis(4-carboxyphenyl)benzene)] as
pi electron-rich tetra-topic carboxylate ligand. This pi electron-
rich conjugate was offered the luminescent properties for MOF in
the presence of analytes. It reported that the mutual existence of
energy along with electron transfer mechanisms improved the
selectivity for PA. also, the linker unsaturated alkene moieties
(–CH@CH–) facilitated the palladium detection [240].
Wang, et al, structured the new (Tb) terbium-(UPC-11) based
metal–organic framework (MOF), [Tb3(NO3)(BPTA)2(H2O)6]
*3Diox
8H2O (H4BPTA:[1,10 -biphenyl ]-2, 20 , 5, 50 -tetracarboxylic
acid, Diox:= 1,4-dioxane using tetracarboxylate ligand via
solvothermal reaction for detection of Nitroaromatic Compounds.
This MOF shows quenching of emission because of the energy
transfer from ligand to the electron-deficient molecules. In order,
this MOF enhances the potential for the detection of analytes.
Herein, MOF provided the solvent dependant photoluminescence
properties. Also, it offered the moderate selectivity toward the
Fe3+ as well as Cu2+ ions in DMSO. It concludes that this MOF sen-
sor provides a high potential for the detection of nitroaromatic
compounds [241]. The luminescence-based 3D MOF [Zn2(TCPPE)]
was used for the detection of volatile organic compounds, using
the tetraphenylethene as a ligand along with H4TCPPE {tetrakis[4
-(4-carboxyphenyl)phenyl]ethene} as a linker. The vibrations and
rotations of phenyl rings from TCPPE4- are limited in the rigid
framework, furthermore, complex demonstrated strong blue lumi-
nescence. Although, it has been reported that the tetrapheny-
lethene based MOF small pore size and low dimensional
channels could saturate the analytes efficiently in the core. As a
result, it increased the interaction ability among analytes and
MOF, thus increased the sensing ability of MOF towards the ana-
lytes. The authors concluded that the MOF sensor provided strong
fluorescence and offered the gas adsorption along with sensitivity
to the volatile organic compounds [242].
Li, et al, investigated the first time new kind of strategy for the
construction of nanoscale UiO-MOF (Mi-UiO-66 and-UiO-67) by
using the esterified maleimide containing organic linkers. It has
been reported that the maleimide not quenches the fluorescence
as it or not thiol adduct, So it could convert into conjugated form
for enhancing the fluorescence property of maleimide. Further-
more, the authors reported that the ester-based maleimide deriva-
tive is highly selective to thiol and reactive fluorescence probes for
it. Furthermore, it enhanced the sensitivity of the sensor towards
the thiol group based analytes in living cells. In conclusion, authors
claimed that this MOF offered the fluorescent-based sensor for the
detection of cysteine and glutathione with detection sensitivity 10-
11
M. Although, it demonstrated the fluorescence imaging of
Cystine and glutathione in a living cell [243]. The aldehyde sensing
was reported by Wu, et al. they have synthesized 3D, 3d  4f MOF
(MOF), {[Tb-Zn(L)-(CO3)2(H2O)]n} using ligand HL [4-(4-carboxy
phenyl)-2,2:6,2-terpyridine] via solvothermal conditions. These
ligands were embedded in both 3d and 4f ions into similar MOFs.
Concurrently, the HL with a large conjugated p electronic system
offered the ideal luminescent chromophores, which could relocate
the energy to the luminescent centers efficiently. As a result, it
reported that prepared MOF provides the luminescence sensing
of formal, acetaldehyde and propanal [244]. The highly selective
and sensitive detection of nitroaniline and metal ions was studied
by Yu, et al .for this they have prepared the Zn3L3*(DMF)2 (1) and
Zn3L3(DMA)2*(H2O)3 (2) by using the ligand L.(L: 4,40 -stilbene
dicarboxylic acid) MOF for the detection of nitroaniline and metal
ions with high sensitivity and selectivity. This linker offers the
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
aromatic dicarboxylate ligand with a highly conjugated p system,
due to emissive linker could be used in the new topologies MOF
along with good photophysical properties. Thus, this linker was
provided luminescent property in the presence of the analyte (ni-
troaniline). As a result, it has been observed that MOF exhibited
the fluorescence quenching for nitroaniline with the low detection
limit [245].
Legrand and co-author prepared and used Al-MIL-101 MOF
based sensor for detection of sulfide, produced by living cells using
the 2-amino/azidoterephthalate linker. This type of sensor was
based on short-pulse laser excitation of luminescent MOF and it
achieved the analysis of living cell sulfide as well as sulfide release
molecules at submicromolar levels [246]. The first luminescent
metal–organic framework based sensor designed for quantitative
as well as simultaneous luminescent revealing of temperature
and humidity. the prepared the dual-functional luminescent sen-
sor based on the europium metal–organic framework, (Eu-MOF)
{[Eu2(L)3(H2O)2(DMF)2]16H2O}n, using H2L {1,4-bis(5-carboxy-1H
benzimidazole-2-yl) benzene)} as a ligand via solvothermal reac-
tion. This ligand was furnished the temperature and humidity
sensing, the MOF provides the 1D and open channel (filled by
water molecules) which played an important role in the sensing.
This MOF assembly provided the base for the mounting self-
calibrated ratiometric thermometer. The author was providing
the cryogenic temperature and humidity (33.0% to 85.1% RH) by
using this MOF sensor. Therefore, it provided the novel sensor for
the detection of temperature and humidity [247].
Fe3+ and Cr2O7 detection were studied by Li, Liu, et al, using a
bifunctional MOF sensor. They have prepared pyrazoyl-carboxyl
bifunctional ligand-based microporous lanthanide (Ln)-MOF, [Ln
(Hpzbc)2(NO3)]
H2O (, Ln: Nd3+, Sm3+, Eu3+, Gd3+, Tb3+, Er3+, and
Yb3+ ions) and H2pzbc [3-(1H-pyrazol-3-yl) benzoic acid] as a
ligand, with one-dimensional channels ornamented through
nitrate anions with Pyrazoyl groups, have been assembled. It
showed high sensitivity and selectivity towards Fe3+ and Cr2O7.
This strategy of sensor offered the high capture capacity for carbon
dioxide, because of this MOF provides the multiple binding sites
[248]. Also, one more study was reported for detection of Fe3+
using fast responsive and high sensitive MOF nanosheets for lumi-
nescent sensing of Fe3+. In that, the MOF (NTU-9-NS) was synthe-
sized by using Ti2(HDOBDC)2*(H2DOBDC) (H2DOBDC: 2,5-
dihydroxyterephthalic acid), Which proposed the high sensitivity
for Fe3+. This sensor was giving a low detection limit (0.45 lM).
therefore, the author concluded that this could furnish the base
for designing and analysis of biological as well as environmental
luminescent sensors [249]. Nowadays, luminescent based MOFs
sensor has gained much attention for the reorganization of envi-
ronmental nitroaromatic pollutants and heavy metal ions (Fe3+).
One more study has reported the detection of nitroaromatic and
heavy metal. For this luminescent Zn(II)-MOF [Zn3(L)2(bipy)(l3-
OH)2]3H2O (bipy: 4,40 -bipyridine) by using 9H-carbazolyl-3,6-
dicarboxylic acid (H2L) as a rigid ligand. Due to the charge transfer
transition from the organic ligand to metal ions, the luminescent
quenching has happened. Thus, prepared MOF offered three-
dimensional networks, although it provided the high sensitivity
and selectivity for nitroaromatic compounds, also Fe3+ via fluores-
cence quenching. Simultaneously, it can recycle after sensing stud-
ies by using the distilled water and DMF [250].
Consideration of human health and environmental protection
the detection of nitroaromatic picric acid having opportunity to
the researcher, the present work investigated the water-stable
MOF, Eu NDC using H2NDC (1,4-aphthalenedicarboxylicacid)as a
linker for selective detection of impurity as well as a known toxi-
cant picric acid. This linker gives the significant advantages for
MOF including water and thermostability, although it provides
an excellent antenna chromophore for sensitizing Eu3+ ions. NDC
33
has enhanced the interaction with Picric acid, due to the double
benzene nuclei are electron richer as compared to most known
Ln-MOFs. Theses MOFs were provided the photoinduced electron
transfer along with the self-absorption mechanism, and due to that
mechanism, this MOF provides rapid, selective as well as sensitive
detection of picric acid. Also, it showed the long term stability and
same quenching efficacy with a 37.6 ppb detection limit [251]. Iron
deficiency and its overloading having enormous importance in
human life, there is a need to detect the level of iron in physiolog-
ical fluids /water. Also nitroaromatic (2, 4-DNP) having a health
hazards problem and there is the need to developed the sensor
for the detection of its level in the environment. The present study
was focused on the detection of Fe3+ and 2, 4-dinitrophenol (2,4-
DNP). In brief, the lanthanide-based MOF (Ln-MOFs) [Ln(L2)(HLe)
(H2O)2]n (Ln: Eu, Gd, Tb, and Dy), [H2L: 5-(imidazol-1-yl) isoph-
thalic acid], for detection OF Fe3+ and 2, 4- dinitrophenol (2,4
DNP) was prepared via solvothermal conditions. Due to the inter-
rupt the energy transfer from the mechanism, the coordination
framework to the Ln3þ center, it shows the luminescent quenching.
It exhibited novel, the dual luminescent sensor for detection of 2,
4-DNP and Fe3+. Due to luminescent quenching, the MOF sensor
provides a high sensitivity as well as selectivity for the detection
of an analyte [252].
Cong and co-author investigated ternary metal nanoparticle-
based metal–organic framework MNPs@-MOF (M: Ag, Cu) for
hydrogen peroxide detection. In that, this the ternary composites,
ultra-small MNPs encapsulate in the anionic MOF electrochemi-
cally reduced graphene oxide [(MNPs@Y-1, 4-NDC-MOF/ERGO)]
was constructed. This MNP based anionic MOF, prepared by using
a cationic exchange strategy; moreover electrochemical determi-
nation was carried out by electrochemical reduction method.
These hybrid composites induced a synergic effect, therefore it
increased the catalytic activity, enhanced the conductivity, and
improved the Selectivity. Therefore, it provides an extended linear
range along with a low detection limit (0.18 lM). Besides this, it
showed high stability and excellent selectivity. Thus, the investiga-
tor concluded, it could apply for the determination of H2O2 from
living cells. Ultimately, it provides the oxidase measurement.
Meanwhile, it could use in biosensing, catalysis, and biomedicine
[253]. Recently, due to neurological activity and thyroid function,
iodide ion has acquired remarkable awareness as compared to
the other biologically important anions. Therefore there is a need
to detect the iodide in the aqueous phase. The present investiga-
tion enhanced the application area of MOF for selective as well
as sensitive detection of iodide. The synthesis of [Cd2.5(PDA)
(tz)3], MOF was carried out by using 1,4  phenylenediacetate
(PDA), and 1,2,4  triazolate(tz). It provides the emission due to
intra  ligand p* ? p as well as p* ? n transitions of two aromatic
ligands linked with the metal ions. Thus, the 3D, Cd-MOF sensor
with high luminescent properties towards the iodide ions with a
detection limit of 0.63 lM. Even though, the sensor was showed
the negligible luminescent quenching property for other common
ions such as NO3, H2PO4 [254].
The strong oxidant Hypochlorite (ClO–), majorly used in the
household and tap-water sterilization process. The residual matter
of this oxidant results in some threat to human health. Herein
authors developed the 3D, Lanthanide based metal–organic frame-
work Ln-MOF {Eu2Cu(IN)5(CO3)(H2O)]
3H2O}n, (HIN: isonicotinic
acid), and hypochlorite detection was successfully carried out
through oxidation process among colorless ions. Moreover, this
luminescent sensor gives the 10-5mol/L detection limit. Also, it
has been reported the first novel MOF based sensor for detection
of hypochlorite in the presence of other colorless ions [255]. The
novel, 3D, zinc-MOF was prepared for the detection of Cr(III), Cr
(VI) ions and p-nitrotoluene (p-NP). For this MOF preparation,
the solvothermal method was preferred along with semirigid
34 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
V-shaped multicarboxylate used as a ligand. Briefly, {[Zn2(l3-OH)
(cpta)(4,40 -bipy)]
H2O}n (1) (4,40 -bipy = 4,40 -bipyridine) was pre-
pared by solvothermal method, using V Shaped 2–4(-carboxyphe
noxy)terephthalic acid (H3cpta) as a multicarboxylate ligand. In
that the tetramer [Zn4 (l3-O)2O10N4] second building units were
organized by using the cpta3 and 4,40 -bipy ligand. Besides this,
it showed fluorescence and more selectivity in the presence of
the above-mentioned compounds. Furthermore, it gives the low
detection limit for Cr3+, Cr2O2- 7 , and p-NP; 5.55, 6.91and
4.01  106 M respectively [256]. Until now one more work was
present the detection of picric acid using MOF based luminescent
sensing. Wang and prepared the zinc (Zn) metal nodes and lumi-
nescent organic ligand, 9- henylcarbazole-3,6-dicarboxylic acid
(PDA) as linkers based MOF, Zn4O(C20H11NO4)3 (C4H9NO) (H2O)]

(C4H9NO)2(H2O)3}n (Zn–PDA2) for detection of PA. This MOF
affords the ligand-based emission sensor for detection and
metal–ligand charge transfer related emission. Also, gives the syn-
ergetic effect through hydrogen bonding and electron transfer
mechanism, therefore it enhanced the accuracy and sensitivity of
sensor towards the picric acid detection. Although, it has been
claimed the new dual emitting luminescent sensor for picric acid
detection by visually and selectively. Besides, it provided the
naked-eye and luminescent detection limitations in favor of Picric
acid; 0.45 lg and 25 ppb, respectively [257].
MicroRNAs (miRNAs) reported as a biomarker for cancer, and it
is valuable for the molecular diagnosis. For the detection of
biomarkers, there is needed to develop the ultrasensitive, simpli-
fied and stabilized method. Herein, the electrochemiluminescence
(ECL) ruthenium MOF (Ru-MOF) sensor was prepared and the
determination of miRNA-141 was carried out. In that cDNA immo-
bilized on the functionalized nanospheres, nanoFe3O4@SiO2@Au,
whereas the signal unit was Ru-MOF labeled by signal DNA (sDNA).
This composite detected the biomarker miRNA Along with, the
0.3Fm detection limit as well as fM to 10 pM linear range. Also,
it showed high selectivity, stability, precision, and reproducibility,
besides this it has the potential for mRNA detection [258]. Nowa-
days, the quick detection of hazardous heavy metal ions and
organic has been a key challenge, because it was harmful to the
environment and social safety. Therefore authors developed 3D,
Cd-L-MOF, {Cd2(BPDPE)2(chdc)2(H2O)2]
4H2O}n (BPDPE:4,40 -bis
(pyridyl)diphenyl ether and H2chdc: 1,4-cyclohexanedicarboxylic
acid), through the hydrothermal reaction. It exhibited good stabil-
ity and good performance for the detection of analytes. The
quenching mechanism offered by the ligand to ligand energy trans-
fer in presence of cationic analytes, thus the fluorescence quench-
ing effects for silver ions, TNP, Fe3+, and Ag+ with high selectivity
and sensitivity. It offered the regeneration capacity by the wash
of DMF and recyclability for TNP [259]. Although, a new report
has been carried out the detection of Fe3+ by using the luminescent
Cd(II)-MOF sensor. Briefly,1,6-bis(5,6-dimethylbenzimidazolyl)
hexane used as ligand (L), [2-nitroterephthalic acid (2-H2NTP)
and 4-H2CPA] to assembled two Cd(II)-Metal organic framework,
{[Cd2(L)2(2-NTP)2]
0
.5H2O}n and [Cd(L)(4-CPA)]n through
hydrothermal method. Additionally, it shows the 3.54 lM detec-
tion limits as well as it gives the promising luminescent probes
for selective detection of Fe3+ ion [260]. The specific detection of
small biomolecules and ions has been tremendous importance
for human life as well as environmental studies. Metal ions (Fe3+
and Cr2O2- 7 ) deficiency could develop serious disorders; also the
chromium ions show the carcinogenesis. Besides this great effort
has been made for detection of biomolecules, herein Kun Fan and
co-authors, first time developed the three-dimensional iridium
(Ir)-(III)-containing three MOF by using methyl-3-(pyridin-2-yl)
benzoic acid (ppy-COOH) as linker along with N, N-
dimethylformamide (DMF), N, Ndimethylacetamide (DMA) and
N, N-diethyl formamide (DEF) via solvothermal method. Out of this
[Cd3{Ir-(ppy-COO)3}2(DMF)2(H2O)4],
6H2O
2DMF furnish the lumi-
nance in presence of Fe3+ and Cr2O7 and biomolecules (nucleoside
phosphates) by pleasing the advantage of its exceptional lumines-
cence as well as good water stability. It demonstrated the selective
luminance quenching for Fe3+ and Cr2O2- 7 in aqueous media, with
67.8 and 145.1 ppb detection limits, respectively. Also, this lumi-
nescent sensor provided the selective detection of ATP2- over
ADP2- and AMP2- in aqueous [261]. However, one more sensor
was developed for the detection of Cr2O2- 7 by using Cd (II) MOF.
The synthesis of MOF was carried out by using a solvothermal
method. It shows the 3D along with a double-walled structure
and 1D channel. Thus it exhibited high sensitivity as well as selec-
tivity towards the anion detection [262].
The detection method of Valine and Ni2+ furnish some draw-
backs, like a requirement for complicated instruments tedious
extraction process, high costs and long analysis time. Hence, the
advanced new development of a simplistic, responsive, and cheap
analytical process to detect the Ni2+and Val is of enormous impor-
tance. So, bifunctional 3D, Ln series based MOFs [Ln(ADA)1.5(phen)]
n, (H2ADA:1,3-adamantanediacetic acid) was synthesized by via
green as well as environmental hydrothermal method. It exhibited
high thermal stability under 350c. Furthermore, it reported that
this bifunctional MOF chemosensor exhibited the luminescence
turn off for Ni2+ and turn on the mechanism (antenna effect) for
valine. The ligand to metal charge transfer mechanism furnishes
the luminescent detection of analytes. It showed a high sensitivity
value as compared to the WHO and Chinese environmental quality
STD. Thus, the author was concluded that this sensor more sensi-
tive chemosensor for Ni2+ with a 0.2–0.6 mM concentration range
[263]. In low quantity or absence of lactase enzyme the lactose
based Sevier clinical syndrome ‘‘lactose tolerance” was developed
in humans. At present techniques, it exhibited a certain limitation
or drawbacks including time and cost, etc. Thus, it is more impor-
tant to regulate lactose intake, therefore Squaramide based lumi-
nescent MOF Co  DBPY {(Co(bpy)(dbda)
H2O}n] sensor was
developed for detection lactose in aqueous solution as well as milk
by using 4,4’-bipyridine (bpy) and 3,3’-((3,4- dioxocyclo-but-1-en
e-1,2-diyl)bis(azanediyl))dibenzoic acid (H2dbda). The lactose and
Squaramide interaction decline the electron transfer from nitrogen
lone pair towards pi orbital, thus it hampers the PET process and it
improved the emission toward the lactose. As a result, it exhibited
selective detection of lactose in the presence of another monosac-
charide and gives a lower limit of detection (30 lM). Hence author
was concluded that it might be used in the clinical application
because it offers the highly sensitive, selective, easy as well as
quantitative detection of lactose [264]. The diagnosis of vitamin
D deficiency, Fanconi syndrome, and hyperparathyroidism; phos-
phate has been used as a key biomarker. Also, the deficiency of iron
produces the disorder like skin ailments, anemia, and insomnia,
etc. therefore there is a need to develop a facile, fast responsive,
selective and sensitive sensor for the detection of phosphate and
iron in aqueous media. The europium based MOF sensor in exis-
tence of L (6-[1-(4-carboxyphenyl)-1H- 1, 2, 3-triazol-4-yl]
nicotinic acid) ligand exhibited the dual responsive luminescent-
based sensor for the detection of phosphate ions as well as Fe3+.
It has been shown the quenching of luminescent MOFs in the exis-
tence of metal ions. It might be based on the energy transfer mech-
anism (binding of metal cations with the organic linker), the
collapse of the framework and an ion-exchange approach (replace-
ment of the metal cations in the framework with targeted metal
ions. As a result, it shows the selectivity and sensitivity of MOF
towards the phosphate ions a well as Fe3+ [265].
Yet another study were designed the two luminescent Cd(II)
metal–organic frameworks (MOFs) { Cd (II)-MOF} formulated as
[Cd(L)(atpa)]n and [Cd(L)(tbta)(H2O)]n [H2atpa: 2-
aminoterephthalic acid, H2tbta: tetrabromoterephthalic acid)as a
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
ligand and using linker (L) 1,4-bis(benzimidazol-1-yl)-2-butene]
though hydrothermal method. It has been reported that the lumi-
nescent quenching of MOFs causing with toxic metal ions recog-
nized to ion exchange, crystal structures decomposition,
competition absorption between metal ions with Cd-MOFs, in
addition to strong framework-metal ions interactions. Further-
more, this was used for the detection of copper, mercury and chro-
mate ions in water. Moreover, both the MOF were exhibited high
sensitivity towards the metal ions [266]. Another study reported
the water-stable, as well as 3D sensor, [Cd3(L)2(bipy)(H2O)2]

H2O, [H3L: 9-(4-carboxy-phenyl)-9H-carbazoly- 3,6-dicarboxylic
acid, bipy: 4,40 -bipyridine] was used for the detection of uranyl
ions using solvothermal process. Due to the resonance energy
transfer (RET) from the MOF to uranyl ions might cause the fluores-
cence quenching, thus, it showed the high sensitivity and selectiv-
ity of MOF towards the ions [267]. Also, the detection of Cr2O-2 7 and
picric acid detection were carried out by using 3D [Mn2(HBTC)2
(TIAB)]n MOF[1,2,4,5-tetrakis(1-imidazolyl) benzene (TIAB) and
1,3,5-benzenetricarboxylic acid (H3BTC)] via heating. This ligand
gives the luminescent properties for MOF sensor in the presence
of the analyte. It offered the luminescent propertied which open
the new arena for detection of analytes, thus it used as a bifunc-
tional luminescent sensor for the detection of Cr2O2– 7 and nitroaro-
matic compounds [268]. Up till now, another study reported the
picric acid and Fe3+ trace nitro-explosive detection through lumi-
nescent zinc-(II)-MOF, [Zn(BPDPE)2(dca)2]n ,(BPDPE = 4,40 -bis(pyr
idy)diphenyl ether, H2dca = Dextro-camphoric acid). It has been
reported that the nitro-group was carried out by increasing its
electrostatic interaction towards the e- deficient nitro-group
through excitation migration. In that the helical chains linking to
central metal ions, and demonstrated ligand-based emission in
the solution method, which explored the arena for the bifunctional,
highly selective and responsive luminescent sensor for a picric acid
along with metal ions [269].
A further investigator reported that detection of Fe3+ and Al3+
and picric acid by using the cobalt-based luminescent cobalt-
based MOF{[Co3(phen)2(HL)2]
(H2O)2}n using p-conjugated lumi-
nescent ligand H4L(3,30 ,5,50 -azoxybenzenetetracarboxylic acid)
which offer outstanding electron-transferring capability, (phen:
Phenanthroline) using solvothermal process. This, MOF contains
ligand having four carboxylic sites, which furnish the high interac-
tion between MOF and metal ion. Although it’s carboxylic groups
and benzene rings enhanced the reorganization capacity via
host–guest interactions including a hydrogen bond, p-p interac-
tions, thus, the prepared MOF offered high selectivity and sensitiv-
ity for metal ions and explosives [270]. One more detection study
of Fe3+ and Cr2O-2 7 was reported by Feng Guo. They were synthe-
sized a new, 3-D, Tb-III-MOF{[TbL(H2O)]∙2H2O}n by using a semi-
rigid organic linker 4,4,400 -s-triazine-1,3,5-triyltri-m-
aminobenzoate(H3L) via hydrothermal method. This organic linker
provides green luminescent properties as well as used as a dual
responsive luminescent sensor for the detection of ions [271]. Also,
a new, work reported the Fe3+ and Cr2O2 2
7 or /CrO4 detection was
carried by zinc-based polymeric MOF luminescent sensor. The [Zn
(oba)2(bpy)2] were synthesized by using ligand oba (4,40 -
oxybisbenzoic acid(and bpy (4,40 -bipyridine) using the solvother-
mal method. The present metal ions provide a significant quench-
ing effect for MOF via the energy transfer process. These metal ions
were absorbing the excitation energy and reduce the light
absorbed by MOF. And as result it offered the quenching effect.
Moreover it exhibited the highly sensitive, selective along with
good thermal as well as hydrolytic activity [272]. Even though,
one more study was an attempt to detected the Fe3+, CrO2 4 and
acetone by zeolitic imidazolate-MOF (ZIF-8). In that, they prepared
the two host–guest hybrids AlQ3@ZIF-8 (ZA-1 and ZA-2) with
different concentrations of AlQ3(Tris(8-hydroxyquinoline)
35
aluminum) into the cavities of ZIF-8. This composite was showed
the excellent thermal and chemical stability, it provides high
porosity. Also due to the present of AlQ3, it enhanced photolumi-
nescence, although it prevents the aggregation in MOF and
increases the photochemical properties of MOF. As a result, this
MOF offered the detection of metal ions as well as volatile organic
molecules [273].
One new study reported the Cr2O2- 7 detection through 3D, Pb(II)-
MOF, {Pb(AIA)2}n, assembled by the assembly of rigid linker 5-
aminonicotinic acid (HAIA) and Pb(II) using a hydrothermal condi-
tion. It provides the Lewis basic sites and luminescent property in
the structure, and because of this prepared MOF could be used as
Lewis basic catalyst intended for knoevenagel condensation reac-
tion by good catalytic effect as well as recyclability, although it
worked as a luminescent sensor to Cr2O2– 7 among excellent selec-
tivity and reusability [274]. In recent times MOF was provided
the new arena for the detection of new chemical moieties, antibi-
otics, etc. Chongliang prepared the luminescent MMMs sensors
(MMM: mixed matrix membranes) were prepared using
{Eu2(TDC)3(CH3OH)2
(CH3OH)}n (Eu-TDC), (TDC: thiophene-2,5-
dicarboxylate) as filler, plus as matrix the 502 glue of the
Evo-bond brand (EVOB) was used. Due to the inner filter effect,
the fluorescence quenching of Eu-TDC MMMs mechanism for of
nitroimidazole occurred. Thus, it shows the fluorescence stability
and low detection limit (metronidazole and dimetridazole:
0.58 lg/mL and 0.51 lg/mL, respectively). While this sensor illus-
trated simple as well as sensitive detection of nitroimidazole [275].
In this investigation, the enzyme-assisted analysis of hydrogen
peroxide using luminescent MOF nanosheets was prepared by
using 5-aminoisophthalic acid (H2aip) as bridging ligand. This
detection mechanism was based on the quenching effect of
o-benzoquinone, the oxidation product of catechol, on its emission.
This approach further developed for the quantification of glucose
plus activity assay of glucose oxidase via multi-enzyme cascade
catalysis. This MOF exhibited the high detection ability because
of nanosheets provided the stable fluorescence in suspension along
with unstable intermediate capture capacity. The H2O2 offered new
potential for the detection of relevant biomolecules and enzymes
[276]. The aspartic acid was successfully determined by a novel
MOF based approach. Herein, Guanfeng synthesized the post-
modification copper-based Tb-MOF (Cu/Tb@Zn-MOF). Briefly, the
copper served for aspartic acid as a selective site in MOF, thus it
has been reported that MOF offered the turn-on fluorescence probe
for aspartic acid. Furthermore, the MOF sensors were showed more
selectivity for aspartic acid along with 0.54 ppm detection limit
[277]. The terbium (III) framework, [Tb (DBB)(H2O)2], prepared
from 4-(3,5-dicarboxylatobenzyloxy) benzoic acid (DBB) with ter-
bium salt using hydrothermal condition, for Fe3+ and acetone
detection. Moreover, MOF showed the 3D structure based on two
dimensional double sheets linked with porous channels by ligand,
this tricarboxylate ligand gives large steric hindrance and rich
coordination modes. It shows the luminescence and the interac-
tions between the host materials with the guest molecules, like
electrostatic interactions, hydrogen bonding, and p–p stacking.
As a result, the MOF gives the luminescent detection in solid as
well as the aqueous state. Furthermore, it worked as a sensor for
sensitive detection of acetone and Fe3+ ion, for Fe3+ detection limit
as 109 M in an aqueous [278].
A magnesium-based novel fluorescent MOF [Mg(ATDC)(H2O)2]
n, in presence of electron-rich ligand H2ATDC (20 -amino-1,10 :40 ,1
00
-terphenyl-4,400 -dicarboxylate) synthesized and were used for
the detection of 2,4,6-Trinitrotoluene (TNT). In that, the Mg-
based framework holds two dimensional [Mg(COO)2]n sheet and
coupled with ATDC2- to created 3D framework along with accessi-
ble –NH2 groups, which could be advantageous to detect small
molecules. Theses MOF provided bi-responsive fluorescence along
36 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
with high selectivity for TNT as well as chromium (III) due to a
photoinduced excitation of Mg-MOF [279]. Also, the author studied
and reported the detection of TNT by using the Eu-MOF,
[(CH3)2NH2][Eu3(l3-OH)(1,4-BDC)3(HCOO)3] as a luminescent sen-
sor. Authors find out the fluorescent response mechanism by using
UV absorption spectral analysis and it can be ascribed to competi-
tive absorption among Eu-MOF and analytes. Thus, it exposed the
sensitive as well as selective detection of picric acid and tetryl.
Furthermore, for all these explosive limit of detection was found
20–140 lg/mL [280]. Uric acid detection was reported by Li Tan,
2019, besides this they were prepared the terbium MOF
(Me2NH2)2[Tb2(L)2]
(H2O)6 (ZJU-158-Tb, ZJU: Zhejiang University)
and L [1-(3,5-dicarboxylatobenzyl)–3,5-pyrazole dicarboxylic acid]
as ligand for luminance sensing of uric acid. Also, it exhibited host–
guest interaction; therefore it gives high sensitivity as well as
selectivity in aqueous solution for uric acid detection. It provides
a low limit of detection for acid up to 7 nM. Even though, novel
MOF sensor was offered the uric acid naked eye detection for
artificial urine as well as serum [281].
In the recent past, cancer biomarker protein tyrosine kinase-7
(PTK-7) sensing was carried out by developing the novel MOF
based biosensing phenomenon. Investigator prepared the bimetal-
lic MOF on MOF by Zn-Zr and used for the detection of the biomar-
ker. The organic linkers in MOFs offer a source of hydrogen
bonding, pi-pi stacking, along with electrostatic interactions
among negatively charged nucleic acid sequences. The aptamer
was immobilized onto the MOF-on-MOF substrates, specific bind-
ing of analytes with the aptamer generate an aptamer structural
changes. This new Zn-MOF-on-Zr-MOF-based aptasensor reported
the low limit of detection 0.84 and 0.66 pg∙mL1, the detection was
carried out by electrochemical impedance spectroscopy as well as
differential pulse voltammetry; respectively in that order. Further-
more, it exhibited the selectivity, sensitivity, stability, repro-
ducibility along with acceptability. Also, it creates a new
platform for application in cancer diagnosis in the early stage
[282]. The copper ions detection in water was carried out by using
bonded-luminescent foam based on europium- polyurethane com-
plexes (Pt-TCPP/H4TCPE@UiO-66NPs). This complex was prepared
by using platinum meso-tetra(4-carboxyphenyl)porphyrin
(Pt-TCPP), 1,1,2,2-Tetra(4-carboxy phenyl)ethylene (H4TCPE) and
1,4-dicarboxybenzene (BDC) as co-linkers via one spot synthesis.
Pt-TCPP was established to use as a signal reporter during NO sens-
ing area, although H4TCPE used as a luminescence reference
towards the construction of a ratiometric sensor. It provided a
low limit of detection up to 0.28 lM [283].
8. MoFs as imaging platform
Nowadays, the early detection and diagnosis of diseases are
critical to increasing the survival rate of the patients [284]. In this
sense, medical imaging technology plays a key role. The most com-
monly used imaging modalities are magnetic resonance imaging
(MRI), computed tomography (CT), ultrasound (US) and positron
emission tomography (PET) [285]. MRI, CT and US modalities pro-
vide anatomical images using intrinsic contrast that originates
from differences in the magnetic properties of the water molecules,
in X-ray attenuation, or the reflection of ultrasound waves. The use
of extrinsic contrast from contrast agents (CAs) is not always
required, but it is crucial in some cases to properly visualize the
region of interest [286,287]. Unlike the other modalities, PET
images originate from the direct detection of a radiotracer, that
is, they are based on extrinsic contrast from exogenous molecules.
Consequently, no anatomical information is obtained and PET
images are usually co-registered with another imaging modality,
CT or MRI, which provides the anatomical context. This section of
the review will focus on the description of the in vivo biomedical
application of MOF as CAs in the main clinical imaging modalities
(Fig. 14).
8.1. Magnetic resonance imaging (MRI)
MRI is one of the most powerful imaging techniques used in
clinical diagnosis due to its versatility, being capable of providing
both morphological and functional information with excellent
image quality, especially from soft tissues, with the advantage of
using non-ionizing radiation [288]. The MRI signal comes from
the protons of the water molecules, which are excited by radiofre-
quency pulses in the presence of an external magnetic field, and
the MR images originate from the spatial encoding of this signal
using magnetic field gradients. As for the image contrast, it comes
from the differences in intensity of the water signal of the different
tissues, which depends on the concentration of water in each tis-
sue, the relaxation times, T1 and T2, of the water protons, and the
mobility of the water molecules (diffusion, flow) [289]. Also, this
intrinsic contrast can be further enhanced by the use of contrast
agents (CAs). Since the beginning of the 21st century, the develop-
ment of more powerful and sensitive materials that can be used as
MRI CAs has undergone exponential growth [290-292]. MRI CAs
can be sorted into two main types: T1 contrast agents, which are
commonly called positive contrast agents due to the signal
enhancement they produce on T1-weighted images; and T2 or neg-
ative contrast agents, which produce darkening on T2-weighted
images. The ability of an MRI CA to shorten the relaxation times
of the water protons and, therefore, induce contrast, is defined in
terms of a parameter named relaxivity (r1 or r2), which is expressed
in mM1
s1. The ratio r2 /r1 indicates the capacity of the material
to be used as a T1 or T2 contrast agent. Lower values of r2/r1 (be-
tween 1 and 3) lead to T1 type, higher values (>10) to T2 type,
and the intermediate values, between 3 and 10, can be considered
as dual T1 and T2 contrast agents [293,294]. For clinical applica-
tions, the most commonly used are the Gadolinium (Gd) com-
plexes. However, it has been demonstrated that these complexes
present toxicity due to the unexpected release of free Gd and its
subsequent accumulation in the brain or kidneys [295]. MOFs have
emerged as a promising alternative to Gd-complexes due to their
low cytotoxicity and much higher relaxivities, resulting in greater
contrast enhancement with lower doses [296]. The pioneering
work on the use of MOF as MRI CAs, published by Horcajadas
et al.[297], described the development of porous iron carboxylate
nano MOFs (Materials of Institut Lavoisier/ MIL-100 and MIL-
88A), which presented very high relaxivities and induced a marked
darkening of both liver and spleen after intravenous injection.
Similarly, Wang et al.[135], reported a procedure for the in situ
growth of Zeolitic Imidazolate Framework (ZIF-8) MOFs shell on
Prussian Blue MOFs core (PB@ZIF-8). Due to the iron content of
PB, these MOFs produced a darkening in a heterotopic model of
cervical cancer after intravenous injection. The incorporation of
iron into MOFs has also been described by Huang et al. [82]. The
author’s employed Materials of Institut Lavoisier-53 (MIL-53) as
a microreactor to grow polypyrrole (PPy) nanoparticles in situ for
the fabrication of PPy@MIL-53 nanocomposites. The iron-
containing MIL-53 was used as an MRI CA for monitoring the dis-
tribution of the nanocomposites in a heterotopic model of breast
cancer after intratumoral administration. This route of administra-
tion was very likely chosen because of the large size of the
PPy@MIL-53 nanocomposites, close to micrometers. Although
intratumoral administration has been proven to be useful in some
cases [298], this route of administration does not make any sense
for imaging-based diagnosis. Likewise, a similar protocol and sim-
ilar limitations can be observed in the study reported by Yao et al.
[299], in which a nanocomposite based on MIL-100 was able to
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212 37

Fig. 14. MOFs based various imaging platform for cancer (taken with permission from W. Zhu, J. Zhao, Q. Chen, Z. Liu, Nanoscale metal–organic frameworks and coordination
polymers as theranostic platforms for cancer treatment, Coordination Chemistry Reviews. 398 (2019)).

include iron and manganese into the MOF structure, promoting a
darkening of the tumor in T2-weighted images in model of colon
cancer after intratumoral administration. Indeed, considering the
size of the nanocomposite (around 50 nm), it is surprising that
the authors did not perform an intravenous administration, since,
as mention earlier, intratumoral administration is useless in terms
of diagnostic applications. Regarding other metal entrapment into
MOFs, Wang et al. [300] reported that nano MOFs coated with sil-
icon dioxide (nMOFs@SiO2) were able to internalize gadolinium
and europium. The nanocomposite, with around 100 nm in size,
showed high T1 and T2 relaxivities and also strong fluorescence
in vitro experiments. One hour after the intravenous administra-
tion of nanocomposites, the liver showed hyperintensities on T1-
weighted images and hypointensities on T2-weighted images, indi-
cating the accumulation of MOFs in the tissue. Using a heterotopic
model of glioblastoma multiforme, the same image contrast was
observed in the tumor tissue, but only after intratumoral adminis-
tration, suggesting that these MOFs cannot reach the tumor
through the vasculature. Recently, another study by Quin et al.
[301] reported the development of zwitterionic nano MOFs loading
manganese and gadolinium. The pharmacokinetics of these MOFs
could be followed by dynamic T1-weighted MRI after their
intravenous administration. These zwitterionic nano MOFs were
completely cleared from the body 24 h after the administration,
despite their size (around 50 nm). The authors suggested that a
plausible explanation might be that these particles disintegrate
into smaller sizes, and were cleared by the urine. However, another
explanation might be that they are very avidly taken up by the
mononuclear phagocyte system (MPS) and therefore their resi-
dence time in the bloodstream is significantly shortened. Finally,
really interesting work was published last year by Guo et al.
[302] in which the ZIF-8 was modified for the fabrication of a
pH-responsive material. The authors described the turn-on of a
19
F MRI signal induced by the acidic environment of the tumor,
suggesting that these nanocomposites could potentially be used
as pH-sensitive CAs for 19F MRI. It is also worth mentioning that
these MOFs were able to efficiently reach the tumor after their
intravenous injection, which, as mentioned above, in most cases
is the preferred route of administration for tumor diagnosis.
8.2. Computed tomography (CT)
CT is also a very powerful and non-invasive modality of medical
imaging, capable of generating 3D images of high spatial and tem-
38 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
poral resolution of internal structures. CT provides excellent visu-
alization of bone structures, whereas it is limited in distinguishing
between different soft tissues that have similar densities [303]. CT
is based on X-ray attenuation, which is mainly determined by the
photoelectric effect, this being proportional to the third power of
the atomic number of the material (Z3). Therefore, to improve
CAs for CT, materials should be selected among those with high
atomic numbers [304,305]. Thus, currently available CAs for clini-
cal CT imaging are iodine derivatives (Z = 53). However, these CAs
contain small amounts of free iodine [306] that may lead to impor-
tant side effects, such as thyroid dysfunction [307,308].
The application of nano MOFs as CT CAs was described for the
first time by deKrafft et al. [309]. In this work, the authors synthe-
sized UiO-66 coated with (silica) SiO2, which resulted in nanostruc-
tures with hydrodynamic diameters of about 200 nm. After
intravenous administration, these UiO-66@SiO2 nanoplatforms
accumulated in the spleen and liver, as could be expected accord-
ing to their size, which very likely induced their rapid uptake by
the MPS. This behavior certainly limits their potential application
for in vivo imaging, being only candidates for liver and spleen
imaging. In another work, Su et al. [310] reported the coating of
ZIF-8 with ZrO2 to promote higher biocompatibility and reduce
its toxicity, which was confirmed both in vitro and in vivo
(Fig. 15). They also added doxorubicin to the ZIF-8 nano MOFs
and loaded them with ionic liquid (ZIF-8/DOX@ZrO2@IL) to carry
out enhanced microwave thermal therapy. After intravenous injec-
tion in mice bearing H22 hepatocellular carcinoma xenografts,
they observed contrast enhancement in the tumor and tumor
growth inhibition after 14 days. These results suggest that ZIF-8
nano MOFs are promising systems for theranostic applications.
8.3. Positron emission tomography (PET)
PET is based on the emission of positrons by some unstable
atoms, named radioisotopes. These positrons can be described as
subatomic particles, analogous to electrons, but with a positive
charge. When both particles encounter, electron–positron annihi-
lation occurs, and the 2 masses of the particles transform into 2
c-rays emitted in the opposite direction, at exactly 180°from each
other. Detectors placed at 180° can identify the emitted c-rays that
hit both detectors concurrently, and by identifying those coinci-
Fig. 15. ZrO2 coated ZIF-8 MOFs based biocompatible platform for cancer therapy and Imaging.
dences, the source origin can be reconstructed in space, rendering
3D images [311]. Regarding MOFs as CAs for PET imaging, really
interesting work was reported by Chen et al. [76], in which the
authors designed and synthesized 89Zr-UiO-66 nano MOFs for
tumor targeting. The nano MOFs had around 100 nm in hydrody-
namic diameter and the tumor targeting, using F3 peptide, was
confirmed by in vivo and ex vivo imaging in an orthotopic model
of breast cancer after intravenous administration of MOFs. Nano-
MOFs based on ZIF-8 was also proposed as PET CAs by Duan
et al. [312]. In this work, the authors described a one-pot method
to precisely tune the size of the nanocomposite, resulting in hydro-
dynamic diameters ranging from 50 to 150 nm. The in vivo phar-
macokinetics were affected by the size, the 60 nm nano MOFs
showing prolonged blood circulation times and higher tumor
uptake in a heterotopic model of breast cancer after intravenous
injection.
8.4. Multimodal imaging
Even with the advances achieved in single imaging modalities,
there are still limitations in the diagnosis of diseases, such as miss-
ing detection of micrometastases in cancer [313]. To overcome
these limitations, numerous studies have focused on the develop-
ment of multimodal platforms by integrating various image-
enhancing behaviors [314,315]. Regarding multimodal imaging
using MOFs as CAs, Shang et al. [88] reported a fascinating work,
using Au@MIL-88 nanoparticles for in vivo dual-modality CAs,
MRI and CT. The nanoparticles presented around 100 nm in hydro-
dynamic diameter and enabled in vivo enhancement of imaging
sensitivity, both MRI and CT. These MOFs exhibited high perfor-
mance after intravenous injection in a heterotopic model of brain
cancer, whereas in the orthotopic model, the results were very
promising.
Similarly, Zhang et al. [100] published the development of a
new procedure to synthesize nano MOFs based on 5-
bromobenzene-1, 3-dicarboxylic acid (BBDC). Gd-nano MOFs
exhibited a hydrodynamic diameter of approximately 200 nm.
The in vivo evaluation of these CAs showed that 10 min after intra-
venous administration in normal mice, both liver and kidneys
showed shorter T1 relaxation times, which was also observed in
cervical cancer xenografts.
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212 39

to toxicity include the type of linker, the surface modifying agent

MOF type Metal Application Refs. and type of metal incorporated (Fig. 16). The literature published
MIL-100/MIL-88A Fe MRI [297] on the toxicity aspects of MOFs gives contradictory inferences
PB@ZIF-8 Fe MRI [135] [317]. In a study involving nanoZIF-8 having a size of around
PPy@MIL-53 Fe MRI [82] 200 nm was evaluated against cancerous cell line (mucoepider-
MIL-100 Fe/Mn MRI [298] moid carcinoma of the lung [NCI-H292], colorectal adenocarci-
nMOFs@SiO2 Gd/Eu MRI [299] noma [HT-29], and promyelocytic leukemia [HL-60]. The results
nMOFs Gd/Mn MRI [300] demonstrated the absence of any toxicity even at a concentration
ZIF-8 19
F MRI [301] of 109 lM) [318]. A similar study involving toxicity study of
UiO-66@SiO2 Zr CT [308] nanoZIF-8 having a size of around 90 nm on HeLa and J774 cells
ZIF-8@ZrO2 Zr CT [309] revealed cytotoxicity IC50 values of 436 and 109 lM respectively
89 [319]. The toxicity of nano MOFs was also assessed on HepG2
UiO-66 Zr PET [76]
64 and MCF7 cells. The results demonstrated toxicity depending on
ZIF-8 Cu PET [312]
Au@MIL-88 Fe/Au MRI/CT [88] the solubility of MOFs. These results were also supported by
BBDC Gd/Yb MRI/CT [100] in vivo against zebrafish embryos [320]. As discussed earlier,
although multiple factors are responsible to the toxicity of MOFs
such as size, shape, morphology, etc., the major factors which have
9. Toxicity aspects of MOFs a significant effect on the toxicity of MOFs are the used metal ion,
type of organic linker used and the type of solvent used for the syn-
With growing interest in research on MOFs and nano MOFs, thesis of MOFs.
toxicity concern of this versatile carrier is also getting a lot of The type of metal used in MOFs is an area of concern when it
attention. Although this material exhibits unique properties, high comes to toxicity. The most commonly used metal ions in MOFs
surface area, and its size, shape along composition can be modu- include iron, zinc, copper-cobalt, zirconium, cadmium, nickel, and
lated, toxicity remains a big question. In the case of MOFs such other transition metals [321]. Although other metal ions such as
as iron-based MOFs and zirconium-based MOFs, the metal coun- gallium, titanium are being explored the research on these metals
terpart has already been studied for its possible toxicity and the is still in the budding phase. Amongst these metals, iron, and cop-
same has been established [316]. But, in the case of MOFs, the syn- per possess the least toxicity owing to their biological use in the
thesis method, the elemental composition, and size might con- body while cadmium possesses the highest toxicity risk. While car-
tribute to its toxicity as they do affect the degradation. Although boxylate linker is directly removed from animals via the urine and
very few studies have been performed on the toxicity of MOFs, feces, iron ions cause short-term oxidative stress in the liver and
there have been studies related to the same. Apart from the size spleen, and the remaining iron is metabolized and excreted in
and shape of MOFs, the other parameters which can contribute urine and feces [322]. There are chances that the metal ions might

Fig. 16. Schematic representation of toxicological aspects of MOFs (outermost circle shows various cell lines on which toxicity studies have been performed; Middle circle
shows toxicity aspects of MOFs; Inner circle represents various factors related to MOFs which affects toxicity of MOFs.
40 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
get oxidized which can have toxic effects on cells. According to the
data obtained using in vivo toxicity studies in animal for lethal dose
upon oral administration, the safer metals which can be used in
MOFs include Mg2+ (LD50 MgSO4 = 5000), Ca2+ (LD50 CaCl2 = 1940),
Fe3+ (LD50 FeCl3 = 450), Fe2+ (LD50 FeCl2 = 984) and Zn2+ (LD50 Zn
(OAc)2 = 100–600) [323]. Apart from the above-mentioned metals,
metals that could be appropriated for the synthesis of biocompat-
ible MOFs are biologically inert cations i.e. gold, silver, zirconium,
and titanium [324].
Various linkers such as carboxylates, phosphonates, sulfonates,
imidazolates, phenolates, and amines have been explored for the
synthesis of MOFs. There are very few toxicity investigation reports
on these linkers and it lacks extensive toxicity profiling. According
to a few reports, exposure to these linkers is directly associated
with multiple health issues. Few linkers such as terephthalic acid
on exposure cause health issues such as mild irritation to the res-
piratory tract and irritation to the mouth, eye, nose, and skin [325].
Similarly, long term exposure to trimesic acid irritates the eyes and
skin [326].
The effect of solvent used for the synthesis of MOFs had also
been studied for their toxic effects. According to published litera-
ture, the presence of chloroform in MOFs after synthesis results
in adverse effects on human health, causing hepatic and renal tox-
icity in several species. Apart from hepatic and renal toxicity, oral
uptake of chloroform solution causes instantaneous unconscious-
ness, transient hypotension, and acute hypoventilation [10]. Simi-
larly, when the MOFs are synthesized using dimethylformamide
(DMF), it might lead to abdominal pain, nausea, vomiting, jaundice,
alcohol intolerance, and rashes for short duration exposure while
long-duration exposure may lead to liver damage and other
adverse health effects [327]. In the case of acetone mediated syn-
thesis of MOFs, the presence of acetone in MOFs acetone may cause
dermal and ocular irritation in small doses while severe exposure
may cause respiratory tract irritation or neurotoxicity in addition
to hematological disorders [328].
Recent research has shown that the surface properties of MOFs
also affect their toxicity. It has been well established that the sur-
face properties decide the interaction of nanoparticles with various
components inside the body. Similarly, the MOFs interaction with
the biological molecule and biological fluids largely depends on its
surface properties. In research involving heparin-coated MIL-100
Fig. 17. UiO-66/Py-PGA-PEG MOFs for in vivo cancer therapy.
(Fe) synthesized using [Fe3OH(H2O)2(BTC)2], H3BTC and trimesic
acid and having hydrodynamic size: 180 ± 59 nm, demonstrated
reduced cell recognition, complement activation, and reactive oxy-
gen production compared to non-coated MIL-100(Fe) [329]. Simi-
larly, surface modification of IRMOF-3 (synthesized using [Zn4O
(BDC-NH2)3]nDEF, H2BDC-NH2, and 2-amino terephthalic acid with
N, Ń-diethyl formamide as solvent having a hydrodynamic size of
240 ± 10 nm demonstrated selective toxicity against HeLa cells
(human cervix adenocarcinoma) over healthy NIH3T3 cells (mouse
embryonic fibroblasts) [123]. In another research, the external sur-
face of MIL-100(Fe) was modified using chitosan which demon-
strated enhanced intestinal barrier bypass capability compared
with non-coated MIL-100(Fe) [330]. Although there are multiple
in vitro studies done to assess the toxicity of MOFs, the in vivo tox-
icity studies are quite few and needs extensive research for con-
firming the safety of different MOFs. To assess in vivo toxicity of
iron (III) carboxylate, MOFs i.e. MIL-88A, MIL-88B and MIL-100,
the MOFs were injected in a rodent intravenously at a dose of
220 mg/kg. Acute toxicity of MOFs was determined by analyzing
assessed by animal behavior, water, and food consumption,
changes in the whole body and organ weights, biochemical param-
eters, oxidative stress, oxidative metabolism, macro and micro-
scopic histological observations [323]. No significant change was
observed in behavior, food consumption, and body weight. The
histopathological results demonstrated the absence of in vivo tox-
icity of MIL-88A, MIL-88B, and MIL-100. Based on a similar line, the
toxicity of UiO-66/Py-PGA-PEG was determined in animals
(Fig. 17). The MOFs were injected at a dose of 10 and 50 mg/kg
body weight via the intravenous route. The toxicity was assessed
concerning body weight, histology (heart, liver, spleen, lungs, kid-
neys, intestine and stomach), and biochemical parameters (ALT,
AST, and alkaline phosphatase (ALP)) [76]. The obtained results
demonstrated the absence of any significant changes which con-
firmed the biocompatibility of UiO-66. Iron-based MOFs (MIL-
127 (Fe) was found to be safe orally even at a dose of 1 g/kg in ani-
mals [331]. The research so far shows the absence of any severe
toxicity related to MOFs but the research is a very early stage
and is mostly confined to iron-based MOFs. The extensive study
needs to be conducted on different metal-based MOFs for confirm-
ing the safety as well as biocompatibility of MOFs to prove it as a
safe material for biomedical use.
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
10. Recent advancement in MOFs based therapeutic approaches
10.1. Advancements in MOFs based radiotherapy and delivery of
nucleic acid
With fast progress in the field of MOFs based therapy of cancer,
multiple alternative therapeutic approaches have been employed
for effective treatment of cancer. Various approaches as an alterna-
tive to conventional chemotherapy have been developed using
MOFs based platforms. Recently, MOFs were explored for their
use in radio-sensitization (Fig. 18). Tumor hypoxia characteristi-
cally happens within a solid tumor with insufficient oxygen supply,
sharply decreasing radiotherapy therapeutic effectiveness and con-
siderably increasing the risk of recurrence of local tumors. In an
effort by researchers, folic acid altered enzyme-like hafnium-
based manganoporphyrin metal–organic structure nanoparticles
(MnTCPP – Hf – FA MOF NPs) were designed to triumph over
radioresistance induced by hypoxia and to avoid a postoperative
recurrence. Hf, a high-Z component acted as an effective X-ray
energy absorber and turned O2 and H2O into reactive oxygen spe-
cies to cause apoptosis of cells. The MnTCPP ligand has an enzyme-
like capacity to decay endogenous H2O2 into O2 catalytically to
enhance RT in hypoxic tumors. In vitro studies disclosed that after
intravenous injection, the MOF NPs can efficiently slow down the
development of melanoma and avoid postoperative tumor recur-
rence with only one X-ray irradiation [332]. Multifunctional nanos-
cale radiosensitizers can improve tumor tissue radiosensitization
and decrease unnecessary organ harm. However, the tumor’s con-
stant hypoxia environment limit their radiotherapy applications. A
stable nanocomposite was developed in one of the studies to tri-
umph over the hypoxia characteristics using 1,4- benzenedicar-
boxylic acid generated from Zr-MOF as an inhibitor of Carbonic
Anhydrase IX (CA IX) and quercetin (QU) as a radiosensitizer. To
achieve the synergetic dual sensitization therapy, QU was encapsu-
lated in the Zr-MOF arrangement. Zr-MOF-QU displays great
potential for in vitro and in vivo radiotherapy sensitization features
from staining and colony assays with immunofluorescence
Fig. 18. MOFs based nanoplatform for radio-sensitization.
41
c-H2AX. Mechanisms to alleviate hypoxia-induced resistance and
sensitization of tumor tissues to enhance radiation cell apoptosis
have been discovered to restrain CA IX phrases by the Zr-MOF
decomposition product and increase QU sensitivity in RT [333]. It
is well recognized that selective delivery of the photosensitizers
to cancer cell mitochondria can improve photodynamic therapy
(PDT) effectiveness. Although the cationic Ru-based photosensitiz-
ers accumulated in the mitochondria, with less incisive photons of
short wavelength, they involve excitation, restricting their imple-
mentation in PDT. By improving radiotherapy (RT) and allowing
radio dynamic treatment (RDT), researchers found X-ray based
cancer treatment through nano-scale metal–organic frameworks
(nMOFs). Here they have reported the Hf-DBB-Ru as nMOF specif-
ically targeted for RT-RDT with mitochondria. The cationic struc-
ture, built from Ru-based photosensitizers, displays powerful
mitochondria-targeting properties. Hf-DBB-Ru effectively pro-
duces hydroxyl radicals from the Hf6 SBUs and singlet oxygen from
the DBB-Ru photosensitizers resulting in RT-RDT impacts after X-
ray irradiation. Mitochondrial-targeted RT-RDT depolarizes the
mitochondrial membrane to begin cancer cell apoptosis, resulting
in important colorectal tumor regression in mouse models [334].
Recently a researcher reported the reasonable design of hafnium
(Hf4+) and tetrakis (4-carboxyphenyl) porphyrin (TCPP) consisting
of Nanoscale metal–organic frameworks (NMOF). In Hf-TCPP
NMOFs, although TCPP is a photosensitizer to enable photody-
namic treatment (PDT), Hf4+ could be used as a radio-sensitizer
to improve radiotherapy (RT) with a powerful X-ray attenuation
capability. That polyethylene glycol (PEG)-coated NMOFs demon-
strate effective tumor homing following intravenous injection
and therefore be used for in vitro coupled RT & PDT to achieve a
notable anti-tumor impact. Hf-TCPP NMOFs demonstrate effective
mouse body clearance to minimize worries about their potential
long-term toxicity [56].
Logical researchers revealed the utilization of metal-natural
nanoscale structures (NMOFs) to co-convey cisplatin and pooled
little meddling RNAs (siRNAs) to upgrade remedial viability by
quieting different medication obstruction (MDR) qualities and
42 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
resensitizing cisplatin-safe ovarian disease cells. UiO NMOFs with
hexagonal-plate morphology were fitted with siRNAs (Bcl-2, P-
glycoprotein [P-gp], and survivin) by embodiment and surface
coordination separately. NMOFs shield siRNAs from nuclease
weakening, improve cell retention of siRNA and support the break
of siRNA from endosomes to quiet MDR qualities in cisplatin-safe
ovarian malignancy cells. Co-conveyance of cisplatin and siRNAs
with NMOFs brought about a request for size improvement
in vitro chemotherapeutic sufficiency as expressed by cell reason-
ability test, laddering of DNA and recoloring of Annexin V [71].
The basic issue of the profundity infiltration hindrance of pho-
tograph activated remedial modalities can be overwhelmed by
sonodynamic treatment (SDT). In any case, a significant test is
the disclosure of sono-sensitizers with raised sono-sensitization
adequacy and brilliant security. One research distinguishes the
extraordinary capability of carbon nanostructure (PMCS) got from
metal – natural structure (MOF) to carry on as an exceptional sono-
sensitizer. Excitingly, the predominant sono-sensitization effect of
PMCS is believed to be emphatically identified with the porphyrin-
like macrocycle in MOF derived nanostructure contrasted with
nebulous carbon nanospheres attributable to their most notewor-
thy involved atomic orbital (HOMO)– least abandoned sub-
atomic orbital (LUMO) break in the assembling of exceptionally
responsive oxygen species (ROS). The cavitation procedure bol-
stered by nanoparticles, including the perception of cavitation,
bubbles, and microjets, is additionally caught by the rapid camera
just because. High assembling of ROS in ultrasound PMCS is
approved by estimation of electron turn reverberation and shading,
trailed by cell obliteration and raised adequacy of tumor restraint
(85%) [335].
Efficient transfection of genetic molecules like DNA generally
depends on vectors capable of reversibly absorbing and releasing
these molecules and protecting them from nuclease digestion.
Due to the absence of particular interactions with DNA, non-viral
vectors meeting these demands are uncommon. Design of four is
reticular metal–organic frameworks (Ni- IRMOF-74-II to -V) with
gradually tuned pore size from 2.2 to 4.2 nm to accurately include
single-stranded DNA (ssDNA, 11–53nt) and to accomplish reversi-
ble communication between MOFs and ssDNA in a researcher’s
study. The entire nucleic acid chain within the pores provides out-
standing protection and Xray diffraction visualizes the geometric
circulation of the enclosed ssDNA. Two MOFs in this series show
outstanding transfection effectiveness in mammalian immune
cells, 92% in main mouse immune cells (CD4 + T cells) and 30%
in human immune cells (THP-1 cells), unmatched by commercial
agents (Lipo and Neofect) [336]. Using UiO-66-N3, (Zr6O4OH4(C8-
H3O4-N3)6), the first novel class of nucleic acid-MOF nanoparticle
conjugates was synthesized. Using a strain-induced click response
between DNA appended with dibenzyl cyclooctyne and azide func-
tionalized UiO-66-N3 conjugates, the MOF nanoparticle surface
was functionalized with oligonucleotides. Because of the tiny size
of the pore, altered surface and covalent coupling approach
between nucleic acid and MOF nanoparticles when distributed in
aqueous NaCl, their colloidal stability, transfection, and cellular
uptake capacities increased, which are unique compared to
unfunctional MOF nanoparticles. Throughout the chemical trans-
formation, the structure of the framework was maintained and
the surface DNA quantified. This fresh and modular nanoparticle
class concept can be used for programmable atom equivalent
assembly techniques based on nucleic acid as well as an intracellu-
lar distribution agent where both oligonucleotide characteristics
and the structure of MOF can be helpful [183]. A flexible approach
was implemented using the ‘‘click chemistry” technique to alter
metal–organic framework nanoparticles (NMOFs) with nucleic
acid chains. NMOFs functionalized with nucleic acid are used for
the preparation of stimulus-responsive load carriers (fluorescence
samples or anti-cancer drugs). Two distinct NMOFs based on
nucleic acid that responds to stimuli were provided. One scheme
includes pH-sensitive NMOFs being prepared. The NMOFs are
being loaded anti-cancer drug fluorophores or doxorubicin with
pH-responsive duplex DNA caps. in the NMOFs. The capping units
are unlocked at pH = 5.0 leading to load discharge. As a targeting
unit for the nucleolin biomarker present in cancer cells, the
AS1411 aptamer is combined with the locking units. NMOFs
charged with pH-sensitive doxorubicin and specifically AS1411
aptamer-reformed pH-responsive NMOFs demonstrated selective,
targeted cytotoxicity to MDA-MB-231 breast cancer cells. A second
scheme includes the synthesis of NMOFs charged with fluo-
rophores or doxorubicin and enclosed as metal ion-dependent
DNAzyme / substratum locking units. The locking units of nucleic
acid are cut off in the presence of the corresponding metal ions,
leading in load release. Including the ATP aptamer sequence in
the Mg2+ -dependent DNAzyme loop domain also synthesizes ‘‘in-
telligent” Mg2 + -ion-dependent doxorubicin-loaded NMOFs.
Unlocking these NMOFs only works efficiently when ATP and
Mg2+ ions are present, acting as supportive triggers. The ‘‘intelli-
gent” carrier offers sense-and-treat features since ATP in cancer
cells is over-expressed. The doxorubicin-loaded NMOFs triggered
by ‘‘intelligent” ATP / Mg2+ show selective cytotoxicity towards
cancer cells of MDA-MB-231. Metal-ion-dependent DNAzymes
are effective as ion-responsive locks for drug-loaded NMOF carri-
ers, DNAzyme-capped fluorophore-loaded NMOFs, the efficient
introduction of DNAzyme-capped fluorophore-charged NMOFs as
functional units for the design of multiplexed ion-sensing and
logic-gate systems [200]. Intracellular delivery and functionaliza-
tion of genetic molecules play critical roles in theranostics based
on genes. In specific, growing attention has been given to the deliv-
ery of plasmid DNA (pDNA) with secure non-viral vectors for effec-
tive intracellular gene expression; however, some constraints
remain. Using biomimetic mineralization and coprecipitation,
using a simple one-pot technique, pDNA is encapsulated into ZIF-
8 (ZIF-8) and ZIF-8 (ZIF-8) polymer vectors. In both nanostructures,
the pDNA molecules are discovered to be well spread and take
advantage of their enzyme degradation safety. Also, by using a
25 kD capping agent for polyethyleneimine (PEI), the nanostruc-
tures display increased load ability, better pH-responsive release,
and greater pDNA-related affinity. The cellular absorption of pro-
tected pDNA and endosomal escape are significantly enhanced
from in vitro studies with the superior ZIF-8-PEI 25 kD vector,
resulting in effective gene expression with elevated transfection
efficacy, comparable to costly business agents [337].
10.2. Advancements in MOFs based combination therapy
Checkpoint immunotherapy blockade (CBI) produces lasting
therapeutic reactions by blocking T-cell inhibitory tumor pathways
with pre-infiltrated T-cells and/or high mutational load to activate
antitumor immunity but is ineffective against poorly immunogenic
tumors. As immunomodulatory adjuvants to increase CBI, photo-
dynamic therapy (PDT), immunogenic radiotherapy, and
chemotherapy were therefore examined (Fig. 19). The production
of dysregulated hormones has been associated with tumorigenesis
and the bad prognosis of different cancers. This paper reports the
use of a metal–organic Cu-porphyrin (nMOF) structure to mediate
synergistic hormone-triggered chemodynamic therapy (CDT) and
light-triggered PDT. Combining radical therapy based on CDT and
PDT with a programmed cell death ligand 1 blockade efficiently
expands CDT and PDT’s local therapeutic impacts to remote tumors
through abscopal impacts on elevated estradiol mouse tumor mod-
els. Various published research defines the possibility to combine
radical nMOF-mediated treatment with CBI in hormonally dysreg-
 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
Fig. 19. Advanced MOFs for combination therapy of cancer (taken with permission
from W. Zhu, J. Zhao, Q. Chen, Z. Liu, Nanoscale metal–organic frameworks and
coordination polymers as theranostic platforms for cancer treatment, Coordination
Chemistry Reviews. 398 (2019)).
ulated tumor phenotypes to elicit systemic antitumor immunity
[338].
Photodynamic therapy (PDT) may kill local tumors and mini-
mize ordinary tissue harm, but the elimination of metastases is
ineffective. Checkpoint immunotherapy blockade has achieved
the latest clinical success, but only owing to inadequate enabling
the host immune system causes restricted levels of systemic anti-
tumor reaction for most cancers. There are multiple reports which
suggest that combined PDT with a fresh chlorine-based metal–or-
ganic (nMOF) structure, TBC-Hf, and a small molecular
immunotherapy agent that inhibited 2,3-dioxygenase (IDO) indo-
leamine, encapsulated in antitumor systemic immunity nMOF
channels. In colorectal cancer models, synergistic combination
therapy accomplished efficient local and remote tumor rejection.
After the immune system is activated by the PDT-induced small-
molecule immunotherapy agent and immunogenic cell death, they
identified elevated infiltration of T cells in the microenvironment
43
of tumors. In this combination therapy, they also clarified in the
presence of tumor-associated antigens to T cells, the underlying
immunological mechanisms and disclosed compensatory roles of
neutrophils and B cells. The nMOF-enabled PDT can considerably
improve the blockage of checkpoint immunotherapy for cancer,
providing clinical advantages for the therapy of many cancers that
are difficult to treat [142]. Apart from phototherapy, Immunother-
apy has also gained a lot of importance in cancer therapy. A com-
bination of immunotherapy with phototherapy can prove quite
beneficial for cancer patients. Immunogenic photodynamic ther-
apy (PDT) may improve reaction rates by primary cancer
immunotherapy, but tumor hypoxia significantly limits its effec-
tiveness. According to several published literature, FeTBP acts as
a novel nanophotosensitizer for tumor hypoxia and effective PDT
sensitivity, non-inflammatory tumors are primed for cancer
immunotherapy. Fe-TBP was constructed from porphyrin ligands
and iron-oxo clusters and sensitized PDT under both normal and
hypoxic circumstances. FeTBP mediated PDT considerably
enhanced the effectiveness of anti-programmed death-ligand 1
(a-PD-L1) therapy and caused abscopal impacts in a colorectal can-
cer model of the mouse, leading in > 90% regression of cancers.
Mechanical trials disclosed that PDT mediated by Fe-TBP caused
important cytotoxic T cell tumor infiltration [339]. Similarly, Wang
et al. developed a therapeutic nanosystem for mixed gene therapy
and photodynamic treatment (PDT) based on chlorine e6-modified
DNAzyme (Ce6-DNAzyme). The easily designed nanoparticles of
ZIF-8 could deliver the therapeutic DNAzyme effectively into can-
cer cells without degradation. The pH-responsive nanoparticles of
ZIF-8 disassemble with the concomitant release of the guest DNA-
zyme payloads and the host Zn2 + ions that serve as messenger
RNA-addressing motors and DNAzyme cofactors for the activation
of gene therapy respectively. The auxiliary photosensitizer Ce6
could generate reactive oxygen species (ROS) for the imaging-
guided gene-photodynamic treatment and provide fluorescence
modality [340].
10.3. Advancements in MOFs based biosensing
Biosensors have excellent potential to diagnose cancer accu-
rately and early. It has been revealed that functionalized MOFs
have been prepared using porous UIO-66-NH2 as a nano container
for charging electroactive dyes and dsDNA as a gatekeeper to cap
MOFs. These functionalized MOFs (MB@UIO and TMB@UIO) were
used as proof-of-concept manufactured and used as a homoge-
neous electrochemical biosensor to identify let-7a and miRNA-21
simultaneously. The suggested biosensor showed outstanding
sensing efficiency with elevated sensitivity and excellent selectiv-
ity due to it’s elevated porous and superior gating impact of dsDNA
relative to ssDNA. Target miRNAs recognition and hybridization of
PX impels the generation of complexes of RNA-DNA, separating
from MOFs and allowing the release of electroactive colors. Com-
pared to the missing target miRNAs, two powerful signals were
registered depending on the concentration of target miRNAs. Con-
current detection of let-7a and miRNA-21 was accomplished, with
detection limits down to 3.6fM and 8.2fM respectively similar or
smaller than those of reported approaches focused on single
miRNA detection. However, in human serum samples with ele-
vated precision and consistency, the MOFs-based biosensors were
used for concurrent identification of let-7a and miRNA-21. Other
tumor biomarkers can be easily detected simultaneously and
ultra-sensitively by merely altering the charging dyes and capping
DNA structures[200]. With the vast amount of ongoing research,
there will be many more advancements that will help in the effi-
cient biosensing of various biomarkers. The MOFs can be explored
to develop biosensors which can help in early detection of several
proteins that are over secreted during tumor cell migration and
44 A. Pandey et al. / Coordination Chemistry Reviews 409 (2020) 213212
relapsing. Such biosensors will certainly help in avoiding the
spread of cancer to a different part of the body and also suppress
the relapsing tumors. Although there are immunosensors present
for the detection of few tumor relapsing biomarkers the MOFs
can be explored to develop more sensitive and cost-effective
biosensors for such biomarkers.
11. Conclusion
With recent advancement in the field of material science and
advanced materials, MOFs has evolved in a way to be utilized in
multiple technologies in the biomedical field. With the versatility
in structure and function, MOFs have gained attention from
researchers working in the area of drug delivery, cancer diagnos-
tics, biosensing, and imaging to name a few. With continuous
advancement and research, MOFs will soon be spreading its wings
and become a potential candidate for being used as a single plat-
form for multiple applications in cancer biology and therapy. With
the development of a drug delivery platform having stimuli-
responsive drug release control, it can greatly reduce the adverse
effect on non-cancerous cells with enhanced localization of drugs
in and around tumor cells. The biosensing and diagnostic ability
of MOFs can be greatly enhanced with proper doping and surface
modification to increase the signal to noise ratio. With the use of
other inorganic materials like the 2D materials and quantum dots,
the efficacy of MOFs can be increased both in the field of therapy
and biosensing. During the last few years, several works have
reported the use of MOFs for in vivo imaging applications. Impor-
tant advances have been achieved in terms of coordination of dif-
ferent ions, contrast properties, and in vivo behavior. However,
important limitations and challenges still need to be overcome to
consider MOFs as a realistic alternative to current imaging CAs.
Particularly, the synthetic routes need to be improved to be able
to produce MOFs with smaller and homogeneous sizes, appropriate
functionalization and/or coating are required to improve stability
in physiological media, and, in some cases, to reduce cytotoxicity.
The fine-tuning of shape and size of MOFs can be done by varying
the reaction condition as per need and use. With the progress being
made in the field of MOFs, it can be predicted that sooner or later
MOFs based nanoplatform will see the market in one or several
biomedical fields.
Declatation of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper
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