Journal of Science: Advanced Materials and Devices 7 (2022) 100507

Contents lists available at ScienceDirect

Journal of Science: Advanced Materials and Devices

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

Original Article

An investigation of IRMOF-16 as a pH-responsive drug delivery carrier

of curcumin
Mengru Cai a, 1, Boran Ni b, 1, Xueling Hu a, Kaixin Wang a, Dongge Yin a, Gongsen Chen c,
Tingting Fu a, Rongyue Zhu a, Xiaoxv Dong a, *, Changhai Qu a, **, Xingbin Yin a, ***
a
School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China
b
Department of Gynaecology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
c
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

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

Article history: Metaleorganic frameworks (MOFs) with tunable structures, high porosity, and abundant active sites are
Received 12 May 2022 considered to be promising drug delivery systems (DDSs). In this study, novel MOFs-based nanoparticles
Received in revised form (CUR@IRMOF-16) were successfully prepared using Zn-based IRMOF-16 as a carrier and curcumin (CUR)
2 September 2022
as the model drug. This nanocargo delivery platform has dual capabilities, enabling simultaneous drug
Accepted 13 September 2022
Available online 28 September 2022
delivery and fluorescence imaging. In vitro release experiments showed that nanoparticles were released
more quickly under mildly acidic conditions, which proved their potential for tumor microenvironment-
responsive drug release. Through in vitro cell experiments, it was found that the nano-drug platform had
Keywords:
Metal-organic frameworks
high antitumor cytotoxicity, which may be related to the mechanism of increasing intracellular reactive
Drug delivery oxygen species (ROS), reducing intracellular mitochondrial membrane potential (MMP), and inducing
Curcumin apoptosis. In addition, confocal laser microscopy showed that CUR@IRMOF-16 could localize to the
pH-responsive release nucleus to exert an antitumor effect. Meanwhile, CUR@IRMOF-16 exhibited superior antitumor activity
compared with pure CUR in vitro experiments. The biocompatibility test of IRMOF-16 showed reasonable
biosafety, and no evidence of obvious toxicity was observed in vitro. CUR@IRMOF-16 has unique ad-
vantages with regard to pH response, biocompatibility, and antitumor efficacy, indicating that the nano-
drug platform is a promising drug delivery carrier with an antitumor effect.
© 2022 Vietnam National University, Hanoi. Published by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Metaleorganic frameworks (MOFs) are nanoporous polymeric
materials that are self-assembled from metal ion clusters and
organic ligands [1]. Recently, MOFs have been widely used for drug
delivery due to their potential application advantages, such as
structural chemical diversity, high drug loading capacity, and good
biodegradability [2e6]. One of the main challenges of biomedicine
is to select appropriate carriers to effectively deliver drugs into
the body. Isoreticular metaleorganic frameworks (IRMOFs) are
* Corresponding author.
** Corresponding author.
*** Corresponding author.
E-mail addresses: 201801020@bucm.edu.cn (X. Dong), quchanghai@bucm.edu.
cn (C. Qu), yxbtcm@bucm.edu.cn (X. Yin).
Peer review under responsibility of Vietnam National University, Hanoi.
1
These authors contributed equally to this work.
composed of organic acid ligands and metal cluster Zn4O [7]. MOF-5
was first reported by Yaghi in 1999, with the characteristics of high
specific surface area, good thermal stability, large pore volume,
regular pore structure, and good hydrogen storage performance
[8,9]. To further enhance applications of IRMOFs, Yaghi et al. ob-
tained IRMOFs with different pore volumes by changing the chain
lengths of the organic ligands, such as IRMOF-8, IRMOF-10, IRMOF-
12, IRMOF-14, and IRMOF-16 [10,11]. Interestingly, IRMOF-12
exhibited more efficient hydrogen storage than MOF-5.
The applications of MOFs as promising drug delivery carriers
provide us with new research ideas. Currently, the application of
MOFs in the drug delivery proves its feasibility in drug packaging
[12e15]. However, there is still limited research on the effect of
expanded pore size on drug delivery. Inspired by the above, IRMOF-
16, with the largest pore volume, has been used in drug delivery
research. Compared with MOF-5, IRMOF-16 has longer side chains,
higher specific surface area, and larger pore volume. This study
selected IRMOF-16 as a drug delivery vehicle for the first time.

https://doi.org/10.1016/j.jsamd.2022.100507
2468-2179/© 2022 Vietnam National University, Hanoi. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
M. Cai, B. Ni, X. Hu et al.
IRMOF-16 is composed of Zn4O metal ion clusters and terphenyl-
4,400 -dicarboxylic acid. The current research on IRMOF-16 mainly
focuses on its gas storage and release functions. Studies have
explored the possibility of HO-modified IRMOF-16 under simulated
conditions and theoretically speculated on its use as a drug delivery
vehicle [16e21].
Clinical applications of therapeutic drugs have been limited due to
inherent limitations such as poor physiological stability, nonspecific
targeting, and low cell membrane permeability [22,23]. In many
cases, nonspecific drug release of chemotherapeutics could cause
damage to normal tissues and poor pharmacokinetics. Nanomaterials
can control drug release rate and promote cell internalization to
deliver drugs. Therefore, Nanomaterials could overcome the limita-
tions of chemotherapeutic drugs. CUR is a natural organic chemical
with a 1,7-diarylheptane structure, which comes from the rhizome of
Curcuma Longa L [24]. Modern research has shown that CUR has
special properties such as antibacterial, anti-inflammatory, anti-
tumor, and antioxidant effects [25,26]. However, poor water solubility
and low bioavailability of CUR significantly limit its clinical applica-
tions [27]. Many efforts have been made to improve the inherent
limitations of CUR and increase its clinical value [28e31]. However,
there is still a need to develop a DDS that can release CUR continu-
ously and responsively at a tumor site.
In this study, the rapid precipitation method was used to obtain
nanoscale IRMOF-16, which was used as a delivery carrier for CUR
because of its significant biodegradability and the size of its aperture
that could accommodate the long-chain structure of CUR. The size,
surface morphology, and drug loading performance of the synthe-
sized CUR@IRMOF-16 were characterized by scanning electron mi-
croscopy (SEM), Fourier transform infrared (FTIR) spectroscopy,
powder X-ray diffraction pattern (PXRD), thermogravimetric analysis
(TGA), dynamic light scattering (DLS), BrunauereEmmetteTeller
(BET), and high-performance liquid chromatography (HPLC). In vitro
cell experiments and confocal laser scanning microscopy (CLSM)
confirmed its efficacy and toxicity against HepG2 cells. Apoptosis,
detection of ROS, and MMP experiments were conducted to confirm
its antitumor-related mechanisms.
2. Experimental
2.1. Material
The zinc nitrate hexahydrate was purchased from Shanghai
Aladdin Bio-Chem Technology Co., Ltd. (Shanghai, China); P-ter-
phenyl-4,400 -dicarboxylic acid was acquired from Shanghai Kaishu
Chemical Technology Co., Ltd. (Shanghai, China); triethylamine
(TEA) was purchased from Tianjin Fuchen Chemical Reagent Factory
(Tianjin, China); chloroform was purchased from Beijing Chemical
Plant (Beijing, China); methanol and acetonitrile were obtained
from Thermo Fisher Technology Co., Ltd. (Waltham, USA); dimethyl
sulfoxide (DMSO), EDTA-pancreatin, and DMEM were purchased
from Sigma Company (St. Louis, USA); the penicillin-streptomycin
mixture and phosphate buffer saline (PBS) were obtained from
Beijing Solab Technology Co., Ltd. (Beijing, China); fetal bovine
serum was obtained from Zhejiang Tianhang Biotechnology Co., Ltd.
(Huzhou, China); curcumin (CUR) was purchased from Shanghai
Yuanye Co., Ltd. (Shanghai, China); Annexin V-FITC apoptosis
detection kit, mitochondrial membrane potential assay kit with JC-1,
and reactive oxygen species assay kit were all from Biyuntian
Biotechnology (Shanghai, China); 3-(4,5-dimethylthiazol-2-yl)-2,5-
dipheny-ltetrazolium bromide (MTT) was obtained from Beijing
Biodee Biotechnology Co., Ltd. (Beijing, China); 40 ,6-diamidino-2-
phenylindole (DAPI) was purchased from Shanghai Beyotime
Biotechnology Co., Ltd. (Shanghai, China). All chemicals were of
analytical grade or higher.
2
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
2.2. Instrument
SEM images were taken using a high-performance field-
emission scanning electron microscope (Zeiss, Oberkochen, Ger-
many). 1 mg of the sample was dispersed in 5 mL of methanol and
sonicated for 30 min. Then the suspended droplets were placed on
silicon wafers, and then gold was sprayed on the sample surface
for 10 min. The Fourier transform infrared (FTIR) spectroscopy was
performed in the range of 4000-400 cm1 using an FTIR spec-
trometer (Thermo Scientific, Waltham, USA). The samples were
weighed to about 10 mg and then dispersed with KBr under dry
conditions. The X-ray diffraction (XRD) was measured utilizing an
X-ray powder diffraction instrument (Nippon Science Group
Corporation, Tokyo, Japan) in the range of 3e50 at a scanning
range of 2q using Cu-Ka (l ¼ 1.541 nm) radiation at 40 Kv and
40 mA. The thermogravimetric analysis (TGA) curves were recor-
ded using DTG-60/60 simultaneous thermogravimetry/differen-
tial thermal analyzers (SHIMADZU, Kyoto, Japan) from 30  C to
600  C at a rate of 10  C/min under N2 flow. The particle size was
determined using a Malvern Nano Zetasizer S90 (Malvern, Melvin,
US). 10 mg of the samples were dispersed in 10 mL anhydrous
ethanol and treated with ultrasound for half an hour. The surface
area and pore size of samples were measured by nitrogen
adsorption/desorption at 77 K using an ASAP 2460 analyzer
(Micromeritics, Atlanta, USA). Samples were degassed at 150  C
for 12 h before detection.
2.3. Synthesis of IRMOF-16
IRMOF-16 was synthesized according to the fast precipitation
method [32]. P-triphenyl-4,400 -dicarboxylic acid (0.06364 g) and
zinc nitrate hexahydrate (Zn(NO3)2$6H2O) (0.12519 g) were dis-
solved in 350 mL of N,N-dimethylformamide (DMF). Then, trie-
thylamine (TEA) was added quickly while stirring at 600 rpm on a
multi-point intelligent magnetic stirrer for 2 h (Henan Abbot Sci-
ence and Technology Development Co., Ltd., Zhengzhou, China).
The reaction liquid was centrifuged in a centrifuge (Shanghai
Fishier Analytical Instrument Co., Ltd., Shanghai, China). After
soaking in trichloromethane for three days, the sediment was
placed in a vacuum drying oven at 120  C for vacuum drying
(vacuum degree 0.01 MPa) for 12 h to activation. IRMOF-16 was
stored in a desiccator.
2.4. Drug loading
The drug loading experiment was conducted following the
solvent adsorption method in methanol. Three factors: the drug
loading times (6 h, 12 h, and 24 h), the mass ratios of MOF to CUR
(3:2, 1:1, and 2:3), and the concentrations of CUR (1 mg/mL, 2 mg/
mL, and 3 mg/mL) were determined using L9(34) orthogonal tests.
The supernatant obtained in the above experiment was diluted, and
the drug concentration was evaluated using a Thermo Scientific
UltiMate 3000 HPLC system (Waltham, MA, USA). The mobile phase
was a mixture of acetonitrile and water containing 4% acetic acid
(48:52), the column temperature was 30  C, the flow rate was
1.0 mL/min, and the detection wavelength was 430 nm. The drug
loading capacity and drug loading effiency were calculated ac-
cording to the formula below.
weight of drug 2 CUR @ IRMOF  16
drug loading capacity ðDLCÞ¼
weight of CUR @ IRMOF  16
 100%
(1)
M. Cai, B. Ni, X. Hu et al.
weight of drug 2CUR@IRMOF 16
drug loading efficiencyðDLEÞ¼
weight of CUR
100%
(2)
The CUR@IRMOF-16 was dried and stored in a dryer for subse-
quent experiments.
2.5. In vitro drug release
The in vitro release of CUR was studied following the dialysis
method [33]. Typically, 5 mg of CUR@IRMOF-16 was put into the
dialysis bag (the cut-off size of the dialysis bags was 8000e14000),
drowned in PBS with 5% tween 80 medium at pH 5.5 and pH 7.4,
shaking at 100 rpm at 37  C. At the specified time point, 1 mL of CUR
solution was taken out, and an equal amount of fresh buffer was
replenished. The concentration of CUR was determined by HPLC.
The concentrations were calculated by interpolation from the
calibration curves using linear regression models. The CUR cali-
bration curves were linear over the concentration range from
0.00004 mg/mL to 0.7 mg/mL (y ¼ 1481.3x - 3.4549, R2 ¼ 0.9999,
Table S6 and Fig. S3). The cumulative release rate was calculated
using the formulae below:
n X
t 1
CC ¼ Ct þ Ct (3)
V 0
MR
Drug release ¼  100% (4)
ML
Cc represented the adjusted concentration of CUR at time t, Ct
was the measured concentration at t, v was the volume of the
derived samples, and V was the volume of release solution. MR and
ML were the amounts of released drug and loaded drug [equation
(4)], respectively. The zero-order drug release equation, first-order
drug release equation, Higuchi equation, and RitgerePeppas
equation were used to fit the drug release properties of
CUR@IRMOF-16 in vitro.
2.6. Cell culture
Guangzhou Jeniobio Biotechnology provided the HepG2 cells.
The cells were cultured in a high-glucose DMEM containing 10%
fetal bovine serum (FBS) and 1% penicillin-streptomycin solution at
37  C in a 5% CO2 incubator.
2.7. Cell viability
The in vitro cytotoxicity of IRMOF-16 and CUR@IRMOF-16 to
HepG2 cells was evaluated using MTT assays. The HepG2 cells were
seeded into 96-well plates with 8000 cells/well, and treated with
different concentrations of IRMOF-16 (IRMOF-16: 5, 10, 15, 20, 25, 30,
35 mg/mL) and CUR@IRMOF-16 (CUR: 3, 6, 9, 12, 15, 18 mg/mL) for 24 h
and 48 h. The MTT solution was added to each well (20 mL, 5 mg/mL)
and then incubated at 37  C for 4 h. The medium was removed, and
150 mL DMSO was added to each well. After shaking the 96-well plate
for 10 min, the absorbance was measured at 490 nm using a
microplate reader (BioTek Instruments, Inc., Vermont, USA).
2.8. Nuclear morphology
The HepG2 cells were cultured with 1  105 cells/well in 24-well
plates and then treated with IRMOF-16 (IRMOF-16: 5, 15, 35 mg/mL)
3
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
and CUR@IRMOF-16 (CUR: 9 mg/mL) for 24 h. The culture medium
was sucked out from each well, and 4% tissue fixative solution was
fixed for 10 min, and then the cells were gently washed with PBS
twice. The DAPI solution (200 mL, 10 mg/mL) was added to each well.
Cells were stained for 10 min in dark conditions and washed twice
with PBS. The nucleus morphology was observed under a Nikon
Research Inverted Microscope ECLIPSE Ts2R (Nikon, Tokyo, Japan)
and photographed randomly.
2.9. Cell apoptosis
The HepG2 cells were cultured into 6-well plates with 4  105
cells/well and inoculated for 12 h, and treated with IRMOF-16
(IRMOF-16: 35 mg/mL) and CUR@IRMOF-16 (CUR: 9, 18 mg/mL) for
24 h. The collected cells were washed with PBS twice. Then, 295 mL
Annexin V-FITC binding solution, 5 mL annexin V-FITC staining so-
lution, and 10 mL PI staining solution were added successively. After
incubating for 20 min in the dark, flow detection was performed.
2.10. Mitochondrial membrane potential (MMP)
The HepG2 cells were cultured in 12-well plates with a density
of 2  105 cells/well and inoculated for 12 h, and then treated with
IRMOF-16 (IRMOF-16: 35 mg/mL), CUR, and CUR@IRMOF-16 (CUR:
9 mg/mL) for 24 h. After removing the medium, the cells were
washed gently with PBS. The JC-1 working solution was added to
each well for 30 min, and then the cells were washed twice with JC-
1 buffer solution in the ice bath. The cells were observed under a
fluorescence inverted microscope.
2.11. Cellular uptake experiment
The HepG2 cells were inoculated in a laser confocal dish at a
density of 1  105 cells/well and cultured for 12 h, and then CUR
and CUR@IRMOF-16 (CUR: 9 mg/mL) were added for 24 h. The
culture medium was sucked out, and the cells were washed twice
with PBS, followed by lysosome staining with LysoTracker Red for
20 min and nuclear staining with DAPI solution. After washing with
PBS three times, 1 mL PBS was added for observation under a laser
confocal microscope.
2.12. Reactive oxygen species (ROS)
The intracellular ROS level was measured using a reactive oxy-
gen species assay kit (Beyotime Biotechnology, Shanghai, China).
The HepG2 cells were seeded with 3  105 cell/well in 6-well plates
and grew for 12 h, and then treated with CUR (CUR: 9 mg/mL) and
CUR@IRMOF-16 (CUR: 9 mg/mL) for 24 h. The medium was dis-
carded, and the DCFH-DA working solution diluted with serum-free
medium (1.2 : 1000) was replaced for 20 min. The DCFH-DA was
oxidized to DCF by ROS. After washing 3 times, observations were
carried out under an inverted fluorescence microscope at 488 nm
and 525 nm.
2.13. Statistical analysis
All experiments were performed with at least three indepen-
dent replications, and data were expressed as means ± SDs. Com-
parisons were analyzed using one-way variance analysis (ANOVA).
*p < 0.05 and ***p < 0.001 were considered to be statistically
significant.
M. Cai, B. Ni, X. Hu et al.
3. Results
3.1. Synthesis and characterization
The synthesized IRMOF-16 was obtained according to the rapid
precipitation method and characterized by SEM, TEM, XRD, FTIR,
TGA, and DLS [34]. The SEM and TEM image shows the synthesized
IRMOF-16 were smooth and spherical (Fig. 1a and c). The FTIR
image (Fig. 2d) indicates that IRMOF-16 was successfully synthe-
sized. The absorption peaks are at 826 cm1 and 749 cm1, which
are caused by different types of CeH bonds in the phenyl group that
demonstrate the presence of terphenyl-4,400 -dicarboxylic acid and
the formation of the structural framework of IRMOF-16 [35]. The
peak at 522 cm1 is the absorption peak of the ZneO bond in the
Zn4O tetrahedral metal cluster [36]. The peaks at 1700e1380 cm1
are mainly characteristic CeO vibration peaks. The CeO vibration
peaks of the carboxylic acid functional groups are mainly located in
this region. The peak at 1590 cm1 is the asymmetric stretching
vibration of the COO bond in terphenyl-4,400 -dicarboxylic acid,
while the peak at 1394 cm1 is the symmetric stretching vibration.
The CeO bond of the carboxyl group on terphenyl-4,400 -dicarbox-
ylic acid is not broken, and the carboxyl group is bridged with the
metal cluster. The wide peak at 3500 cm1 indicates the presence of
a small amount of weakly bound water in the material [13]. In
Fig. 1. (a) SEM image of IRMOF-16; (b) SEM image of CUR@IRMOF-16; (c) TEM image of IRMOF-16; (d) TEM image of CUR@IRMOF-16.
4
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
addition, the peak at 2200 cm1 may be contributed by NeC]O in
the residual DMF. The XRD pattern of IRMOF-16 was compared
with the simulated PXRD pattern of an original IRMOF-16 crystal
[37]. As shown in Fig. 2a, the peak positions of the synthesized
IRMOF-16 are in general agreement with the simulated pattern of
IRMOF-16 [37]. The FTIR and XRD results indicated that IRMOF-16
was successfully synthesized. The TGA curve of IRMOF-16 is
shown in Fig. 2b. The small weight loss at about 100  C might be
caused by the evaporation of absorbed water in the skeleton [38].
The weight loss of the skeleton was obvious when the temperature
was around 300  C, indicating that IRMOF-16 could maintain the
framework structure and had good thermal stability below 300  C.
It can be observed from Fig. S1a that the particle size of IRMOF-16 is
about 284.6 nm, which is consistent with the SEM result. The sharp
peak reveals that the particle size of IRMOF-16 is relatively
concentrated, which indicates that the synthesized IRMOF-16 has a
small particle size difference and is suitable for drug loading
experiments. Fig. 2c shows the result of the N2
adsorptionedesorption experiment of IRMOF-16. The Bru-
nauereEmmetteTeller (BET) surface area of IRMOF-16 is 94.15 m2/
g, and the total volume in pores is 0.162 cm3/g with a pore diameter
of 6.495 nm. The results show that the synthesized IRMOF-16 has a
nanoporous structure, which also proves that IRMOF-16 is suitable
for subsequent experiments.
M. Cai, B. Ni, X. Hu et al. Journal of Science: Advanced Materials and Devices 7 (2022) 100507

Fig. 2. (a) XRD patterns of IRMOF-16 and IRMOF-16 (simulation); (b) thermogravimetric (TG) analysis of IRMOF-16, CUR, and CUR@IRMOF-16; (c) BET isotherm of IRMOF-16 and
CUR@IRMOF-16 at 77 K by N2; (d) FTIR spectra of CUR, IRMOF-16, and CUR@IRMOF-16.

3.2. Drug loading
According to the results of the orthogonal experiment, the
optimal drug loading conditions were as follows: the drug loading
time was 6 h, the weight ratio of IRMOF-16 to CUR was 2:3, and the
concentration of CUR was 3 mg/mL. Under these conditions, the DLC
reached 65.67%, and the DLE reached 43.78% (Tables S2eS4). And the
CUR@IRMOF-16 obtained under this condition has good reproduc-
ibility (Table S5). The high drug loading capacity may be attributed to
the large pore size of IRMOF-16 and the high affinity of CUR and
IRMOF-16 [39,40]. Then, CUR@IRMOF-16 was characterized by SEM,
TEM, DLS, FTIR, and DTG. The nanoparticles remained spherical with
little change in particle size (Fig. 1b and d). And the DLS proved the
particle size of CUR@IRMOF-16 was 288.3 nm (Fig. S1b). Fig. 2d
shows the FT-IR spectra of IRMOF-16, CUR, and CUR@IRMOF-16. In
the FT-IR spectrum of IRMOF-16, the characteristic peaks at
1590 cm1 and 1394 cm1 indicate that the COOH group of tri-
phenyl-4,400 -dicarboxylic acid is deprotonated upon reaction with
metal ions [41]. In the spectrum of CUR, the band at 3510 cm1
represents the OeH vibration of the phenolic group. Other charac-
teristic peaks of the CUR are found at 1630 cm1 (C]C vibration),
1602 cm1 (benzene ring stretching vibration), 1505 cm1 (C]O

Fig. 3. (a) Zeta potential of CUR and CUR@IRMOF-16; (b) drug release curve of CUR@IRMOF-16 in PBS containing 5% tween 80 at pH 7.4 and 5.5 (n ¼ 3, mean þ SD).

5
M. Cai, B. Ni, X. Hu et al. Journal of Science: Advanced Materials and Devices 7 (2022) 100507

vibration), 1429 cm1 (olefinic CeH bending vibrations), 1280 cm1
(aromatic CeO stretching vibrations), and 1029 cm1 (CeOeC
stretching vibrations) [13]. The spectral comparison of CUR@IRMOF-
16 and IRMOF-16 exhibits that the CUR@IRMOF-16 spectrum has
three signals at 1505 cm1, 1630 cm1, and 3530 cm1, corre-
sponding to the C]O, C]C, and OeH functional groups of CUR,
respectively. The FT-IR spectra results confirm the presence of CUR in
the CUR@IRMOF-16 sample. Moreover, due to several methanol
washings during the drug loading process, the residual DMF is also
removed, so there is no 2200 cm1 peak in CUR@IRMOF-16. There-
fore, the drug loading process is also regarded as killing two birds
with one stone, which can not only successfully load CUR into
IRMOF-16, but also further remove the residual organic reagents in
the material. As shown in Fig. 1b, IRMOF-16, CUR, and CUR@IRMOF-
16 have good thermal stability before 300  C. The weight losses of
IRMOF-16, CUR, and CUR@IRMOF-16 were 8%, 9%, and 6%,
respectively, at 100  C (Fig. S2). This may be related to the moisture
contained in MOFs and drugs. And there was a slight weight loss at
200  C, probably due to the volatilization of residual DMF. When it
exceeds 300  C, CUR begins to degrade with a large amount of
weight loss. The weight loss procedures of IRMOF-16 and
CUR@IRMOF-16 are relatively similar, indicating a loss of CUR crys-
tallinity in IRMOF-16 [42]. However, the decomposition rate of
CUR@IRMOF-16 was slower than that of CUR, which may be related
to the protective effect of IRMOF-16 on CUR. Liang et al. also
demonstrated the protective effect of ZIF-90 on the enzyme at high
temperature [43]. Liang et al. attributed this protective effect to MOF/
biointerface, which would greatly improve the activity and stability
of the drug [44]. After adsorb-ing CUR, the BET surface area of
CUR@IRMOF-16 was 34.0035 m2/g, and the total volume in pores
was 0.21201 cm3/g (Fig. 2a). Also, the z-potential values changed
from 5.99 to 6.38 mV after CUR loading (Fig. 3a). There is little

Table 1
The fitting curve of CUR@IRMOF-16 by different mathematical models under pH values of 7.4 and 5.5.

Model Equation (0e120 h) R2 (0e120 h) Equation (120e240 h) R2 (120e240 h)

pH ¼ 5.5 Zero-order kinetic equation Mt ¼ 0.03258 þ 0.12976t 0.99537 Mt ¼ 3.96229 þ 0.0925t 0.99078
First-order kinetic equation Mt ¼ 70.91282(1-e0.00201t) 0.99709 Mt ¼ 58.48983(1-e0.00244t) 0.99419
Higuchi equation Mt ¼ 1.65995t1/2 - 4.05712 0.97872 Mt ¼ 2.45341t1/2 - 12.09704 0.99417
RitgerePeppas equation ln(Mt) ¼ 0.95671lnt-1.38276 0.99069 ln(Mt) ¼ 0.79979lnt-1.12342 0.9928
pH ¼ 7.4 Zero-order kinetic equation Mt ¼ 0.00403 þ 0.17035t 0.9984 Mt ¼ 2.33912 þ 0.14988t 0.99063
First-order kinetic equation Mt ¼ 206.77841(1-e0.0008577t) 0.99871 Mt ¼ 189.17327(1-e0.0009394t) 0.99046
Higuchi equation Mt ¼ 2.17086t1/2 - 5.31217 0.97352 Mt ¼ 3.96667t1/2 - 23.56886 0.9889
RitgerePeppas equation ln(Mt) ¼ 0.98201lnt - 1.68884 0.99852 ln(Mt) ¼ 0.91717lnt - 1.27283 0.98927

Fig. 4. (a) Cytotoxicity study of IRMOF-16 on the HepG2 cells determined by MTT assay; (b) Cytotoxicity study of IRMOF-16 on the L02 cells determined by MTT assay; (c) Apoptosis
assays for HepG2 cells after treatment with IRMOF-16 for 24 h; (d) Fluorescent microscopic images of the DAPI-stained HepG2 cells following 24 h treatment with different
concentrations of IRMOF-16.

6
M. Cai, B. Ni, X. Hu et al.
difference in z-potential values before and after drug loading, which
proves that the drug is successfully loaded into the pores of MOFs.
Negative surface charges can prolong the circulation time of nano-
particles in vivo and avoid clearance by the reticuloendothelial sys-
tem (RES) [45].
3.3. In vitro drug release
To investigate the in vitro release performance of CUR@IRMOF-
16, two different pH values (pH 5.5 and pH 7.4) were selected. As
shown in Fig. 3b, CUR continued to be released within 240 h and
showed a pH-responsive drug release. CUR@IRMOF-16 NPs slowly
released CUR in PBS with a pH of 7.4, and the CUR released by the
system at the end of 240 h was less than 25%, which was beneficial
to avoid the dissipation of CUR before reaching the target. The
sustained release of CUR@IRMOF-16 was related to the encapsu-
lation of IRMOF-16 by shells that played a protective role around
the CUR. In addition, the sustained release of CUR was related to its
affinity with Zn ions.
The cumulative release rates of CUR@IRMOF-16 at different pH
values were fitted to the release equation to determine the release
characteristics. It can be seen that CUR@IRMOF-16 has an obvious
two-stage release behavior. The first stage is the initial release from
0 to about 120 h. Then, the shape of the release curve changes and
remains different from 120 to 240 h. Separate kinetic analyses were
performed using these two distinct time ranges, and the results are
shown in Table 1. The zero- and first-order kinetic equations describe
Fig. 5. (a) Cytotoxicity study of CUR on HepG2 cells determined by MTT assay; (b) cytotoxicity study of CUR on L02 cells determined by MTT assay; (c) cytotoxicity study of
CUR@IRMOF-16 on HepG2 cells determined by MTT assay; (d) cytotoxicity study of CUR@IRMOF-16 on L02 cells determined by MTT assay; *p < 0.05 and ***p < 0.01.
7
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
the in vitro release kinetics of the drug. At a pH of 5.5, CUR@IRMOF-
16 conformed to the first-order kinetic equation and exhibited a
sustained-release effect. At a pH of 7.4, CUR@IRMOF-16 conformed to
the first-order kinetic equations in the first stage (0e120 h) and the
zero-order kinetic equations in the second stage (120e240 h). The
Higuchi model is a model used to study the release mechanism. The
correlation coefficients of the Higuchi equation were less than 0.99,
indicating that there was a deviation in fitting the release behavior of
CUR@IRMOF-16 with this model [46]. The RitgerePappas model is a
model used to judge the matrix dissolution and drug diffusion
behavior during drug release [47]. The results show that the co-
efficients of lnt values of this model are greater than 0.89, indicating
that the in vitro drug release behavior of CUR@IRMOF-16 is mainly
caused by the dissolution of CUR@IRMOF-16. The ability of IRMOF-16
to load CUR is as high as 65.67%, and it can release CUR continuously
and is Ph-responsive; therefore, CUR@IRMOF-16 shows significant
advantages in tumor therapy [48].
3.4. The biosafety evaluation of IRMOF-16
The good biosafety of NPs was the basis for its application in the
treatment process. As shown in Fig. 4a, the survival rates of the
HepG2 cells incubated with IRMOF-16 for 24 and 48 h are both
greater than 85%, indicating that IRMOF-16 is nontoxic to HepG2
cells at a concentration range of 35 mg/mL. Similarly, IRMOF-16 was
safe and nontoxic to L02 cells at a concentration range of 35 ug/mL
(Fig. 4b). DAPI staining was used to observe the effect of IRMOF-16
M. Cai, B. Ni, X. Hu et al.
on the nucleus morphology. As shown in Fig. 4d, the nucleus
morphology of the HepG2 cells incubated with different concen-
trations of IRMOF-16 did not change significantly. To further verify
the biological safety of IRMOF-16, an apoptosis experiment was
carried out. A certain dose of IRMOF-16 did not induce apoptosis of
HepG2 cells, which proved the safety of IRMOF-16 once again
(Fig. 4c).
3.5. The cytotoxicity of CUR@IRMOF-16
The antitumor efficacy of CUR@IRMOF-16 in vitro was investi-
gated through the MTT experiment. The viability of HepG2 cells
incubated with CUR (Fig. 5a) or CUR@IRMOF-16 (Fig. 5c) was
significantly reduced. The toxicity of CUR and CUR@IRMOF-16 was
significantly enhanced with an increase in concentration and pro-
longed incubation time. Interestingly, the toxicity of CUR@IRMOF-
16 was greater than that of CUR within 24 h, which may have
been related to the enhanced cellular uptake of CUR@IRMOF-16 by
HepG2. However, the toxicity of CUR was greater than that of
CUR@IRMOF-16 within 48 h, which may have been due to the slow
release of CUR in CUR@IRMOF-16 after cellular uptake, and CUR
directly exerted an antitumor effect. This result indicates that
CUR@IRMOF-16 has the potential to sustain its efficacy in vivo. In
addition, we also demonstrated the toxicity of CUR and
CUR@IRMOF-16 to L02 cells (Fig. 5b and d). It was clearly observed
Fig. 6. (a) Reactive oxygen species assays for HepG2 cells after treatment with CUR and CUR@IRMOF-16; (b) cellular uptake assays for HepG2 cells after treatment with CUR and
CUR@IRMOF-16.
8
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
that CUR@IRMOF-16 had a higher survival rate compared to pure
CUR. This is related to the slow release of CUR in IRMOF-16.
3.6. Cellular uptake experiment
To study and determine the localization of CUR@IRMOF-16 in
HepG2 cells, the intracellular distribution of the nano platform was
analyzed by confocal laser microscopy. The intracellular fluores-
cence imaging results (Fig. 6a) presented that the intracellular
green fluorescence of CUR@IRMOF-16 is more obvious than that of
pure CUR, indicating that the cellular uptake of CUR@IRMOF-16 by
HepG2 cells is stronger. The translocation of CUR@IRMOF-16 in
HepG2 cells was significantly higher than that of CUR, possibly due
to the passive targeted delivery of nano IRMOF-16 [49]. In addition,
the green fluorescence is more distributed in the nucleus and
lysosome, indicating that nanoparticles could be localized to the
nucleus and lysosome to play an antitumor role.
3.7. Reactive oxygen species (ROS)
CUR was shown to be a compound with excellent antitumor
effect, which can effectively induce apoptosis of HepG2 cells by
elevating intracellular reactive oxygen species [50,51]. Thus, the
level of ROS was detected, and the results showed that
CUR@IRMOF-16 significantly increases intracellular ROS in HepG2
M. Cai, B. Ni, X. Hu et al.
(Fig. 6b). Similarly, CUR also induced the production of ROS in L02
cells, but the production of ROS in L02 cells by CUR@IRMOF-16 was
not obvious, which may be due to the increased uptake of
CUR@IRMOF-16 by HepG2 cells due to the enhanced permeability
and retention (EPR) effect. The lower production of ROS in L02 cells
by CUR@IRMOF-16 was also related to the sustained release of CUR,
while the EPR effect enhanced the uptake of nanoparticles by
HepG2 cells, so the production of ROS by CUR was greatly increased
in HepG2 cells. As shown in Fig. 6, the significant increase in green
fluorescence indicates a significant increase in intracellular ROS,
which may be related to the activation of the apoptotic pathway.
3.8. Cell apoptosis
The nucleus morphology was observed to further evaluate the
antitumor effect of CUR@IRMOF-16. Cells treated with CUR@IRMOF-
16 had strong nuclear fluorescence, accompanied by nuclear pyk-
nosis and rupture, which proved that CUR@IRMOF-16 might induce
apoptosis (Fig. 7a). The membrane potential of cells was further
tested to explore the effect of CUR@IRMOF-16 on mitochondria. As
shown in Fig. 7c, the enhanced green fluorescence and reduced red
fluorescence under the fluorescence microscope indicate that
mitochondrial membrane potential is decreased and the mitochon-
dria are damaged, which may be one possible way by which
CUR@IRMOF-16 induces apoptosis. Therefore, apoptosis experi-
ments were conducted to demonstrate the possible antitumor
mechanism of CUR@IRMOF-16. It was found that CUR@IRMOF-16
had the effect of inducing cell apoptosis and showed a
concentration-dependent effect at the same time (Fig. 5b).
Fig. 7. (a) fluorescent microscopic images of DAPI-stained HepG2 cells following 24 h treatment with CUR and CUR@IRMOF-16; (b) apoptosis assays for HepG2 cells after treatment
with CUR@IRMOF-16 for 24 h, **p < 0.05 and ***p < 0.01; (c) MMP assays for HepG2 cells after treatment with IRMOF-16, CUR, and CUR@IRMOF-16; *p < 0.05 and ***p < 0.01.
9
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
3.9. In vivo biodistribution
In vivo biodistribution was assessed by in vivo fluorescence
imaging using cy5.5-labeled CUR and cy5.5-CUR@IRMOF-16
(N ¼ 4). cy5.5-labeled CUR and cy5.5-CUR@IRMOF-16 showed
different biodistributions (Fig. 8a). Systemic accumulation was
observed in the cy5.5-labeled CUR group, especially in the liver,
which may be related to hepatic metabolism. The cy5.5-labeled
CUR@IRMOF-16 group showed a certain degree of tumor target-
ing within 1 h. The EPR effect enhanced the phagocytosis of the
nanosystem by tumor tissue. cy5.5-labeled CUR@IRMOF-16 mainly
accumulated in the tumor site from 12 h. In vitro fluorescence
imaging could be used to analyze drug retention in major organs
and tumors (Fig. 8b). cy5.5-labeled CUR is distributed in various
organs, and cy5.5-labeled CUR@IRMOF-16 is mainly distributed in
tumor sites. EPR effect and proton sponge effect resulted in stronger
accumulation of cy5.5-labeled CUR@IRMOF-16 in tumors.
4. Discussion
There are many studies on MOFs as antitumor drug delivery
vehicles [52,53]. To improve drug delivery efficiency, more and
more MOFs have been synthesized and reported [54,55]. Currently,
drug delivery strategies based on different principles have been
developed, including surface adsorption, pore encapsulation, co-
valent binding, and using functional molecules as building blocks
[56]. Tuning the organic ligands of MOFs is the most facile and
rey's group
effective way to tune their properties. In 2006, the Fe
conducted the first study of MOFs as drug delivery vehicles [57].
M. Cai, B. Ni, X. Hu et al.
Fig. 8. The biodistribution of different NPs. (a) In vivo biodistribution images of cy5.5-labeled CUR and CUR@IRMOF-16 at 1, 4, 8, 12 and 24 h, (b) fluorescence distribution images of
tumors and different organs 24 h after injection.
They used iron-based metaleorganic frameworks MIL-100 and
MIL-101 as porous matrices, and ibuprofen was used as a model
drug for drug delivery. Each gram of MIL-101 could load 1.376 g of
ibuprofen, which was significantly more than 0.347 g/g of MIL-100.
The difference in drug loading between the two was mainly due to
their different pore sizes, and both had good sustained-release ef-
fects [58].
According to previous studies, IRMOF-1 has been used as a
drug delivery carrier with CUR. When a MOF has been modu-
lated by introducing a functional group into the structure, the
drug loading capacity has been higher than that of IRMOF-1 [14].
Studies on the influence of pore size on MOFs have been inspired
by this result. In this work, we synthesized IRMOF-16, which had
the same topology as IRMOF-1. In order to avoid other factors
affecting drug delivery as much as possible, IRMOF-16 was syn-
thesized with full reference to the synthesis method of IRMOF-1
[14]. IRMOF-16 was successfully synthesized with a drug loading
capacity of 65.67%. The synthesized IRMOF-16 is a mesoporous
material; that is, the pore size is in the range of 2e50 nm. As a
mesoporous material, IRMOF-16 has a relatively large specific
surface area and large pore size, which is more conducive to
transporting reactants or solvents and is also conducive to the
loading and release of drugs. Micro and macroporous materials
have different properties than mesoporous materials. The more
micropores, the larger the specific surface area and the stronger
10
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
the adsorption performance, but the smaller the pore size, the
longer the void space, which is not conducive to the diffusion of
reactants. Macropores are too large for common reactants or
solvents but facilitate the exposure of other pores. In the follow-
up, the research scope of pore size is further expanded, and the
corresponding drug loading laws of materials with different pore
size types are discussed. The large specific surface area provides
more active sites for the adsorption of CUR. This work indicated
that it was feasible to match the structure by changing pore size
using different organic ligands. In this study, the drug delivery
system was constructed using IRMOF-16 as the carrier for the
first time. The high drug loading capacity of IRMOF-16 carrying
CUR was due to its excellent BET surface area (94.15 m2/g) and
the large volume in pores (0.162 cm3/g). Dang et al. compared
the adsorption of different MOFs to CUR and found it was
obvious that without the effects of substituent incorporation, the
MOFs with the higher surface area could load more CUR [13].
The high drug loading capacity of IRMOF-16 for CUR is also
related to its high affinity for CUR. There is a b-diketone functional
group in the CUR structure, and its 1,3-diketone can be automati-
cally converted into a tautomeric form of ketoeenol, while
ketoeenol is more stable and can easily chelate metal ions such as
Zn2þ and Cu2þ [39]. Xing et al. [40] prepared nanoparticles by
utilizing the chelation between CUR and Zn2þ, which was more
easily released under acidic conditions due to the acid-labile
M. Cai, B. Ni, X. Hu et al.
coordination bond of Zn(II)eO. However, this strategy is limited in
the packet-carrying capacity of CUR. The use of MOFs for CUR de-
livery still shows great appeal.
It was amazing that the CUR was stably released even after
160 h, which showed the excellent slow-release feature of
CUR@IRMOF-16. CUR@IRMOF-16 could release more CUR under a
pH of 5.5. The pH-responsive drug delivery system showed its
advantage for tumor treatment. To save time and cost, we only
conducted a 240-h re-lease experiment. The percentage of total
drug release did not reach 80% at 240 h; the drug may have been
located inside some micropores that needed more time [46]. Due to
the complex action of CUR and zinc ion center, CUR@IRMOFs can be
released slowly at a constant speed, and the release time can last for
more than 10 days. Pore adsorption, surface adsorption, p-p
conjugation, and electrostatic adsorption can occur between MOFs
and CUR. Various forces have a significant influence on the loading
capacity and release rate of CUR. In addition, the structure and
properties of MOFs also have certain effects on their drug delivery
behavior, such as porosity, functionalization, size, crystallinity, and
surface charge. In order to reduce administration frequency,
improve patient compliance, and reduce side effects, drugs are
often designed as sustained-release preparations. Boi et al. [59]
designed and developed alginate microspheres for loading adria-
mycin to control its release rate and reduce its toxicity. Meng et al.
[60] designed and developed a quaternized pectin montmorillonite
composite membrane to delay the release of 5-Fu, which could
improve the problem of frequent drug administration caused by
short half-life.
As novel drug delivery vehicles, the biosafety of MOFs deserves
attention. In recent years, numerous studies have reported on the
biosafety of MOFs in vitro and in vivo [61e66], which have indi-
cated that they have good biosafety at a certain dose. In the MTT,
DAPI staining, and the cell apoptosis assays, IRMOF-16 showed
great biocompatibility since it did not affect the nucleus
morphology or induce apoptosis. After comprehensive testing for
IRMOF-16, the safe dose of IRMOF-16 for HepG2 cells reached
35 mg/mL. As compared with other biological materials, the safe
concentration of IRMOF-16 is lower. However, in vitro pharmaco-
dynamic tests found that CUR@IRMOF-16 could exert a good anti-
tumor effect within the safe concentration range. As compared
with pure CUR, the toxicity of CUR@IRMOF-16 decreased in the
same time frame, which was attributed to sustained-release
properties of IRMOF-16.
In this study, we synthesized IRMOF-16 and successfully ob-
tained CUR@IRMOF-16. IRMOF-16 has great biodegradability and
could load more CUR than other MOFs [13,14]. Researchers can
design more drug delivery systems based on IRMOF-16.
5. Conclusions
We designed a new multifunctional drug delivery system, i.e.,
CUR@IRMOF-16, to enhance antitumor efficiency by enhancing
cellular uptake and inducing apoptosis. The in vitro drug release
results showed that CUR@IRMOF-16 had sustained-release ca-
pacity over 10 days and exhibited pH sensitivity. The experimental
cytotoxicity results indicated that CUR@IRMOF-16 had good
antitumor activity. CUR@IRMOF-16 showed good intracellular
uptake and nuclear localization in the fluorescence imaging
analysis. Through the apoptosis experiment, it was found that
CUR@IRMOF-16 induced tumor cell apoptosis by promoting a
decrease in mitochondrial membrane potential. However, the
antitumor mechanism of CUR@IRMOF-16 needs to be further
verified, and the in vivo antitumor effects of the drug delivery
system should also be studied in further works in more detail.
11
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
Funding
This research was funded by the Fundamental Research Funds
for the Central Universities (No. 2020-JYB-ZDGG-046), the Beijing
Natural Science Foundation (No. 7202121), and the National Nat-
ural Science Foundation of China (No. 81703715), Young Elite Sci-
entists Sponsorship Program by CACM (CACM-QNRC2-A03).
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jsamd.2022.100507.
References
[1] O. Yaghi, G. Li, H. Li, Selective binding and removal of guests in a microporous
metal-organic framework, Nature, 378 (1995) 703e706, https://doi.org/
10.1038/378703a0.
[2] Joseph Della Rocca, Demin Liu, Wenbin Lin, Nanoscale metal-organic frame-
works for biomedical imaging and drug delivery, Acc. Chem. Res. 44 (2011)
957e968, https://doi.org/10.1021/ar200028a.
[3] J. Gandara-Loe, B.E. Souza, A. Missyul, G. Giraldo, J.C. Tan, J. Silvestre-Albero,
MOF-based polymeric nanocomposite films as potential materials for drug
delivery devices in ocular therapeutics, ACS Appl. Mater. Interfaces 12 (2020)
30189e30197, https://doi.org/10.1021/acsami.0c07517.
[4] Aba nades Lazaro Isabel, C.J.R. Wells, R.S. Forgan, Multivariate modulation of
the Zr MOF UiO-66 for defect-controlled combination anticancer drug de-
livery, Angew. Chem., Int. Ed. 59 (2020) 5211e5217, https://doi.org/10.1002/
anie.201915848.
[5] Xiaoti Yang, Tang Qiao, Ying Jiang, Meining Zhang, Ming Wang, Lanqun Mao,
Nanoscale ATP-responsive zeolitic imidazole framework-90 as a general
platform for cytosolic protein delivery and genome editing, J. Am. Chem. Soc.
141 (2019) 3782e3786, https://doi.org/10.1021/jacs.8b11996.
[6] C. Orellana-Tavra, M. Ko €ppen, A. Li, N. Stock, D. Fairen-Jimenez, Biocompatible,
crystalline, amorphous bismuth-based metal-organic frameworks for drug
delivery, ACS Appl. Mater. Interfaces 12 (2020) 5633e5641, https://doi.org/
10.1021/acsami.9b21692.
[7] Zehan Mai, Dingxin Liu, Synthesis and applications of isoreticular metal-
organic frameworks IRMOFs-n (n ¼ 1, 3, 6, 8), Cryst. Growth Des. 19 (2019)
7439e7462, https://doi.org/10.1021/acs.cgd.9b00879.
[8] H. Li, M. Eddaoudi, M. OM Yaghi O'Keeffe, Design and synthesis of an
exceptionally stable and highly porous metal-organic framework, Nature 402
(1999) 276e279, https://doi.org/10.1038/46248.
[9] D. Saha, Z. Bao, F. Jia, S. Deng, Adsorption of CO(2), CH(4), N(2)O, and N(2) on
MOF-5, MOF-177, and zeolite 5A, Environ. Sci. Technol. 44 (2010) 1820e1826,
https://doi.org/10.1021/es9032309.
[10] Steven S. Kaye, Anne Dailly, Omar M. Yaghi, Jeffrey R. Long, Impact of prep-
aration and handling on the hydrogen storage properties of Zn4O(1,4-
benzenedicarboxylate)3 (MOF-5), J. Am. Chem. Soc. 129 (2007)
14176e14177, https://doi.org/10.1021/ja076877g.
[11] H. Furukawa, K.E. Cordova, M. O'Keeffe, O.M. Yaghi, The chemistry and ap-
plications of metal-organic frameworks, Science 341 (2013), 1230444, https://
doi.org/10.1126/science.1230444.
[12] R.C. Alves, Z.M. Schulte, M.T. Luiz, P. Bento da Silva, R.C.G. Frem, N.L. Rosi, M.
Chorilli, Breast cancer targeting of a drug delivery system through post-
synthetic modification of curcumin@N3-bio-MOF-100 via click chemistry,
Inorg. Chem. 60 (2021) 11739e11744, https://doi.org/10.1021/acs.inorgchem.
1c00538.
[13] Y Thi Dang, Minh-Huy Dinh Dang, Ngoc Xuan Dat Mai, Linh Ho Thuy Nguyen,
Thang Bach Phan, Hai Viet Le, Tan Le Hoang Doan, Room temperature syn-
thesis of biocompatible nano Zn-MOF for the rapid and selective adsorption of
curcumin, J. Sci.: Adv. Mater. Devices 5 (2020) 560e565, https://doi.org/
10.1016/j.jsamd.2020.09.009.
[14] M. Cai, L. Qin, L. Pang, B. Ma, J. Bai, J. Liu, X. Dong, X. Yin, J. Ni, Amino-func-
tionalized Zn metal-organic frameworks as antitumor drug curcumin carriers,
New J. Chem. 44 (2020) 17693e17704, https://doi.org/10.1039/D0NJ03680C.
[15] R.K. Alavijeh, K. Akhbari, Biocompatible MIL-101(Fe) as a smart carrier with
high Loa1ding potential and sustained release of curcumin, Inorg. Chem. 59
(2020) 3570e3578, https://doi.org/10.1021/acs.inorgchem.9b02756.
[16] Yamil J. Colon, Rajamani Krishna, Randall Q. Snurr, Strong influence of the H2
binding energy on the MaxwelleStefan diffusivity in NU-100, UiO-68, and
M. Cai, B. Ni, X. Hu et al.
IRMOF-16, Microporous Mesoporous Mater 185 (2014) 190e196, https://
doi.org/10.1016/j.micromeso.2013.10.031.
[17] Ege Dundar, Justyna Rogacka, Lucyna Firlej, Carlos Wexler, Philip Llewellyn,
Boulet Pascal, Bogdan Kuchta, Low-temperature mechanism of adsorption of
methane: comparison between homogenous and heterogeneous pores, Col-
loids Surf 496 (2016) 86e93, https://doi.org/10.1016/j.colsurfa.2015.11.063.
[18] Stephen K. Brand, Yamil J. Colo  n, Rachel B. Getman, Randall Q. Snurr, Design
strategies for metal alkoxide functionalized metal-organic frameworks for
ambient temperature hydrogen storage, Microporous Mesoporous Mater 171
(2013) 103e109, https://doi.org/10.1016/j.micromeso.2012.12.020.
[19] Marianna Kotzabasaki, Emmanuel Tylianakis, Emmanuel Klontzas, George
E. Froudakis, OH-functionalization strategy in Metal-Organic Frameworks for
drug delivery, Chem. Phys. Lett. 685 (2017) 114e118, https://doi.org/10.1016/
j.cplett.2017.07.053.
[20] E.N. Koukaras, T. Montagnon, P. Trikalitis, Dimitrios Bikiaris, Aristides
D. Zdetsis, George E. Froudakis, Toward efficient drug delivery through suit-
ably prepared metal-organic frameworks: a first-principles study, J. Phys.
Chem. C 118 (2014) 8885e8890, https://doi.org/10.1021/jp410282m.
[21] S. Mura, J. Nicolas, P. Couvreur, Stimuli-responsive nanocarriers for drug de-
livery, Nat. Mater. 12 (2013) 991e1003, https://doi.org/10.1038/nmat3776.
[22] W.K. Kim, Y. Pyee, H.J. Chung, H.J. Park, J.Y. Hong, K.H. Son, S.K. Lee, Antitumor
activity of spicatoside A by modulation of autophagy and apoptosis in human
colorectal cancer cells, J. Nat. Prod. 79 (2016) 1097e1104, https://doi.org/
10.1021/acs.jnatprod.6b00006.
[23] S. Li, C. Zhang, W. Cao, B. Ma, X. Ma, S. Jin, J. Zhang, P.C. Wang, F. Li, X.-J. Liang,
Anchoring effects of surface chemistry on gold nanorods: modulating auto-
phagy, J. Math. Chem. B 3 (2015) 3324e3330, https://doi.org/10.1039/
C5TB00076A.
[24] B. Joe, M. Vijaykumar, B. Lokesh, Biological properties of curcumin-cellular
and molecular mechanisms of action, Crit. Rev. Food Sci. Nutr. 44 (2004)
97e111, https://doi.org/10.1080/10408690490424702.
[25] A. Giordano, G. Tommonaro, Curcumin and cancer, Nutrients 11 (2019) 2376,
https://doi.org/10.3390/nu11102376.
[26] A.S.S.R.A. Sharma, Curcumin: preventive and therapeutic properties in labo-
ratory studies and clinical trials, Antioxid. Redox Signaling 10 (2008)
511e545, https://doi.org/10.1089/ars.2007.1769.
[27] T. Feng, Y. Wei, R.J. Lee, L. Zhao, Liposomal curcumin and its application in
cancer, Int. J. Nanomed. 12 (2017) 6027e6044, https://doi.org/10.2147/
IJN.S132434.
[28] H. Liang, X. Sun, J. Gao, B. Zhou, Chitosan coordination driven self-assembly
for effective delivery of curcumin, Int. J. Biol. Macromol. 165 (2020)
2267e2274, https://doi.org/10.1016/j.ijbiomac.2020.10.097.
[29] Z. Li, Q. Lin, D.J. McClements, Y. Fu, H. Xie, T. Li, G. Chen, Curcumin-loaded
core-shell biopolymer nanoparticles produced by the pH-driven method:
physicochemical and release properties, Food Chem 355 (2021), 129686,
https://doi.org/10.1016/j.foodchem.2021.129686.
[30] L.M. Lim, K. Hadinoto, High-payload buccal delivery system of amorphous
curcumin-chitosan nanoparticle complex in hydroxypropyl methylcellulose
and starch films, Int. J. Mol. Sci. 22 (2021) 9399, https://doi.org/10.3390/
ijms22179399.
[31] N. Liu, Y. Lu, Y. Zhang, Y. Gao, L. Mao, Surfactant addition to modify the
structures of ethylcellulose oleogels for higher solubility and stability of
curcumin, Int. J. Biol. Macromol. 165 (2020) 2286e2294, https://doi.org/
10.1016/j.ijbiomac.2020.10.115.
[32] L. Huang, H. Wang, J. Chen, Z. Wang, J. Sun, D. Zhao, Y. Yan, Synthesis,
morphology control, and properties of porous metal-organic coordination
polymers, Microporous Mesoporous Mater 58 (2003) 105e114, https://
doi.org/10.1016/S1387-1811(02)00609-1.
[33] Hong Dong, Yang Gui-Xin, Xin Zhang, Xiang-Bin Meng, Sheng Jing-Li, Xiao-
Jun Sun, Feng Yu-Jie, Fengming Zhang, Folic acidfunctionalized Zr-based
metal-organic frameworks as drug carriers for active tumor-targeted, Chem.
Eur J. 24 (2018) 17148e17154, https://doi.org/10.1002/chem.201804153.
[34] Mengru Cai, Wulin Liang, Kaixin Wang, Dongge Yin, Tingting Fu, Rongyue Zhu,
Changhai Qu, Xiaoxv Dong, Jian Ni, Xingbin Yin, Aperture modulation of
isoreticular metal organic frameworks for targeted antitumor drug delivery,
ACS Appl. Mater 14 (2022) 36366e36378, https://doi.org/10.1021/acsami.
2c07450.
[35] Sami Ullaha, Mohamad Azmi Bustamb, Mohammed Ali Assiria, G. Abdullah,
A. Al-Sehemia Firas, Abdul Kareemc, Mukhtarb Ahmad, Muhammad Ayoubb,
Girma Gonfad, Synthesis and characterization of iso-reticular metal-organic
Framework-3 (IRMOF-3) for CO2/CH4 adsorption: impact of post-synthetic
aminomethyl propanol (AMP) functionalization, J. Nat. Gas Sci. Eng. 72
(2019), 103014, https://doi.org/10.1016/j.jngse.2019.103014.
[36] Mengru Cai, Liuying Qin, Longtai You, Functionalization of MOF-5 with mono-
substituents: effects on drug delivery behavior, RSC Adv 10 (2020)
36862e36872, https://doi.org/10.1039/d0ra06106a.
[37] David Dubbeldam Youn-Sang Bae, Andrew Nelson, Krista S. Walton, Joseph
T. Hupp, Randall Q. Snurr, Strategies for characterization of large-pore metal-
organic frameworks by combined experimental and computational methods,
Chem. Mater. 21 (2009) 4768e4777, https://doi.org/10.1021/cm803218f.
[38] G.a Chen, X.a Leng, J.a Luo, L.a You, C.a Qu, X.a Dong, H.c,d Huang, X.a Yin,
J.a,b. Ni, In vitro toxicity study of a porous iron(III) metal-organic framework,
Molecules 24 (2019) 1211, https://doi.org/10.3390/molecules24071211.
[39] Xue-Zhou Zhao, Teng Jiang, Long Wang, Hao Yang, Sui Zhang, Ping Zhou,
Interaction of curcumin with Zn(II) and Cu(II) ions based on experiment and
12
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
theoretical calculation, J. Mol. Struct. 984 (2010) 316e325, https://doi.org/
10.1016/j.molstruc.2010.09.049.
[40] Z.H. Xing, J.H. Wei, T.Y. Cheang, Z.R. Wang, X. Zhou, S.S. Wang, W. Chen,
S.M. Wang, J.H. Luo, A.W. Xu, Bifunctional pH-sensitive Zn(ii)-curcumin
nanoparticles/siRNA effectively inhibit growth of human bladder cancer cells
in vitro and in vivo, J. Mater. Chem. B 2 (2014) 2714e2724, https://doi.org/
10.1039/c3tb21625j.
[41] S. Wu, X. Ma, J. Ran, Y. Zhang, F. Qin, Y. Liu, Application of basic isoreticular
nanoporous metal-organic framework: IRMOF-3 as a suitable and efficient
catalyst for the synthesis of chalcone, RSC Adv 5 (2015) 14221e14227,
https://doi.org/10.1039/C4RA16180G.
[42] X. Leng, X. Dong, W. Wang, N. Sai, C. Yang, L. You, H. Huang, X. Yin, J. Ni,
Biocompatible Fe-based micropore metal-organic frameworks as sustained-
release anticancer drug carriers, Molecules 23 (2018) 2490, https://doi.org/
10.3390/molecules23102490.
[43] W. Liang, H. Xu, F. Carraro, N.K. Maddigan, Q. Li, S.G. Bell, D.M. Huang,
A. Tarzia, M.B. Solomon, H. Amenitsch, L. Vaccari, C.J. Sumby, P. Falcaro,
C.J. Doonan, Enhanced activity of enzymes encapsulated in hydrophilic metal-
organic frameworks, J. Am. Chem. Soc. 141 (2019) 2348e2355, https://doi.org/
10.1021/jacs.8b10302.
[44] W. Liang, P. Wied, F. Carraro, C.J. Sumby, B. Nidetzky, C.K. Tsung, P. Falcaro,
C.J. Doonan, Metal-organic framework-based enzyme biocomposites,
Chem. Rev. 121 (2021) 1077e1129, https://doi.org/10.1021/acs.chemrev.
0c01029.
[45] T. Xu, Y. Ma, Q. Yuan, H. Hu, X. Hu, Z. Qian, J.K. Rolle, Y. Gu, S. Li, Enhanced
ferroptosis by oxygen-boosted phototherapy based on a 2-in-1 nanoplatform
of ferrous hemoglobin for tumor synergistic therapy, ACS Nano 14 (2020)
3414e3425, https://doi.org/10.1021/acsnano.9b09426.
[46] G. Chen, J. Luo, M. Cai, L. Qin, Y. Wang, L. Gao, P. Huang, Y. Yu, Y. Ding, X. Dong,
X. Yin, J. Ni, Investigation of metal-organic framework-5 (MOF-5) as an anti-
tumor drug oridonin sustained release carrier, Molecules 24 (2019) 3369,
https://doi.org/10.3390/molecules24183369.
[47] Philip L. Ritger, A. Nikolaos, Peppas, A simple equation for description of so-
lute release I. Fickian and non-fickian release from non-swellable devices in
the form of slabs, spheres, cylinders or discs, J. Contr. Release 5 (1987) 23e36,
https://doi.org/10.1016/0168-3659(87)90034-4.
[48] R.A. Petros, J.M. Desimone, Strategies in the design of nanoparticles for
therapeutic applications, Nat. Rev. Drug Discov. 9 (2010) 615e627, https://
doi.org/10.1038/nrd2591.
[49] E. Linnane, S. Haddad, F. Melle, Z. Mei, D. Fairen-Jimenez, The uptake of metal-
organic frameworks: a journey into the cell, Chem. Soc. Rev. 51 (2022)
6065e6086, https://doi.org/10.1039/d0cs01414a.
[50] W.F. Liang, Y.X. Gong, H.F. Li, F.L. Sun, W.L. Li, D.Q. Chen, D.P. Xie, C.X. Ren,
X.Y. Guo, Z.Y. Wang, T. Kwon, H.N. Sun, Curcumin activates ROS signaling to
promote pyroptosis in hepatocellular carcinoma HepG2 cells, In Vivo 35
(2021) 249e257, https://doi.org/10.21873/invivo.12253.
[51] J. Cao, L.P. Jiang, Y. Liu, G. Yang, X.F. Yao, L.F. Zhong, Curcumin-induced gen-
otoxicity and antigenotoxicity in HepG2 cells, Toxicon 49 (2007) 1219e1222,
https://doi.org/10.1016/j.toxicon.2007.02.006.
[52] C. He, D. Liu, W. Lin, Nanomedicine applications of hybrid nanomaterials built
from metal-ligand coordination bonds: nanoscale metal-organic frameworks
and nanoscale coordination polymers, Chem. Rev. 115 (2015) 11079e11108,
https://doi.org/10.1021/acs.chemrev.5b00125.
[53] Jinyue Zeng, Xiaoshuang Wang, Xianzheng Zhang, Zhuo Renxi, Research
progress in functional metal-organic frameworks for tumor therapy, Huaxue
Xuebao 77 (2019) 1156e1163, https://doi.org/10.6023/A19070259.
[54] R.S. Forgan, The surface chemistry of metal-organic frameworks and their
applications, Dalton Trans 48 (2019) 9037e9042, https://doi.org/10.1039/
c9dt01710k.
[55] T. Simon-Yarza, A. Mielcarek, P. Couvreur, C. Serre, Nanoparticles of metal-
organic frameworks: on the road to in vivo efficacy in biomedicine, Adv.
Mater. 30 (2018), e1707365, https://doi.org/10.1002/adma.201707365.
[56] W. Xu, Y. Kang, L. Jiao, Y. Wu, H. Yan, J. Li, W. Gu, W. Song, C. Zhu, Tuning
atomically dispersed Fe sites in metal-organic frameworks boosts peroxidase-
like activity for sensitive biosensing, Nano-Micro Lett. 12 (2020) 184, https://
doi.org/10.1007/s40820-020-00520-3.
[57] P. Horcajada, C. Serre, M. Vallet-Regí, M. Sebban, F. Taulelle, G. Fe rey, Metal-
organic frameworks as efficient materials for drug delivery, Angew Chem. Int.
Ed. Engl. 45 (2006) 5974e5978, https://doi.org/10.1002/anie.200601878.
[58] M. AL Haydar, H.R. Abid, B. Sunderland, S. Wang, Metal-organic frameworks as
a drug delivery system for flurbiprofen, Drug Des. Dev. Ther. 11 (2017)
2685e2695, https://doi.org/10.2147/DDDT.S145716.
[59] S. Boi, N. Rouatbi, E. Dellacasa, D. Di Lisa, P. Bianchini, O. Monticelli,
L. Pastorino, Alginate microbeads with internal microvoids for the sustained
release of drugs, Int. J. Biol. Macromol. 156 (2020) 454e461, https://doi.org/
10.1016/j.ijbiomac.2020.04.083.
[60] Y.J. Meng, S.Y. Wang, Z.W. Guo, M.M. Cheng, J. Li, D.Q. Li, Design and prepa-
ration of quaternized pectin-Montmorillonite hybrid film for sustained drug
release, Int. J. Biol. Macromol. 154 (2020) 413e420, https://doi.org/10.1016/
j.ijbiomac.2020.03.140.
[61] H. Zhang, W. Jiang, R. Liu, J. Zhang, D. Zhang, Z. Li, Y. Luan, Rational design of
metal-organic framework nanocarrier-based codelivery system of doxoru-
bicin hydrochloride/verapamil hydrochloride for overcoming multidrug
resistance with efficient targeted cancer therapy, ACS Appl. Mater. Interfaces 9
(2017) 19687e19697, https://doi.org/10.1021/acsami.7b05142.
M. Cai, B. Ni, X. Hu et al.
[62] D. Hu, H. Xu, B. Xiao, D. Li, Z. Zhou, X. Liu, J. Tang, Y. Shen, Albumin-stabilized
metal-organic nanoparticles for effective delivery of metal complex anti-
cancer drugs, ACS Appl. Mater. Interfaces 10 (2018) 34974e34982, https://
doi.org/10.1021/acsami.8b12812.
[63] M.D. Rowe, D.H. Thamm, S.L. Kraft, S.G. Boyes, Polymer-modified gado-
linium metal-organic framework nanoparticles used as multifunctional
nanomedicines for the targeted imaging and treatment of cancer, Bio-
macromolecules 10 (2009) 983e993, https://doi.org/10.1021/bm9
00043e.
[64] J. Park, Q. Jiang, D. Feng, L. Mao, H.C. Zhou, Size-controlled synthesis of por-
phyrinic metal-organic framework and functionalization for targeted
13
Journal of Science: Advanced Materials and Devices 7 (2022) 100507
photodynamic therapy, J. Am. Chem. Soc. 138 (2016) 3518e3525, https://
doi.org/10.1021/jacs.6b00007.
[65] Dipranjan Laha, Kunal Pal, Angshuman Ray Chowdhuri, Pravat Kumar Parida,
Sumanta Kumar Sahu, Kuladip Jana, Parimal Karmakar, Fabrication of
curcumin-loaded folic acid-tagged metal-organic framework for triple-
negative breast cancer therapy in in vitro and in vivo systems, New J.
Chem. 43 (2019) 217e229, https://doi.org/10.1039/C8NJ03350A.
[66] S.Y. Li, B.R. Xie, H. Cheng, C.X. Li, M.K. Zhang, W.X. Qiu, W.L. Liu, X.S. Wang,
X.Z. Zhang, A biomimetic theranostic O2-meter for cancer-targeted photo-
dynamic therapy and phosphorescence imaging, Biomaterials 151 (2018)
1e12, https://doi.org/10.1016/j.biomaterials.2017.10.021.