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Metal–Organic Framework (MOF)-Based Drug/Cargo

Review
Delivery and Cancer Therapy
Ming-Xue Wu and Ying-Wei Yang*

biocompatible, i.e., they should be non-

Metal–organic frameworks (MOFs)—an emerging class of hybrid porous toxic or have low toxicity and should be
materials built from metal ions or clusters bridged by organic linkers—have easily degraded by the body’s metabo-
attracted increasing attention in recent years. The superior properties of lism. Furthermore, the release of drugs
in drug-loaded vehicles is expected to be
MOFs, such as well-defined pore aperture, tailorable composition and struc-
effectively controlled. As a result, exten-
ture, tunable size, versatile functionality, high agent loading, and improved sive efforts have been devoted to applying
biocompatibility, make them promising candidates as drug delivery hosts. various controlled drug release systems
Furthermore, scientists have made remarkable achievements in the field of in cancer chemotherapy.[7] More impor-
nanomedical applications of MOFs, owing to their facile synthesis on the tantly, scientists are currently focusing
on the development of multimodal
nanoscale and alternative functionalization via inclusion and surface chem-
treatment systems to satisfy an ever-
istry. A brief introduction to the applications of MOFs in controlled drug/ growing demand for efficient therapeutic
cargo delivery and cancer therapy that have been reported in recent years is strategies.[8]
provided here. Hitherto, metal–organic frameworks
(MOFs) have been designed via diverse
synthetic strategies[9] and studied for
1. Introduction many applications, including gas storage and separations,[11]
[10]

catalysis,[12] sensing,[13] nonlinear optics,[14] an increasing

Cancer is a threat to the health of human beings that causes
millions of deaths annually. Chemotherapy is still the domi-
nant treatment method. However, traditional direct adminis-
tration of therapeutic drugs to patients is no longer applicable
due to intrinsic limitations, including undesirable side effects,
poor pharmacokinetics and poor biodistribution.[1] Thus, var-
ious efforts have been made toward the development of drug
vehicles for controllable drug release that achieve reduced
side effects and enhanced therapeutic efficacy.[2] Accordingly,
during the last few decades, many different types of nanocar-
riers have been developed for this purpose, such as inorganic
mesoporous silica, quantum dots, metal nanoparticles (NPs),
and organic micelles, liposomes, and dendrimers.[3] How-
ever, all nanocarriers have their own limitations in bioappli-
cations; liposomes, micelles, and dendrimers usually suffer
from low loading capacities,[4] and inorganic porous materials
have undesirable toxicity and unacceptable degradability.[5] An
ideal drug-loading system should possess the following basic
requirements: carriers should have a large loading capacity;
carriers should be nanoscale in order to facilitate the release
of drugs by intravenous administration;[6] carriers must be
M.-X. Wu, Prof. Y.-W. Yang
International Joint Research Laboratory of
Nano-Micro Architecture Chemistry (NMAC)
College of Chemistry
Jilin University
2699 Qianjin Street, Changchun 130012, China
E-mail: ywyang@jlu.edu.cn
DOI: 10.1002/adma.201606134
number of potential biomedical applications,[9e,10a,15] and many
others.[7d,9a,15b,16] Figure 1 summarizes the main synthetic
methodologies of MOFs and their applications. In recent years,
MOFs (where “MOF” encompasses all possible dimension
scales) have received extensive attention in the development
of drug delivery and cancer theranostic platforms, particularly
MOFs in the nanoscale regime.[9a,d,15b,17] Compared with tradi-
tional drug carriers, mentioned above, MOFs possess the fol-
lowing obvious advantages:[7b,18] Firstly, their versatile struc-
tures provide MOFs with diverse morphologies, compositions,
sizes, and chemical properties, which endow them with multi-
functionalities and stimuli-responsive drug controlled release.
Moreover, it is notable that the modification of such materials
has no significant alteration of their desirable physicochemical
properties, i.e., MOF-based materials still maintain control-
lable size, shape, and high uniformity.[19] Secondly, large sur-
face areas and high porosities facilitate MOFs with high loading
capacity. Thirdly, weak coordination bonds ensure MOFs are
biodegradable. In short, these desirable properties enable
MOFs to be promising platforms for drug delivery, clinical
tumor therapy, and other disease therapies.
The scope of this review will highlight developments of
MOFs in the fields of controllable drug release and efficacious
treatment of cancer, including drug nanocarriers and cancer
theranostic platforms composed of individual MOFs (Table 1),
stimuli-responsive MOFs (Table 2), and multifunctional MOFs
(Table 3), respectively. The essential demands of MOFs for bio-
applications are also addressed. Finally, the prospects and chal-
lenges for MOFs have been extensively discussed. In contrast
to other excellent reviews that discuss the bioapplications of

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MOFs from a broad perspective, this review differs in that it

Review

will focus on highlighting the applications of MOFs, from indi-
vidual nanocarriers to multifunctional cancer theranostic plat-
forms, and provides an outlook for the development of cancer
theranostic platforms for MOFs and their potential clinical
applications.
2. Individual MOFs as Drug Nanocarriers
MOFs intrinsically possess large surface areas, highly ordered
porosities, and well-defined structures, which endow these
materials with the capability of loading and releasing dif-
ferent cargos, especially therapeutic agents. In 2006, Férey
and co-workers first proposed that MOFs have potential in
drug delivery, owing to their considerable loading capaci-
ties and controlled release behavior.[20] They built up two Cr-
based MOFs, denoted MIL-100 and MIL-101, from trimers of
metal octahedra and di- or tricarboxylic acids, which exhib-
ited remarkable IBU adsorption with 0.35 g g–1 of IBU/dehy-
drated MIL-100 and 1.4 g g–1 of IBU/dehydrated MIL-101.
The release kinetics of IBU were studied in simulated body
fluid at 37 °C, indicating that a complete release of IBU from
MIL-100 occurred after 3 days, and from MIL-101 after 6 days.
Compared with a similar material, MCM-41, these two hybrid
solids showed comparable IBU dosages and kinetics in sim-
ulated body fluid; especially MIL-101(Cr), which may be due
to its larger cage sizes and stronger interactions with IBU.
Notably, this work developed a new method of MOF-based
drug delivery.
Taking into account the toxicity of chromium compounds,
some low toxicity MOFs have been applied for the delivery of
drug molecules. For instance, varieties of available Fe-based
MOFs offer many possibilities to achieve an adequate controlled
release of various pharmacological molecules.[9a,69] In 2008, the
much less toxic iron analogue, MIL-53(Fe), composed of tere-
phthalate anions and trans chains of Fe (III) octahedra, was
Figure 1. Schematics showing the synthesis and applications of MOFs.
Ming-Xue Wu received her
B.Sc. (2014) in chemistry
from Shandong University
of Technology, China. She
became an M.Sc. student
at Jilin University in 2014,
where she performed
research under the direc-
tion of Professor Qiong Jia.
In 2016, she started her
Ph.D. in the research group of
Professor Ying-Wei Yang. Her
research focuses on the fabrication of stimuli-responsive
MOF-based drug nanocarriers to realize efficient cancer
treatment.
Ying-Wei Yang received his
B.Sc. (2000) and Ph.D. (2005)
from Nankai University. From
2005 to 2010, he gained
postdoctoral training at ASU
(with John C Chaput), UCLA
(with Sir Fraser Stoddart) and
UCI (with Zhibin Guan). In
2011, he became an Associate
Professor in the College of
Chemistry at Jilin University
and was promoted to Full
Professor in 2014. His research interests include multi-
functional organic–inorganic hybrid nanomaterials, organic
supramolecular chemistry, and stimuli-responsive (bio)
polymers.
used to adsorb IBU by impregnation of the
solids in a hexane IBU-containing solution
with loading capacity of 20 wt%.[21] Then, the
delivery of IBU was performed in simulated
body fluid at 37 °C under continuous stir-
ring. A complete delivery of IBU took around
21 days, which was proved as zero-order
kinetics. Importantly, this work highlighted
for the first time the unique properties of
MOFs in terms of adapting their pore open-
ings to the dimensions of drugs, to optimize
drug-matrix interactions. Besides, porous
MIL-100 (Fe) was used as a nanocarrier of
antitumor drug doxorubicin (DOX), whereby
a dosage of 9 wt% was received with complete
release after 2 weeks.[7a] Moreover, MIL-100
(Fe) or iron aminoterephthalate have been
applied for encapsulating highly hydrophilic
nucleoside analogues, antivirals cidofovir
(CDV), and azidothimidine triphosphate
(AZT-TP), with high loading capacities of
42 wt%, 29 wt%, and 21 wt%, respectively.[7a]

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Table 1. Examples of individual MOFs as drug nanocarriers.

Review
Individual MOFs as drug nanocarriers
MOFs Major components Drug/cargo Loading percentage Targeted cell lines Ref.
[wt%]
MIL-100/101 (Cr) Trimers of chromium octahedral, 1,3,5-BTC/1,4-BDC IBU 25.8/58 − [20]
MIL-53 (Fe) Fe3+, 1,4-BDC IBU 20 – [21]
Zn-TATAT Zn2+, TATAT 5-Fu 33.3 − [22]
Zn-H2BDP_X Zn2+, H2BDP_X (X = H, NO2, NH2, OH) Mitroxantrone, PAPTA_C − J774 [23]
Zn-CDDB Zn2+, H2CDDB 5-Fu 53.3 HepG2, MDA-MB-435s [24]
Zn2(1,4-bdc)2(dabco) Zn2+, 1,4-BDC, 1,4-diazabicyclo [2.2.2] octane IBU 15 HuH7 [25]
UiO NMOF ZrCl4, amino-TPDC Cisplatin prodrug, siRNA 12.3 ± 1.2 Ovarian cancer cells [26]
Nano-UiO-66-2-NH2 ZrCl4, 1,4-BDC_NH2 5-Fu 27 − [27]
UiO-66_X Zirconium polyhedral, 1,4-BDC_X (X = H, Br, NH2) Caffeine 22.4 ± 3.4 (X = H) − [28b]
21.2 ± 0.7 (X = Br)
13.2 ± 0.2 (X = NH2)
bMOF-1/100 Zinc adenine-SBU, BPDC/Azo-BPDC Etilefrine hydrochloride 10 ± 0.7 (bMOF-1) − [29]
bMOF-4/102 10.2 ± 0.6 (bMOF-4)
9.6 ± 0.8 (bMOF-100)
10.9 ± 0.9(bMOF-102)
MIL-100 (Fe) Fe3+, 1,3,5-BTC DOX 9 − [7a]
Nucleoside 42 −
CDV 29 −
AZT-TP 21 Human peripheral blood
mononuclear cells

Zn-based MOFs have also been reported as nanocar-
riers due to the low toxicity of zinc ion. For example, Wang
et al. have reported a chiral Zn-based MOF constructed from
5,5′ 5′′-(1,3,5-triazine-2,4,6-triyl) tris (azanediyl) triisophtha-
late (TATAT) and Zn2+ for the delivery of anticancer drug
5-fluorouracil (5-Fu).[22] Adsorption of 5-Fu was achieved by
soaking the prepared MOF in 5-Fu containing methanol solu-
tions, and the hydrogen bonding interactions between 5-Fu
and the MOF ensured a loading capacity of 0.5 g g−1. Drug
was released from the drug-loaded MOF by dialyzing the as-
prepared drug vehicle against phosphate buffered saline (PBS)
solution (pH 7.4) at room temperature, and the drug release
process lasted for a week. Barea et al. have reported a series
of isoreticular MOFs composed of Zn2+ and some function-
alized organic linkers 1,4-bis(1H-pyrazol-4-yl)-2-X-benzene
(H2BDP_X; X = H, NO2, NH2, OH).[23] Following this, two
antitumor drugs, mitroxantrone and [Ru(p-cymene)Cl2(pta)]
(RAPTA-C, pta = 1,3,5-triaza-7-phospaadamantane), were
encapsulated in the porous Zn-based MOFs. An et al. reported
that four types of adenine-based MOFs (bMOFs) were selected
for delivery of etilefrine hydrochloride.[29] Among them,
bMOF-1 and bMOF-100 were constructed from a zincadeninate
secondary building unit (SBU) and biphenyl-4,4′-dicarboxylic
acid (BPDC), and bMOF-4 and bMOF-102 were built from the
same SBU with azobenzene-4,4′-dicarboxylic acid (Azo-BPDC).
Drug-loading was accomplished by soaking the bMOFs
in solutions of etilefrine hydrochloride in ethanol, after
which the drug was released into simulated body fluid until
completion. Results showed that the loaded drug was released
over a long time ranging from 49 to 80 days, although an initial
burst release was observed. Cao et al. also synthesized a water-
stable Zn-based MOF–Zn8(O)2(CDDB)6(DMF)4(H2O)] (CDDB =
4,4′-(9-H carbazole-3,6-diyl) dibenzoic acid) and 5-Fu was adsorbed
into the host MOF.[24] The drug delivery capacity of the synthe-
sized MOF was around 53.3 wt% with a delivery time of 3 days.
Usually, there are two methods for drug-loading: one method
is a two-step encapsulation of drugs by immersing the pre-
pared MOFs nanocarriers into drug-containing solutions; the
other is a one-pot encapsulation of drugs. In addition to the
two-step encapsulation of drugs mentioned above, Morsali and
co-workers reported the first example of in situ synthesis of a
drug-loaded MOF at room temperature.[25] IBU-loaded MOF
(Zn2(1,4-bdc)2(dabco))n was studied as a drug delivery system
with loading capacity of 15 wt% and a progressive release over
12 days.
Recently, a series of zirconium-based MOFs, especially
UiO-66 (UiO for Oslo University),[70] have received increasing
attentions.[71] These are composed of Zr6O4(OH)4 secondary
building units (SBUs) and dicarboxylate bridging ligands.
UiO-66 MOFs are desirable candidates for drug delivery because
of their two octahedral (≈11 Å) and tetrahedral (≈8 Å) cages,
nontoxicities, and excellent stabilities.[28] Serre et al. studied the
rationality of a variety of biocompatible MOFs as nanocarriers
combined with experimental and computational systematic
exploration.[28b] Cubic UiO-66 solids were constructed from zir-
conium oxoclusters and terephthalate anions bearing different

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Table 2. Examples of stimuli-responsive MOFs for drug delivery

Single-stimulus-responsive MOFs for drug delivery

Stimuli MOFs Major components Drug/cargo Loading Targeted cell lines Ref.
percentage [wt%]
pH Fe(bbi) Fe2+, bbi DOX 40 Hela cells [30]
PAA@ZIF-8 PAAS, Zn2+, HMeIM DOX 65.5 MCF-7 [31]
UiO-66 ZrCl4, 1,4-BDC AL 51.5 MCF-7, HepG2 [32]
MG-Gd-pDBI Gd3+, pDBI DOX 12 U937 [33]
ZIF-8 Zn2+, 2-methylimidazolate CPT 2 MCF-7 [34]
ZIF-8 Zn2+, 2-methylimidazolate DOX 20 MCF-7, MDA-MB-231, [35]
MDA-MB-468
ZJU-101 Zirconium, BPYDC Diclofenac sodium 35.3 PC12 [36]
PCN-221 ZrCl4, TCPP MTX 28.6 PC12 [37]
Magnetic field Fe3O4/Cu3(BTC)2 2+
Cu , 1,3,5-BTC, Fe3O4 nanorods NIM 14.5-16.7 − [38]
γ-Fe2O3@MIL-53(Al) Al3+, 1,4-BDC, γ-Fe2O3 IBU 10 − [39]
Ions bioMOF-1 Zinc adeninate-SBUs, Procainamide HCl 18 − [40]
biphenyldicarboxylate
MOF-74-Fe(III) Fe2+, Ibuprofen anions 15.9 PC12 [41]
2,5-dioxido-1,4-benzenedicarboxylate
Temperature UiO-66-PNIPAM ZrCl4, 1,4-BDC_NH2, PNIPAM Resorufin, Caffeine, − − [42]
Procainamide
ZJU-64/ ZJU-64-CH3 Zn2+, adenine, terphenyldicarboxylic MTX 13.5/10.6 PC12 [43]
acid
Pressure ZJU-800 ZrOCl2·8H2O, F-H2PDA Diclofenac sodium 58.8 PC12 [44]
Multiple-stimuli-responsive MOFs for drug delivery
pH, competitive agent CP5-capped Zn2+, 1,4-BDC_NH2, 4,4′,4′′-ben- DOX 3.4 HEK293 [45]
UMCM-1-NH-Py zene-1,3,5-triyl-tribenzoic acid, CP5, Py
Zn2+, thermo CP5-capped ZrCl4, 1,4-BDC_NH2, CP5, quaternary 5-Fu 1.5 HEK293 [46]
UiO-66-NH2 ammonium salt
Ca2+, pH, thermo CP5-capped ZrCl4, 1,4-BDC_NH2, CP5, quaternary 5-Fu 3.1 HEK293 [47]
UiO-66-NH2 ammonium salt
pH, redox PEG-RGD-β-CD- PEG-1900, k(ad)RGDS, β-CD-S-S-BCN, DOX 13.4 Hela cells, COS7 cells [48]
SS-MIL-101 MIL-101-N3(Fe)
Amantadine, light β-CD-capped ZrCl4,2′-p-tolyldiazenyl-1,1′:4,4′- RhB − − [49]
UiO-68-azo terphenyl-4,4′′-dicarboxylic acid, β-CD
pH, liposomes Fe-BTC, Zn-BTC Fe2+/Zn2+, 1,3,5-BTC DOX − − [50]

functional groups on the aromatic benzyl ring (UiO-66_X for
X = H, Br, or NH2). Caffeine encapsulation was performed by
simple immersion, indicating that UiO-66 were promising car-
riers of caffeine. In another study, Lin et al. reported the first
example of UiO MOFs for co-delivery of cisplatin and pooled
siRNAs to enhance their therapeutic efficacy by overcoming
drug resistance in ovarian cancer cells.[26] UiO MOF was pre-
pared with ZrCl4 and aminotriphenyldicarboxylic acid (amino-
TPDC) bridging ligands, in which a cisplatin prodrug and
siRNA were sequentially loaded by encapsulating and coordi-
nating to metal sites on the MOF surfaces (Figure 2a). Green
fluorescence was clearly observed in cells incubated with
siRNA/UiO-cis, but not in those treated with siRNA/UiO or
UiO-cis, indicating that the developed siRNA/UiO-cis induce
cell apoptosis (Figure 2b–d). All these results demonstrated
that such a co-delivery method would enhance the chemother-
apeutic efficacy of cisplatin in vitro (Figure 2e). Interestingly,
Ling et al. introduced a continuous flow microreactor tech-
nology for preparation of downsized UiO-66 NPs.[27] High
surface-to-volume ratio of the continuous flow microreactor
facilitated efficient heat transfer, leading to fast nucleation of
UiO-66 NPs in the nanoscale, meanwhile the growth of UiO-
66 MOFs could be controlled by residence time. Furthermore,
the obtained NH2-functionalized nano-UiO-66-2 (nano-UiO-
66-2-NH2) was used for loading 5-Fu, with a loading capacity of
27 wt%. This work provided a facile strategy for the preparation
of MOFs for bioapplications.
3. Stimuli-Responsive MOFs for Drug Delivery
Smart materials have aroused extensive attentions especially in
the field of bioapplications.[72] Among them, stimuli-responsive
MOFs have been appealing candidates for controllable drug

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Table 3. Examples of multifunctional MOFs for cancer theranostics.
Composites
MIL-101-NH2(Fe)@Silica@c(RGDfk)
Mn-bisphosphonate@Lipid@peg-AA
Hep-MIL-100(Fe)
UiO-66/67@PCL-TPGS
Fe3O4@UiO-66
Fe3O4@ZIF-90
Fe3O4@IRMOF-3@FA-RITC
Fe3O4@PAA/AuNCs/ZIF-8
Fe3O4@C@MIL-100(Fe)
Fe3O4/ZIF-8-Au25
Mn3[Co(CN)6]2@SiO2@Ag
PB@MIL-100(Fe)
Mn-IR825@PDA-PEG
Hf-TCPP-PEG
Fc-Gd@SiO2(RBITC)-RGD
UCNP@Fe-MIL-101_NH2@PEG@FAs
Mn∥coordination polymers
UiO-PDT
release. Typically, stimuli-responsive MOFs can be divided
into two categories: single-stimulus- and multiple-stimuli-
responsive MOFs. In this part, we introduce a variety of stim-
uli-responsive MOFs, including single-stimulus-responsive
Adv. Mater. 2017, 1606134
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Review
Multifunctional MOFs for cancer theranostics
Polymer-coated MOFs
Major components Drug/cargo Functionality Targeted cell lines Ref.
Fe3+, 1,4-BDC_NH2, silica shell, Br-BODIPY, Cisplatin prodrug Chemotherapy, Optical HT-29 [51]
ESCP prodrug, c(RGDfk) imaging, Targeting
Mn2+, zoledronic acid, DOPA, DOPC, Zoledronate Chemotherapy, MRI, MCF-7, AsPC-1 [52]
DSPE-PEG2k, cholesterol, anisamide Targeting
Fe3+, 1,3,5-BTC, Rhodamine-labeled heparin Caffeine Stealth property, Low J774.A1, HL60 [53]
inflammatory responses,
Chemotherapy
Poly(ε-caprolactone)-tocopheryl poly(ethylene Cisplatin, Taxol Chemotherapy, Sustained U-87MG, HSC-3 [54]
glycol)-succinate copolymer, UiO-66, UiO-67 release, Reduced toxicity
Magnetic core–shell MOFs
ZrCl4, 1,4-BDC, Fe3O4 DOX Magnetic separation, MRI, HeLa cells, 3T3 cells [55]
Chemotherapy
Zn2+, imidazolate-2-carboxyaldehyde, rat serum 5-Fu MRI, Magnetic thermal − [56]
albumin, PVP, Fe3O4 effect, Chemotherapy
Zn2+, 1,4-BDC_NH2, Fe3O4, PVP, folic acid, Paclitaxel Chemotherapy, MRI, HeLa cells, NIH3T3 [57]
rhodamine B isothiocyanate Targeting, Optical imaging
Zn2+, HMeIM, HAuCl4, GSH, PAA, Fe3O4 DOX MRI, CT, Optical imaging, HepG2, H22 [58]
pH responsiveness
Fe3+, 1,3,5-BTC, Ferrocene, Fe3O4 DHA, Fe(III) Magnetic guidance, MRI, A549, HeLa cells [59]
Optical imaging, pH
responsiveness,
Chemotherapy, Yield ROS
Zn2+, HMeIM, A25(Capt)18−, Fe3O4 − MRI, Targeting, Photo­ L929, HeLa cells [60]
dynamic therapy, Photo-
thermal therapy
Other core–shell MOF nanocomposites
Mn2+,K3[Co(CN)6], PVP, SiO2, AgNO3 DOX MRI, TPF imaging, A549, HeLa cells, [61]
Photothermal therapy, HepG2
Chemotherapy, Light
responsiveness
Fe3+, 1,3,5-BTC, PVP, K3[Fe(CN)6] Artemisinin MRI, Optical imaging, Photo­ HeLa cells [62]
thermal therapy, Chemo-
therapy, pH responsiveness
Mn2+, IR825, polydopamine, PEG − MRI, Photothermal therapy 293T, HeLa cells, [63]
A549, 4T1
HfCl4, TCPP, C18PMH-PEG − Photodynamic therapy, 4T1, HeLa cells, [64]
Radiation therapy NIH3T3
Gd3+, Fc, silica, RBITC, c(RGDfk) − MRI, Targeting U87MG, MCF-7 [65]
NaYF4:Yb, Er, PVP, Fe3+,
1,4-BDC_NH2, − UCL property, MRI, Targeting KB cells, MCF-7 [66]
NH2-PEG-COOH, folic acid
Flexible MOF-based theranostic nanoplatforms
Mn(ClO4)2, non-steroidal anti- NSAIDs Cell imaging, Drug delivery RAW264.7 [67]
inflammatory drugs (NSAIDs),
1,2-bis(4-pyridyl)ethylene
ZrCl4, 1,4-BDC, I2-BDP − Photodynamic therapy B16F10, C26, CT26 [68]
MOFs and multiple-stimuli-responsive MOFs, which are able to
achieve regulated delivery of loaded drugs upon activation by
diverse stimuli, such as pH, magnetic field, ions, temperature,
light, and pressure.
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Figure 2. a) Schematic presentation of siRNA/UiO-cis synthesis and drug-loading. b–d) CLSM images showing cell apoptosis and siRNA (TAMRA-
labeled, red) internalization in SKOV-3 cells after incubation with UiO-cis (b), siRNA/UiO (c), and siRNA/UiO-cis (d) for 24 h. The apoptotic cells
were stained with Alexa Fluor 488 Annexin V conjugate and the nuclei were stained with DAPI. Scale bar represents 10 µm. e) Cytotoxicity of siRNA/
UiO-cis in SKOV-3 cells after 72 h incubation determined by MTS assay. Reproduced with permission.[26] Copyright 2014, American Chemical Society.

3.1. Single-Stimulus-Responsive MOFs for Drug Delivery
3.1.1. pH-Responsive MOFs
Of all porous MOF nanocarriers triggered by external stimuli,
pH-responsive MOFs are the most widely investigated, espe-
cially for cancer therapy, because of the acidic tumor microen-
vironment and the sensitivity of coordination bonds to external
pH.[73] Until now, many investigations have involved the pH-
responsive properties of MOFs for drug delivery and cancer
treatment. For example, Huang et al. reported an Fe (bbi) MOF,
constructed from 1,1′-(1,4-butanediyl) bis (imidazole) (bbi) and
ferrous ions by a deposition method.[30] In situ encapsulation of
DOX was achieved by simply adding DOX into the bbi solution
(Figure 3a) and, as expected, the loaded DOX could be released
upon lowering the pH, due to the sensitivity of the coordination
bond to the acidic environment (Figure 3b). Thus, a layer of
silica was coated on the surface of the MOF to prevent the rapid
decomposition of the hosting material for effective control over
the release of DOX. More importantly, folic acid was conjugated
to the surface of the as-prepared nanocomposites for targeted
drug delivery (Figure 3c). Consequently, the MOF-based drug
vehicle showed pH-dependent progressive release behavior and
good anticancer efficacy.
Another pH-sensitive nanocarrier, poly(acrylic acid)@zeolitic
imidazolate framework-8 (PAA@ZIF-8), was prepared by ion-
exchange between Zn2+ and poly(acrylic acid sodium salt)
(PAAS), followed by reacting with 2-methylimidazole (HMeIM)
in methanol solution.[31] Notably, the obtained PAA@ZIF-8
nanocarrier exhibited high DOX loading capability (1.9 g DOX
g−1 NPs), which may be attributed to electrostatic interactions
between the negatively charged PAA and positively charged
DOX, as well as the coordination interaction of Zn(II)-DOX.
Consequently, confocal laser scanning microscopy (CLSM)
analysis showed that this pH-sensitive drug release formulation
showed a faster drug release in buffer solution of pH value 5.5
than at a neutral pH of 7.4. Such pH-dependent drug nanocar-
riers were taken up by MCF-7 cells through endocytosis and
were nearly nontoxic to live cells, suggesting their potential
bioapplications.
Shi and co-workers also reported a pH-responsive drug car-
rier, UiO-66 MOF, which was applied for alendronate (AL)
delivery owing to its natural drug anchorages of Zr–O clus-
ters.[32] Herein, an ultrahigh dosage of AL, up to 1.06 g AL g−1
UiO-66, was obtained due to strong complexation of Zr–O–P
bonds. Next, the release behavior of AL loaded nanocompos-
ites was assessed at 37 °C in PBS buffer at pH = 5.5/7.4; the
released amounts within 60 h were 59% and 42.7%, respec-
tively. Such release behavior may be attributed to protonation
of the AL at lower pH, which weakens the complexation of
Zr–O–P bonds. Nevertheless, over a prolonged time the release
rate was higher at pH 7.4 than that at pH 5.5; a unique behavior
that is attributed to the higher stability of UIO-66 under acidic
conditions than under neutral and basic conditions.[70] In vitro
cytotoxicity measurements showed that AL-UiO-66 exhibited
higher anticancer efficacy than free AL after 48 h of incubation,
indicating that pH-responsive AL-UiO-66 improved antitumor
efficiency and made UiO-66 a promising carrier for AL delivery.
Interestingly, a Gadolinium (III)-based MOF, Gd-pDBI
(pDBI = 1,4-bis(5-carboxy-1H- benzimidazole-2-yl)benzene),
was proved to be a potential pH-responsive drug vehicle.[33] In
this work, Gd-pDBI was transformed to MG-Gd-pDBI upon
mechanical grinding and showed good aqueous dispersibility.
It was then used for intravenous injection. The pre-synthe-
sized MG-Gd-pDBI showed higher DOX loading capacity than
Gd-pDBI due to its enhanced surface exposure towards DOX.

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Figure 3. a) Schematic presentation of DOX/Fe(bbi)@SiO2–FA. b) In vitro pH-responsive release profiles of DOX·HCl from DOX/Fe(bbi) and DOX/
Fe(bbi)@SiO2. c) CLSM imaging showing that folate receptor mediated endocytosis enhanced HeLa cells uptake. Reproduced with permission.[30]
Copyright 2013, Royal Society of Chemistry.

Moreover, about 44% of drug was released from the nano-
carrier at pH 5 within 5 days, whereas only 22% of loaded
DOX was released at pH 7.4 after 5 days, suggesting that the
obtained MOF possessed pH-responsive drug release. Both
in vitro and in vivo experiments demonstrated the practicality
of the pre-synthesized MG-Gd-pDBI for DOX release and its
desirable biocompatibility without side effects to other major
organ functions.
Tsung et al. reported a pH-responsive ZIF-8 with uniform
70 nm NPs as a theranostic system.[34] Negatively charged
small molecules such as fluorescein camptothecin (CPT) could
be encapsulated into the ZIF-8 NPs by one-pot encapsulation.
The performance of pH-responsive release was driven by the
dissociation of the ZIF-8 framework at the acidic designated
target. Herein, CPT-ZIF-8 treated cells showed increased cell
death compared with free CPT treated cells. Similarly, Zou
et al. reported a one-pot method for synthesis of ZIFs (ZIF-8
and ZIF-67) to encapsulate organic molecules (anticancer drug
DOX and dye molecules, such as rhodamine B, methyl orange,
and methylene blue).[35] Research results demonstrated that the
developed one-pot process could be used to encapsulate target
organic molecules into the same ZIF crystals. ZIF-8 crystals
loaded with 20 wt% of DOX were proved to be efficient nano-
carriers for cancer therapy via pH-responsive release due to the
instability of ZIF-8 under acidic conditions.
Recently, the Qian group described an interesting cationic
nanocarrier, MOF ZJU-101 (ZJU = Zhejiang University), for
delivery of diclofenac sodium, an anionic drug.[36] The cationic
host material was composed of zirconium and 2,2′-bipyridine-
5,5′-dicarboxylate (BPYDC) with high diclofenac sodium
loading capacity of 0.546 g g–1. Diclofenac sodium was released
faster in the inflamed tissues (pH = 5.4) than in normal tis-
sues (pH = 7.4), because the ion exchange between anions in
the PBS and the drug occurred more frequently at acidic con-
ditions, which weaken the Coulombic interaction between the
cationic ZJU-101 and anionic drug. Therefore, pH-sensitive
diclofenac sodium@ZJU-101 was expected to be a promising
anti-inflammatory drug vehicle.
More interestingly, they reported the first example of PCN-
221 MOF as an oral drug carrier.[37] PCN-221 was prepared
from 5,10,15,20-tetrakis (4-carboxyphenyl) porphyrin (TCPP)
and ZrCl4, and then the anticancer drug methotrexate (MTX)
was encapsulated by immersing PCN-221 in MTX solution.
Subsequently, the MTX-PCN-221 with loading capacity of

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0.40 g g–1 was immersed in PBS solution at 37 °C with pH
Review
values of 7.4 and 2.0, respectively. Experimental results exhib-
ited that ≈40% of MTX was released at pH = 2.0 (around
the pH of stomach) after 3 days, whereas 100% of MTX was
released at pH = 7.4 (close to the intestinal pH). Accordingly,
the pH-responsive MTX-PCN-221 was expected to be a prom-
ising oral drug carrier.
3.1.2. Magnetically-Responsive MOFs
Magnetically responsive systems allow for diversity in drug
delivery due to their potential superiorities in magnetic sepa-
ration, magnetic targeting, magnetic resonance imaging
(MRI), and magnetic hyperthermia.[74] Among these, mag-
netically guided anticancer drug delivery is a unique strategy
to concentrate drug-loaded therapeutic probes in tumor sites
to improve therapeutic efficacy, since its first introduction by
Watson et al. in the 1960s.[75] Candidate nanocarriers based
on MOFs for such a delivery approach are usually core–shell
NPs, for example Fe3O4 was often used as a magnetic core with
a MOF shell. For instance, Zhang et al. described a targeted
drug vehicle based on a magnetic MOF, i.e., Fe3O4/Cu3(BTC)2
(HKUST-1, BTC = benzene-1,3,5-tricarboxylate) nanocompos-
ites.[38] Nimesulide (NIM), an anticancer drug, was loaded in
the magnetic nanocarrier by soaking Fe3O4/Cu3(BTC)2 in the
NIM trichloromethane solution. Magnetic measurements
were carried out, suggesting that Fe3O4/Cu3(BTC)2 possessed
desirable magnetic performance for targeted drug delivery and
separation.
In 2014, Guan and co-workers reported a one-step in situ
pyrolysis method for the fabrication of γ-Fe2O3@MOFs. In
their work, γ-Fe2O3@MIL-53(Al) demonstrated its potential
for controllable magnetic separation and drug release.[39] As
expected, the magnetic nanocomposites exhibited controlled
release behavior in physiological saline at 37 °C; that is,
the encapsulated IBU was completely released after 7 days
in three stages: firstly, about 30% of the drug was released
rapidly at the first 3 hours; then, 50% of drug was released
during the next 2 days; finally, the residual 20% of drug was
released over 5 days. These results verified that the magnetic
γ-Fe2O3@MIL-53(Al) material was feasible for drug delivery.
Very recently, versatile magnetically responsive MOF-based
biomedical carriers have been developed and are discussed in
detail in 4.
Figure 4. a) Schematic fabrication process of MOF-74-Fe(II) oxidation to crystal 1 and drug-loading. b) Release profiles of Ibu− in PBS solution under
2.0 and 4.0 MPa, respectively. Reproduced with permission.[41] Copyright 2014, American Chemical Society.
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3.1.3. Ion-Responsive MOFs
Ion-responsive MOFs have introduced a new pathway for drug
delivery. In such drug carriers, strong electrostatic interactions
between the drugs and the frameworks control the diffusion
and release of drugs. Thus, the strong electrostatic interactions
between ionic drugs and ionic frameworks have attracted par-
ticular interest because the release of ionic drugs is a chem-
ical stimuli-responsive process taking place only through ion
exchange. For instance, the Rosi group fabricated an anionic
Zn8(ad)4(BPDC)6O·2Me2NH2·8DMF·11H2O (bioMOF-1) by
introducing biphenyldicarboxylic acid to the mixtures of ade-
nine and zinc acetate dihydrate.[40] Such anionic bioMOF-1
was explored to test its capability to storage and release of pro-
cainamide HCl, a cationic antiarrythmia drug. Because of the
electrostatic interaction between anions and cations, a loading
dosage of 0.22 g g–1 was achieved and the cations in the bio-
logical fluids were expected to trigger the release of procaina-
mide HCl. Therefore, as a controlled experiment, drug-loaded
bio-MOF-1 was placed in a PBS buffer (pH = 7.4) and nanopure
water, which verified that drug release could be triggered by
buffer cations.
Yang and co-workers developed a cationic drug carrier, MOF-
74-Fe(III), through the oxidation of neutral MOF-74-Fe(II).[41]
The cationic MOF exhibited around 15.9 wt% of the loading
capacity of ibuprofen anions (Figure 4a). Interestingly, the
preparation process of MOF could yield hydroxide, resulting in
the presence of two distinctive Ibu− anions in MOF channels,
thus, two different release behaviors were observed. Sodium
ibuprofen and the other coordinated free anions were released
at first, merely because of diffusion or ion exchange between
the drug-encapsulated MOF and PBS solution. The following
release profile of the targeted drug was triggered by phosphate
anions through competitive adsorption (Figure 4b).
3.1.4. Temperature-Responsive MOFs
Generally, temperature-responsive nanocarriers are materials
that are sensitive to slight temperature changes at the physi-
ological temperature of 37 °C. Poly(N-isopropyl acrylamide)
(PNIPAM) is a promising building block for thermosensitive
drug nanocarriers that possess a lower critical solution temper-
ature.[76] When the temperature is lowered to below its cloud
point (Tc, around 32 °C), PNIPAM exhibits hydrophilicity and
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Review
Figure 5. a) Schematic showing the controlled release profiles of UiO-66-PNIPAM. b) Release behavior of drug-loaded UiO-66-PNIPAM in water at
25 °C and 40 °C for seven days. c) Temperature-responsive release behavior of resorufin from UiO-66-PNIPAM in water at 572 nm. Reproduced with
permission.[42] Copyright 2015, Royal Society of Chemistry.

tends to dissolve in water; however, it also forms an aggregate.
Accordingly, Sada et al. demonstrated a switchable UiO-66-
PNIPAM nanocarrier (Figure 5a).[42] Resorufin, caffeine, and
procainamide were loaded in the nanocarrier by soaking the
UiO-66-PNIPAM in guest solutions, then the release behaviors
were assessed at 25 °C or 40 °C (Figure 5b). As expected, the
amount of released drug increased at 25 °C and almost halted
at 40 °C (Figure 5c), which indicated that controlled release was
driven by temperature variation.
Recently, the Qian group synthesized two zinc-based MOFs,
Zn16(ad)8(TP)8O2(H2O)8·4HTP·36DMF·16H2O (ad = adenine,
H2TP = [1,1′:4′,1′′-terphenyl]-4,4′′- dicarboxylic acid for ZJU-
64, and 2′,5′-dimethyl-[1,1′:4′,1′′-terphenyl]-4,4′′-dicarboxylic
acid for ZJU-64-CH3).[43] Anticancer drug MTX was encapsu-
lated into the two MOFs by a simple impregnation method,
with loading a capacity of 13.45 and 10.63 wt% for ZJU-64
and ZJU-64-CH3, respectively. The same amount of MTX was
released from MTX-loaded ZJU-64 and ZJU-64-CH3 at 37 °C
for 72 h, but only took approximately 1.5 and 6 h at 60 °C, sug-
gesting a potential application of ZJU-64 and ZJU-64-CH3 as
temperature-responsive drug carriers.
3.1.5. Pressure-Responsive MOFs
To avoid the premature release of drugs until they reach at path-
ological tissues, above-mentioned responsive MOFs have been
developed with prolonged release time and enhanced thera-
peutic effcacy. In addition to the above commonly mentioned
stimuli, pressure has also been employed for controllable drug
release. Recently, Qian and co-workers reported a Zr-based MOF
builted from (2E,2E′)-3,3′-(2-fluoro-1,4-phenylene) diacrylic

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acid (F-H2PDA) and zirconium cluster with high model drug
Review
diclofenac sodium (DS) loading capacity of 58.80 wt% due to
its enhanced polarity and extended organic spacer.[44] The DS-
release kinetics of such drug-loaded MOF could be adjusted
through varying pressure, resulting in a prolonged release time
between 2–8 days. Such formulation showed a new method for
responsive MOF-based drug delivery.
3.2. Multiple-Stimuli-Responsive MOFs for Drug Delivery
The complexity of the human body environment limits
abilities to precisely deliver drugs in the body using single-
stimulus-responsive MOF drug carriers. However, multiple-
stimuli-responsive MOFs can be used as a better alternative to
improve loading capacities and chemotherapeutic efficiencies.
Pillararenes, one example of rapidly developed supramolecular
hosts, have been widely investigated since their first discovery
by Ogoshi et al. in 2008. This is due to their desirable proper-
ties, including their special structure, facile functionalization,
and desirable host–guest performance.[77] Certainly, this new
class of macrocycles is promoting the development of supramo-
lecular chemistry and materials science.[78] Accordingly, many
host–guest systems based on pillararenes have been devel-
oped,[79] in particular, pillararene-based nanovalves for drug
delivery have recieved increasing attention in recent years.[80] It
is conceivable that the combination of MOFs with pillararenes
will reveal a new method for the bioapplications of MOFs.
Our research group has devoted much effort to design such
versatile drug nanocarriers. According to the rapid development
of gated materials,[81] multiple-stimuli-responsive drug delivery
system (DDS) composed of MOFs and pillararene-based supra-
molecular nanovalves was developed for the first time by our
research group, in collaboration with the Wang group.[45]
UMCM-1-NH2 was used as the host material to store cargoes of
guest molecules, followed by modification of carboxylatopillar[5]
arene (CP5) as a dual stimuli-responsive gatekeeper linked by
Figure 6. Schematic illustration of dual-stimuli responsive DDS based on UMCM-1-NH2 NMOF gated by pillararenes. Reproduced under the terms of
the CC-BY-NC-3-0 unported license.[45] Copyright 2014, The Royal Society of Chemistry.
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positively-charged pyridinium (Py) stalks (CP5-capped UMCM-
1-NH–Py). In acidic tumor tissues or tumor cells, the gatekeeper
of CP5 tended to be neutral, which weakened the noncovalent
binding interactions between CP5 and the stalk, leading to
unblocking of the MOF followed by the release of cargo. Upon
addition of a competitive binding agent (methylviologen salts),
which possess a higher binding affinity to CP5 than Py, CP5
was detached from the stalks, which caused the release of cargo.
We integrated pH- and/or competitive binding agent-responsive
strategies into a single drug nanocarrier (Figure 6), where the
CP5-capped drug nanocarrier showed high encapsulation effi-
ciency, negligible premature release, negligible cytotoxicity,
desirable biodegradability, and biocompatibility. Further studies
of the multiple-stimuli-sensitive nanocarriers based on MOFs
with CP5 rings as gatekeeper have also been carried out in
our group. For instance, we have reported another CP5-capped
UiO-66-NH2 5-Fu nanocarrier.[46] In this work, UiO-66-NH2 was
modified with positively charged quaternary ammonium salt as
stalks (Q) to thread the negatively charged CP5 rings, to form
[2]pseudorotaxanes as stimuli-responsive supramolecular gates
that regulate drug release. Zn2+ can be a competitive binding
agent to trigger the release of 5-Fu because of a higher binding
affinity between Zn2+ and CP5. In addition, increasing tempera-
ture could also weaken the noncovalent bonding interactions
between the CP5 and stalks to stimulate the release of drugs.
Therefore, the dual stimuli-responsive drug nanocarrier based
on CP5-gated MOF outlines a new opportunity for therapy of
central nervous system diseases.
Recently, our group developed a triply-responsive theranostic
hybrid platform based on CP5-gated Zr-MOFs.[47] Positively
charged quaternary ammonium salt stalks were tethered on
UiO-66-NH2 via post-synthetic modification, and then negatively
charged CP5 was encircled on the stalks sitting on the surface
of the MOF through host–guest complexation. As mentioned
above, low pH, increasing temperature, and competitive binding
agents could weaken the supramolecular interactions between
the MOF scaffold and the gating nanovalves of CP5 to control
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Figure 7. Schematic illustration of triple-stimuli-responsive DDS based on CP5-capped UiO-66. Reproduced with permission.[47] Copyright 2015, Royal
Society of Chemistry.
the targeted release of drugs. Therefore, herein, a triple modal
therapeutic trigger was integrated in one system (Figure 7).
Controlled release experiments verified that the prepared thera-
peutic platform was promising for potential bone regeneration
and bone cancer therapy because lower pH and higher con-
centration of Ca2+ in osteoclasts and tumor cells could stimu-
late the release of the therapeutic agents via pH-responsiveness
and Ca2+-competitive responsiveness. Furthermore, high tem-
peratures could damage and kill cancer cells as well as weaken
host–guest interactions to prompt gradually release of the thera-
peutic molecule (5-Fu). Furthermore, the triply-responsive drug
nanocarrier possessed desirable properties, including negligible
premature release, non-cytotoxicity, and good biocompatibility.
In addition, β-cyclodextrin (β-CD) is also one of the most
promising supramolecular macrocycles that can be tethered onto
the scaffold MOFs as gating entitles to regulate targeted drug
release. For example, the Zhang group introduced a multifunc-
tional MOF platform for drug delivery by one-pot post-synthetic
surface modification of MIL-101 (Figure 8a).[48] After encapsu-
lating DOX, MIL-101-N3 (Fe) was coated with β-CD derivative
(β-CD-SS-BCN) and a targeted peptide functionalized polymer,
Lys (adamantane)-Arg-Gly-Asp-Ser-bi-poly(ethylene glycol) (PEG)
1900 (bi = benzoic imine bond, K(ad)RGDS-PEG1900), could be
tethered to the surface of the nanocarrier via a host–guest inter-
action. The proposed drug carrier possessed pH-responsiveness
and redox-responsiveness due to the presence of a benzoic
imine bond in K(ad)RGDS-PEG1900 and disulfide bonds upon
linking β-CD on the MOF. Experimental results indicated that
the suggested DDS possessed enhanced tumor cell uptake and
that reducing agents triggered drug release, resulting in effi-
cient drug delivery and cancer therapy (Figure 8b). Moreover,
surface modification reduced the cytotoxicity of the loaded DOX
on normal cells according to in vitro experiments, meanwhile in
vivo experiments proved high chemotherapy efficacy of the DDS.
Recently, Wang and co-workers reported another dual
stimuli-responsive MOF for on-command cargo release.[49]
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Review
Light-responsive release and competitive binding agent-respon-
sive release were implemented in the system by tethering β-CD
on the surface of UiO-68-azobenzene (β-CD–capped UiO-68-azo)
through supramolecular complexation (Figure 9a). Azobenzene
groups provided photo-controllable cis/trans isomerizations and
the isomerization of azobenzene from trans to cis promoted the de-
threading of the gating β-CD to regulate cargo release (Figure 9b).
Furthermore, a competitive binding agent such as amantadine
could also trigger the dissociation of the gatekeeper from the
azobenzene stalks due to its higher binding affinity toward β-CD
(Figure 9c). Rhodamine B was loaded in the dual-stimuli respon-
sive nanocarrier, indicating β-CD–capped UiO-68-azo was stimuli
responsive and without premature release. This work provided a
promising platform for controllable drug delivery.
Some other attempts have been made to design multirespon-
sive MOFs carriers in addition to the above-mentioned supra-
molecular nanovalves systems. For instance, two biocompatible
MOFs Fe-BTC and Zn-BTC (BTC = 1,3,5-benzenetricarbox-
ylic acid) have been investigated for one-pot encapsulation of
DOX at room temperature.[50] Drug release could be triggered
in the presence of biocompatible liposomes and lower pH, as
carboxylate anions are protonated in acidic environments and
break down the coordination between carboxylic acid group and
metal center, leading to drug release by disruption of the MOF.
Furthermore, stronger electrostatic interactions between DOX
and liposomes also promoted the release of drugs. The obtained
MOFs nanocarrier was initially used to release DOX in the pres-
ence of liposomes and low-acidity conditions, notably affording
new opportunities in stimuli-responsive drug vehicles.
4. Multifunctional MOFs for Cancer Theranostics
Although numerous MOF-based therapeutic platforms have
been widely developed in recent years, there are still many chal-
lenges that need to be addressed such as current treatment
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Review

Figure 8. a) Schematic fabrication process of the multifunctional DDS based on MIL-101 and b) its cancer therapy procedure. Reproduced with permis-
sion.[48] Copyright 2015, Royal Society of Chemistry.

Figure 9. a) Schematic illustration of the synthesis of dual-stimuli-responsive DDS based on UiO-68-azo MOF capped by β-CD. b) Schematic represen-
tation of light triggered release. c) Schematic representation of step-by-step release. Reproduced with permission under the terms of the CC-BY-NC-3.0
unported license.[49] Copyright 2014, The Royal Society of Chemistry.

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modality, which is still limited in traditional chemotherapy and
whose therapeutic efficacy is hampered by multidrug resistance.
Considerable effort has been devoted to the fabrication of multi-
functional theranostic nanomedical platforms, such as versatile
MOF-based diagnostic and/or therapeutic systems, to overcome
aforementioned drawbacks to achieving superior anti-tumor
efficacy, among which core–shell MOFs nanocomposites have
shown marvelous potential as nanomedical platforms. In this
section, we will mainly introduce core–shell structures of MOF
nanocarriers, including polymer-coated MOFs, magnetic core–
shell MOFs, and other core–shell MOF-based nano­composites.
Furthermore, some multifunctional therapeutic nanoplatforms
constructed from MOFs will also be described.
4.1. Polymer-Coated MOFs for Cancer Theranostics
Since the Lin group reported the first example of surface func-
tionalization of a MOF material with a silica shell for the con-
trolled release of metal constituents and luminescence sensing
of dipicolinic acid,[82] an array of multifunctional core–shell
MOF nanocomposites have been developed for biomedical
applications due to their unique advantages, including enhanced
stability, water dispersibility, biocompatibility, and tunable func-
tionality. For instance, in 2008 the Lin group designed Pt-con-
taining nanoscale coordination polymers (NCPs) constructed
from Tb3+ ions and c,c,t-(diamminedichlorodisuccinato) Pt
(IV) (DSCP), followed by a silica coating on the surface of the
as-synthesized NCPs to enhance their biocompatibility and
further functionality (Figure 10).[83] The controlled release
behavior of silica-coated NCPs suggested that the nanocompos-
ites could efficiently control the release of Pt species by varying
the thickness of the silica shell. Silyl-derived c(RGDfK) was
then grafted on the surface of the pre-synthesized nanocompos-
ites to enhance cellular uptake. In vitro experiments exhibited
high anticancer efficacies and good biocompatibility of the Pt-
based NCPs.
Subsequently, they reported core–shell nanostructures of
Mn MOF coated with a thin silica shell and functionalized
Figure 10. Schematic fabrication process of the silica-coated MOF for drug delivery at spe-
cific site of cancer cells. Reproduced with permission.[83] Copyright 2008, American Chemical reactive oxygen species (ROS) production.
Society.
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with c(RGDfK) and rhodamine B.[84] Experimental results veri-
Review
fied the target-specific uptake of the c(RGDfK)-modified Mn
MOF by angiogenic cancer cells and their potential for MRI.
In 2009, they reported another theranostic platform based on
iron-carboxylate MOF MIL-101.[51] In this work, optical imaging
contrast agent, 1,3,5,7-tetramethyl-4,4- difluoro-8-bromome-
thyl-4-bora-3a,4a-diaza-s-indacene (Br-BODIPY), and ethoxy-
succinato-cisplatin (ESCP) prodrug, c,c,t-[PtCl2 (NH3)2 (OEt)
(O2CCH2CH2CO2H)], were post-synthetically modified on the
MOF. Because of the instability of the MIL-101 (Fe) in PBS
buffer, a thin layer of silica was coated on the surface of NPs
to slow down cargo release. Silyl-derived c(RGDfK) was subse-
quently functionalized onto the silica shell to enhance cellular
uptake. As expected, the multifunctional MOF possessed appre-
ciable imaging and anticancer efficacy.
Although the above-mentioned silica-coated MOFs possessed
high drug-loading capacity, such nanoplatforms were limited by
a burst release of drugs. Thus, the Lin group developed a new
cisplatin-containing MOF composed of disuccinatocisplatin
(DSCP) and ZrCl4, which was further stabilized by a lipid layer
composed of cholesterol (chol), 1,2-dioleoyl-sn-glycero-3-phos-
phocholine (DOPC) and 1,2-distearoyl-sn-glycero-3-phosphoe-
thanolamine-N-PEG (DSPE–PEG2 K).[85] A targeting ligand
anisamide (AA) that displayed an affinity for sigma receptors
was functionalized on the surface of the nanocomposites to
enhance cellular uptake. This formulation proved good anti-
cancer efficacy and allowed for the preparation of other lipid-
coated NCPs for nanomedical applications.
Afterwards, they reported another Mn-bisphosphonate MOF
coated with lipid for theranostic applications.[52] The Mn-bis-
phosphonate MOF was constructed from zoledronic acid and
MnCl2 in the presence of 1,2-dioleoyl-sn-glycero-3-phosphate
sodium salt (DOPA), indicating high loadings of the zole-
dronate and considerable MRI property. Accordingly, the MOF
was coated with a lipid/lipid–PEG layer to improve drug-release
kinetics and biocompatibility, and further modified with a tar-
geting group (anisamide) for specific cancer cell uptake. Such a
theranostic nanoplatform demonstrated physiological stability,
biocompatibility and imaging-guided cancer-target specificity,
facilitating a huge potential application in the
field of theranostic MOFs materials.
Horcajada and co-workers introduced
an example of a specific modification of
nanoscale MIL-100(Fe) with heparin to
endow the MOF with appreciable bio-
logical properties via a one-pot method.[53]
Compared with unmodified MIL-100(Fe),
heparin-coated nanocomposites evidenced
their colloidal stability and preserved their
ability to accommodate high caffeine load-
ings with a more progressive release. More
importantly, the heparin-coated MOF showed
potential stealth properties that resulted from
the influence of the coating on the cell tox-
icity and uptake, the activation of the com-
plement pathway, the cytokines production,
macrophage uptake, cytokine profile, and
Certainly, this surface modification method
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paved a new way to the design of desirable MOFs for thera-
Review
nostic applications.
Additionally, Tendeloo and co-workers were able to fabri-
cate poly(ε-caprolactone) coated Zr-based MOFs for anticancer
drug carriers.[54] In this work, poly(ε-caprolactone)–tocopheryl
poly(ethylene glycol)-succinate (PCL–TPGS) copolymer was
engineered on the surface of UiO-66 and UiO-67 MOFs due to
its biocompatibility and non-toxicity. Then, two model drugs,
hydrophilic cisplatin and hydrophobic taxol, were used to inves-
tigate the drug-loading capacity and drug-release behavior of
the drug-loaded nanocarriers. In vitro drug-release measure-
ments indicated a sustained drug release and decreased burst
effects. Moreover, the developed polymer-coated MOFs showed
low toxicity as a result of the MTT assay using two cell lines
(U-87 MG and HSC-3). All of these results suggested that such
polymer-coated MOFs formulations were promising for further
biomedical applications.
4.2. Magnetic Core–Shell MOFs for Cancer Theranostics
The employment of iron oxide as a core to fabricate MOF-based
theranostic probes for cancer diagnosis and therapy have drawn
considerable attentions because of their superior magnetic
properties in, for example, MRI, magnetic hyperthermia, and
magnetic separation. For instance, Fu and co-workers reported
a theranostic Fe3O4@UiO-66 core–shell nanocomposite that
simultaneously performed drug delivery and MRI in vitro and
in vivo.[55] The shell UiO-66 was used to encapsulate DOX and
the strong superparamagnetic core Fe3O4 could be quickly col-
lected under an external magnetic field and ensured its ability
for MRI.
In addition, Ding and co-workers designed another Fe3O4
core–shell MOF (Fe3O4@ZIF-90) for accurate and visible drug
delivery.[56] Considering the deep penetration capacity of mag-
netic field stimulus, an extremely low frequency alternating
magnetic field (ELF-AMF) with a frequency of 20 Hz was
proved to be able to accelerate drug release from the magnetic
ZIF-90 because of the magnetic thermal effect. The Fe3O4@
Figure 11. a) Schematic illustration of the preparation of Fe3O4@PAA/AuNCs/ZIF-8 composite NPs for simultaneous tri-modal cancer imaging and
chemotherapy. b) Photographs of excised tumors from euthanized mice in the three groups. Reproduced with permission.[58] Copyright 2015, Royal
Society of Chemistry.
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ZIF-90 drug carrier combined efficient diagnosis and chemo-
therapy in one system because the magnetic core provided MRI
and magnetic thermal response simultaneously. Significantly,
ZIF-90 was scaled down to 64 nm and modified with rat serum
albumin to improve their stability in a physiological environ-
ment and facilitated targeted delivery.
The Sahu group also developed multifunctional magnetic
core–shell MOFs as theranostic nanoplatforms. They intro-
duced isoreticular MOF (IRMOF-3) coated Fe3O4 NPs for
paclitaxel delivery, followed by modification with fluorescent
molecule rhodamine B isothiocyanate and folic acid.[57] Their
research demonstrated that the integration of targeted drug
delivery, MRI, cell imaging, and chemotherapy was realized
in the multifunctional porous nanoplatform. Subsequently, a
similar IRMOF-3 coated Fe3O4 nanocomposite was developed
as targeted anticancer nanoplatform in their work.[86] Spe-
cially, a biodegradable O-carboxymethyl chitosan (OCMC) was
incorporated on the surface of a Fe3O4 core, instead of Fe3O4,
to improve loading capacity and pH sensitivity. More impor-
tantly, carbon dots (CDs) were encapsulated in the magnetic
nanocomposites to realize optical imaging for the first time.
The hybrid drug carrier exhibited high dosage of 1.63 g DOX
g−1 magnetic MOF with pH responsive drug release, magnetic
guided drug delivery, cancer cell targeting, optical imaging, and
MRI. Effective theranostic efficacy, biocompatibility, and facile
functionality made the magnetic MOF formulation a promising
candidate for biomedical applications.
In 2015, Wang and co-workers reported multifunctional
Fe3O4@poly(acrylic acid)/Au nanoclusters/zeolitic imida-
zolate framework-8 (ZIF-8) NPs (Fe3O4@PAA/AuNCs/ZIF-8
NPs) for cancer diagnosis and visualized-synergistic therapy
(Figure 11a).[58] The obtained nanomedical system possessed
many therapeutic properties, such as facile magnetic separa-
tion, high DOX loading capacity, tri-modal imaging, dual pH-
responsive drug release, and high in vivo tumor inhibition effi-
cacy (Figure 11b). Tri-modal imaging of magnetic resonance,
X-ray computed tomography, and optical imaging was utilized
to combine the superiorities and circumvent the limitations
of different imaging techniques. Thus, such multifunctional
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Figure 12. a) Schematic presentation of magnetic-field-guided DHA-loaded FCM NPs entering considerable potential for nanomedical appli-
tumor cells. b) The anticancer mechanism of the DHA delivery system. Reproduced with per-
mission.[59] Copyright 2016 Elsevier Ltd.
core–shell nanocarriers showed great potential for efficient
theranostic applications.
Another interesting study for the multifunctional magnetic
core–shell MOF theranostic platform was reported by Chen and
co-workers.[59] Multifunctional Fe3O4@C@MIL-100(Fe) (FCM)
nanocomposites were designed for simultaneous delivery of
dihydroartemisinin (DHA) and Fe (III) as cancer theranostic
nanoplatforms (Figure 12a). When Fe (III) reached the acidic
environment of tumor tissue, it would be reduced to Fe (II) and
then reacted with pH-responsive released DHA to yield ROS
that induce cancer cell death. In addition, the magnetic core
of Fe3O4@C, with properties of magnetic guidance and MRI,
was further used to encapsulate CDs for fluorescence optical
imaging (FOI) (Figure 12b). In vitro and in vivo experiments
exhibited dual-modal imaging-guided pH-responsive chemo-
therapy improved diagnostic and therapeutic efficacy for cancer
treatment.
Interestingly, Yang et al. fabricated a cooperative thera-
peutic system based on a multifunctional magnetic core–shell
MOF.[60] The obtained Fe3O4/ZIF-8-Au25 nanocomposites
integrated photodynamic/photothermal therapy, magnetic tar-
geting, and MRI imaging into one theranostic system. Photody-
namic effects were induced because the Au25(Capt)18− clusters
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could produce reactive singlet oxygen (1O2),
Review
and both of the magnetic core clusters, Fe3O4
and Au25(Capt)18−, could provide hyperthemal
effects (Figure 13a). Additionally, Fe3O4 pre-
sented magnetic targeting and MRI imaging
capabilities (Figure 13b). More importantly,
in vivo control experiments verified that the
combined theranostic mechanisms (photo­
dynamic therapy/photothermal therapy/mag-
netism) suggested a higher inhibition effect
than that of photodynamic therapy and/or
photothermal therapy (Figure 13c), and the
multifunctional Fe3O4/ZIF-8-Au25 nanocom-
posites showed high tumor inhibition effi-
cacy without side effects on normal organs.
All of these results confirmed superior thera-
peutic efficacy of the obtained theranostic
nanoplatform, which combined a therapeutic
mechanism and diagnostic capability in one
system, making this system a good candidate
for biomedical applications.
4.3. Other Versatile Core–Shell MOFs
Nanocomposites for Cancer Theranostics
Great effort has been made to design multi­
functional core–shell MOFs as efficient
theranostic nanoplatforms, in addition to
above-mentioned magnetic core–shell MOFs
theranostic systems, and many other versatile
core–shell MOF nanocomposites have shown
cations.[87] For example, Wang and co-workers
introduced a versatile Mn3[Co(CN)6]2@
SiO2@Ag nanocube platform for synergistic
cancer treatment.[61] The inner core of the Mn3[Co(CN)6]2 MOF
structure served as a T1–T2 dual-modal MRI imaging agent and
two-photon fluorescence (TPF) imaging agent; the outer shell of
Ag NPs endowed the system with photothermal therapy capa-
bility and improved TPF imaging at the same time. DOX was
loaded in the multifunctional nanoplatform with a high loading
capacity of 600 mg g−1, and drug release could be triggered
by light due to surface plasmon resonance (SPR) of the noble
Ag NPs. Controlled experiments indicated that the combined
therapeutic effect of chemotherapy and photothermal therapy
was superior to sole chemotherapy or photothermal therapy. All
of these results suggested that the Mn3[Co(CN)6]2@SiO2@Ag
core–shell nanocomposites would be promising candidates for
an imaging-guided cancer synergistic therapeutic platform.
Subsequently, the Chen group fabricated core–shell PB@
MIL-100(Fe) dual MOF (d-MOFs) nanocomposites, integrating
diagnosis and therapy into a single system (Figure 14a,b).[62]
Multimodal imaging was introduced in the nanoplatform
because the d-MOFs possessed T1/T2 and T2 dual-modal MRI
as well as FOI capabilities. More importantly, the inner Prus-
sian Blue NPs were used for photothermal therapy in the NIR
region. Furthermore, the as-prepared nanoplatform with high
artemisinin loading capacity of 848.4 mg g–1 was pH-responsive
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Review

Figure 13. a) Infrared thermal images of a tumor-bearing mouse after injection of Fe3O4/ZIF-8 Au25-5mL as a function of the irradiation time under
808 nm NIR light (0.5 W cm−2). b) MR images before (left) and after (right) injection of Fe3O4/ZIF-8 Au25 in vivo. c) Photographs of the tumor tissues
excised from tumor-bearing mice treated with normal saline, pure NIR laser, pure IZ, pure Au25(Capt)18− clusters with NIR-laser irradiation, IZA with or
without NIR-laser irradiation, and IZA with two types of stimuli (NIR-laser irradiation (L) and magnet remote control (M)) on the 14th day, as well as
corresponding digital photographs of representative mice. Reproduced with permission.[60] Copyright 2015, Royal Society of Chemistry.

due to the degradation of outer MOFs in an acidic patho-
logical environment. In vitro and in vivo experiments proved
that the obtained core–shell PB@MIL-100(Fe) possessed high
antitumor efficiency (Figure 14c,d) by combing multimodal
imaging diagnosis, pH-responsive drug release, and chemo-
photothermal therapy in a single system. Similarly, Zhang and
co-workers reported another PB@mSiO2–PEG multifunctional
nanoplatform with high DOX loading capacity.[88] In vitro and
in vivo experiments showed that such formulation has excel-
lent antitumor capability by integrating MRI, photoacoustic
imaging, pH-sensitive release, and photothermal-chemotherapy
in one system.
Recently, Liu and co-workers reported a core–shell MOF
for imaging-guided photothermal therapy; the first example of
using MOFs as a contrast agent to guide photothermal therapy
of cancer.[63] In their work, Mn-IR825 MOF was the core, which
offered MRI and photothermal conversion properties in the
obtained nanoplatform, and the outer coating of polydopamine
(PDA) was used for facile modification of PEG to confer the
nanocomposites desirable physiological stability. In vitro and
in vivo experiments verified that the Mn-IR825@PDA–PEG
nanoplatform possessed good biocompatibility and high photo-
thermal therapy efficiency. Importantly, it could be degraded in
vivo and showed rapid clearance via the renal excretion system.
The developed work demonstrated great potential of such ther-
apeutic formulation for cancer treatment in vivo.
Interestingly, they also reported a hafnium-based MOF built
from Hf4+ and tetrakis (4-carboxyphenyl) porphyrin (TCPP).[64]
This formulation integrated photodynamic therapy and radia-
tion therapy in one system due to Hf4+, which could intrinsi-
cally perform as a radio-sensitizer to improve radiation therapy,
and the organic building block of TCPP could serve as photo­
sensitizer for photodynamic therapy. Experimental results
exhibited that the developed nanoplatform possessed desirable
biocompatibility owing to the outer coating of the PEG poly-
mers and appreciable antitumor efficacy due to the combina-
tion of photodynamic and radiation therapy. Importantly, this
multifunctional MOF-based nanoplatform showed no obvious
side effects to normal organs and could be cleared away by the
metabolic system of the modal mouse.

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Review
Figure 14. a) Schematic illustrations of the loading and targeting delivery process of d-MOFs in tumors. b) pH-responsive degradation of outer MOFs
for drug release and dual-modal FOI- and MRI-guided cancer therapy in vitro and in vivo. c) Tumor growth curves of mice after controllable treatments.
d) Body weights of mice for varied time periods after controllable treatments. Reproduced with permission.[62] Copyright 2016 Elsevier Ltd.

In addition, developments of core–shell MOF nanocom-
posites for feasible, accurate, and efficient diagnosis have
also attracted increasing attention. For instance, Yang and
co-workers reported a multifunctional MOF for dual-modal
imaging of tumors in vitro and in vivo.[65] The inner core of the
MOF was constructed from 1,1′-dicarboxyl ferrocene (Fc) and
magnetic gadolinium (III) ions, and an outer shell of SiO2 was
used for further conjugation of fluorescent dye RBITC and tar-
geting ligand RGD, to provide their strong luminescence and
targeting capabilities, respectively. The pre-synthesized multi-
functional Fc-Gd@SiO2(RBITC)–RGD nanocomposites, with
properties of low cytotoxicity, good water-dispersion, and high
stability, enabled dual-modal T1- and T2-weighted MRI in vivo,
providing a versatile platform for targeting and imaging of
diagnostic systems.
The Tang group introduced another core–shell UCNP@
Fe-MIL-101_NH2@PEG@FAs for fluorescent/magnetic dual-
mode targeted imaging.[66] In the multifunctional nanocom-
posites, rare-earth-doped upconversion NPs (UCNPs) were
used as the core to present upconversion luminescence (UCL)
properties, and an outer shell of Fe-MIL-101_NH2 MOF was
used for MRI, followed by modifying with NH2-PEG-COOH to
improve biocompatibility and stability. Subsequently, folic acid
was modified on the surface of the as-synthesized nanocom-
posites for targeted imaging. In vitro and in vivo experiments
verified that the tumor targeted dual-mode UCL/MR imaging
nanoplatform possessed high sensitivity, low toxicity, and good
biocompatibility. Their work opened new avenues to imaging-
guided cancer therapies by integrating the advantages of both
UCNPs and MOFs in a single system.
4.4. Flexible MOF-Based Theranostic Nanoplatforms
Recent development of MOF preparation techniques have paved
the way toward multitargeted nanomedical applications in both
diagnosis and therapy, due to the facile integration of multi-
functional components via inclusion and post-synthetic modifi-
cations of MOFs, together with the mature synthesis of MOFs.
In addition to the aforementioned strategies, drug molecules
as building blocks for MOFs are a straightforward approach to
enable the development of future theranostic or multimodal
NPs. For example, Dastidar and co-workers reported various
MnII MOFs by incorporating nonsteroidal anti-inflammatory
drugs (NSAIDs) and the organic linker 1,2-bis(4-pyridyl)ethylene
(L) as part of the material for cell imaging and drug delivery.[67]
Both of the synthesized MOFs showed potential for cell imaging
and drug delivery because the imaging agent L and the drug
molecules were part of the coordination framework. Moreover,
good biocompatibility and biodegradability as well as comparable
anti-inflammatory responses of the MOFs endowed such formu-
lations with extensive potentials for theranostic bioapplications.

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Recently, such formulations have also been studied as
Review
therapeutic systems, in which carboxyl-functionalized diiodo-
substituted BODIPYs (I2-BDP) were incorporated into the
UiO-66 MOF for photodynamic therapy via solvent-assisted
ligand exchange (SALE).[68] The obtained UiO-PDT nanocrys-
tals possessed low cytotoxicity in the dark with enhanced cel-
lular uptake and photostability, together with high efficiency to
generate 1O2 for further photodynamic therapy of cancer treat-
ment. All of these results demonstrate interesting strategies of
designing functional MOF-based biomedical nanoplatforms.
5. Demands of MOFs for Bioapplications
Considering the demands of MOFs for bio- and related applica-
tions, properties such as the toxicological compatibility, biodeg-
radability, and stability of MOFs need to be addressed. Firstly,
MOF materials should be toxicologically compatible in terms of
bioapplications, therefore it is essential that the MOF building
blocks are non-toxic. Currently, Fe, Zn, Zr, Mn, Mg, and Cu are
frequently applied for the construction of MOFs due to their
appropriate toxicity determined by oral lethal dose 50 (LD50),
i.e., 30 g kg–1 for Fe, 350 µg kg–1 for Zn, 4.1 g kg–1 for Zr,
1.5 g kg–1 for Mn, 8.1 g kg–1 for Mg, and 25 g kg–1 for Cu,
exhibiting their acceptable toxcity for bioapplications.[9e] As for
exogenous organic building blocks, terephthalic acid (LD50 =
5 g kg–1), trimesic acid (LD50 = 8.4 g kg–1), 1-methylimidazole
(LD50 = 1.13 g kg–1), and 2-methylimidazole (LD50 = 1.4 g kg–1),
are generally available for bioapplications. Furthermore, some
endogenous MOFs based on endogenous organic linker have
been obtained. Ideally, such formulations would reduce severe
side effects.[29,40] In addition, some bioactive coatings are also
acceptable solutions; for example, the above-mentioned MIL-
100(Fe) with heparin coating was endowed with enhanced bio-
logical properties such as lower immunoresponse, improved
stability, and reduced cell recognition. To date, in vitro toxico-
logical experiments have been conducted to assess the cytotox-
icity of MOF-based nanocarriers determined by cell viability on
various cell lines[89] Still, further efforts should be devoted to
the evaluation of toxicity in vivo, not only to the observation of
body and organ weights, but also to investigate metabolic path-
ways of such nanocarriers in vivo.[7a,69a,90]
For bioapplications, the biodegradability and stability of
MOFs are other important concerns that need to be empha-
sized. The decomposition of MOF nanocarriers at a desired
region is recommended to avoid endogenous accumulation.
Much research on the stabilities of diverse MOF materials
under simulated physiological conditions have been reported,
for example, MIL-101 (Fe) possessed poor stability in phosphate
buffer, while MIL-100 (Fe) is stable in water but decomposed
after several days.[7a,51] Thus, the stability and degradation
mechanism of various MOF carriers in vitro and in vivo need
further systematic investigation.
6. Conclusion
In summary, we have reviewed recent significant progress made
in adapting MOFs for drug delivery, especially for cancerous
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therapy and/or diagnosis. As outlined here, many remarkable
MOF-based platforms have been developed for novel nano-
medical applications, ranging from individual MOF systems,
to functionalized MOF formulations, to current collaborative
systems. However, there are still many challenges that need to
be addressed for these systems before such nanocomposites
can be applied clinically. Firstly, more effort should be made to
fabricate versatile nontoxic or low-toxicity and good biocompat-
ible MOFs to achieve prolonged blood circulation and to ensure
that the decomposition products can be processed through
the body’s metabolic system. Despite many excellent reports,
research on the toxicity of MOFs and their biodegradation is still
in its infancy. Future work may be focused on the fabrication
of non-toxic MOF carriers by selecting endogenous building
blocks or functionalizing MOFs with bioactive substances to
reduce side effects. Additionally, the stability and degradation
mechanism of MOF-based nanocarriers need systematic studies
in vitro, and systematic in vivo investigations are essential to
optimize the performance of MOFs before clinical applications.
To emphasize an important point, it is not enough to investi-
gate the therapeutic effect of nanocarriers and their effect on
normal organs; further efforts need to be devoted to analyzing
the metabolic mechanisms and metabolic pathways of nanocar-
riers in vivo. Importantly, subsequent long-term monitoring of
organism is also indispensable. Furthermore, current studies
of imaging and therapeutic applications are far from being
applied clinically, and a comprehensive understanding of the
mechanism of absorption–distribution–metabolism–excretion is
needed. Finally, future endeavors should focus on the fabrica-
tion of multimodal MOF-based theranostic platforms combined
with different mechanisms, for achieving excellent efficacy in
anticancer or other diseases. Although theranostic MOFs for
clinical applications are still a long-standing challenge in nano-
medical development, scientists have made significant progress.
It is expected that promising developments to MOFs for clinical
applications will be made.
Acknowledgements
The authors thank the National Natural Science Foundation of China
(51673084, 51473061) and the JLU Cultivation Fund for the National
Science Fund for Distinguished Young Scholars for financial support.
The authors would also like to thank the journal editors and the
reviewers who raised valuable points that help to improve the quality of
the presentation of this review article.
Received: November 14, 2016
Revised: December 18, 2016
Published online:
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