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Biocompatible MIL-101(Fe) as a Smart Carrier with High Loading

Potential and Sustained Release of Curcumin
Roya Karimi Alavijeh and Kamran Akhbari*
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ABSTRACT: The purpose of this study was the investigation of the potential of MIL-101(Fe) for load and sustained release of
curcumin (CCM), as an anticancer drug, with pH stimulus. The reasons for choosing this type of metal−organic framework (MOF)
are its high surface area, acceptable stability in a water medium, and its biocompatible components (iron and terephthalic acid) with
low toxicity to normal cells. The obtained results from UV−vis analysis confirmed that this MOF is a smart carrier with a higher
release rate in acidic pH (pH 5), which is a condition similar to that in cancer cells, than that at pH 7.4 (in normal cells). Therefore,
this MOF is a pH-stimulus-controlled release carrier with 56.3% drug loading content and sustained drug release over 22 days. In
order to evaluate the cell viability after treatment with free CCM, MIL-101(Fe), and MIL-101(Fe)@CCM, the cytotoxicity
investigation using MTT assays was performed against HeLa and HEK 293 cell lines up to 48 h. Obtained results showed that MIL-
101(Fe)@CCM exhibited more cell growth inhibition effect on HeLa cells in comparison with HEK 293. One of the reasons for the
high loading and sustained release of CCM was surface adsorption of this drug and its interactions with open metal sites in MIL-
101(Fe). In the end, the kinetic models of drug release were evaluated, and the obtained results showed that in this case diffusion is
the main driving force for the drug release process.

1. INTRODUCTION their high stability. Therefore, it is difficult to degrade and

One of the leading causes of death in the world is cancer. The
main problems for overcoming this issue are poor delivery of
cancer therapeutics and their inadequate distribution in tumor
cells. A promising strategy to address this challenge is the use
of nanocarriers because they can increase drug circulation
times and improve the safety profile.1 In recent years,
pharmaceutical industries are focusing on the application of
sustained-release formulations that include any drug delivery
system with the ability to slow release of drug molecules over
an extended period. These systems lead to reduced side
effects.2 There are many organic and inorganic compounds
which are candidates for use as drug delivery systems (DDS)
such as nanoemulsions,3 hydrogels,4 micelles,5 liposomes,6 and
mesoporous silica.7 These candidates have both advantages
and some drawbacks. For example, organic carriers are
biocompatible, but in some cases their loading capacities are
low. Inorganic carriers with well-defined porosity have high
loading capacity, but the main problem of these materials is
subsequently remove after drug release process.8 Metal−
organic frameworks constructed from organic linkers and
inorganic nodes with features such as ultrahigh porosity, high
surface area, and thermal stability are appropriate candidates in
many fields such as catalyst,9 gas storage,10 synthesis of
nanomaterials,11 chemical sensors12 antibacterial activity,13 and
especially drug delivery.14 Among reported MOFs, iron
carboxylate MOFs are good candidates for biological
application because of their low toxicity and biodegradability.
MIL-101(Fe) is a mesoporous carrier with pore sizes of 12 Å ×
29 Å; 16 Å × 34 Å and composed of nontoxic components.15
This MOF is constructed from terephthalic acid (H2BDC) as
Received: September 16, 2019

© XXXX American Chemical Society https://dx.doi.org/10.1021/acs.inorgchem.9b02756

A Inorg. Chem. XXXX, XXX, XXX−XXX
Inorganic Chemistry
an organic linker and iron as an inorganic node. Iron exists in
blood plasma at approximately 22 μM. According to kinds of
literature, both components show little toxicity in the body.
Therefore, based on the above mentioned reasons, we have
chosen MIL-101(Fe) as a carrier for delivery of curcumin as an
anticancer drug. Curcumin (CCM) is a natural chemo-
therapeutic agent which is a pigment from turmeric. This
compound has attracted considerable attention because of its
therapeutic effects such as antitumor, antioxidant, and
antibacterial activities. The diketo group in the curcumin
structure exhibits keto−enol tautomerism (Scheme S1). CCM
is hydrophobic molecule, insoluble in water but soluble in
polar solvents such as DMSO, ethanol, methanol, and
chloroform. Aqueous curcumin solution is achievable by
adding surfactants, lipids, cyclodextrins, albumins, biopoly-
mers, and so on, although using surfactant is the best method
for preparing high concentration solutions of curcumin in
water. One of the features of curcumin is its chemical reactivity
with reactive oxygen species (ROS) that consists of free radical
oxidants and molecular oxidants. There are active sites in the
structure of curcumin with the ability to reduce ROS, and the
results obtained from investigations by different groups
revealed that phenolic O−H which is more efficient in the
reduction of ROS leads to the formation of phenoxyl radicals
that are less reactive species than earlier ROS. This phenoxyl
radical can convert to curcumin by water-soluble antioxidants
such as ascorbic acid. Therefore, this compound has
antioxidant and anticancer activities, but the main problem
for its administration is due to hydrophobicity and poor
bioavailability. Therefore, various efforts have been made to
encapsulate CCM.16 There are many studies on the develop-
ment of controlled DDS. Some of them consist of stimuli such
as pH, light irradiation, magnetic field, and temperature
increasing. Among them, pH variation is the most widely used
stimulus to induce the release of active molecules in a medium
with a controlled manner. In this case, two factors are effective:
(I) the solubility of the active molecule and (II) the stability of
the carrier.17 In this work, the drug loading capacity of MIL-
101(Fe) for curcumin as an anticancer drug considering pH
stimulus condition was investigated (pH 7.4 for normal tissue
and pH 5 for simulation of cancer cells condition). In the end,
kinetic analysis of drug release was studied. On the basis of the
results obtained at the two pH values, it can be concluded that
MIL-101(Fe) is a pH-sensitive carrier and can act as a smart
DDS with a sustained-release manner.
2. MATERIALS AND METHODS
2.1. Materials and Techniques. All chemicals were used as
commercially obtained and without further purification. IR spectra
were recorded using an Equinox 55 FT-IR spectrometer (Bruker,
Bremen, Germany) in ATR form, in the range of 400−4000 cm−1
with 4.0 cm−1 resolution and 16 scan numbers. UV−vis spectra were
recorded by Rayleigh spectrophotometer in the range of 300−550
nm. The PXRD patterns were recorded with a Rigaku Ultima IV
powder diffractometer using Cu Kα radiation (λ = 1.54056 Å) with
step-size of 0.01671°. Simulated XRD powder patterns based on
single-crystal data were prepared using the Mercury software. BET
surface area MIL-101(Fe) and MIL-101(Fe)@CCM were calculated
from the N2 adsorption isotherms at 77K with Belsorp mini II
apparatus. ZP was measured with Zetasizer Nano Series, Malbern
ZS90 Instrument at water medium. The samples were characterized
with a scanning electron microscope (Philips XL 30) with gold
coating and transmission electron microscopy (TEM Philips EM
B https://dx.doi.org/10.1021/acs.inorgchem.9b02756
pubs.acs.org/IC Article
208S). Fluorescence images were obtained by OPTIKA B500TiFL
microscope.
2.2. Synthesis of MIL-101(Fe). MIL-101(Fe) was synthesized
according to previous literature.18 Briefly, 2 mmol of FeCl3.6H2O, 2
mmol of terephthalic acid and 1.8 mL of acetic acid were mixed in 50
mL of N,N-dimethylformamide (DMF). This mixture was refluxed at
110 °C for 24 h. At the end of the reaction, the brick-red precipitated
product was isolated with the centrifuge. The yield of the reaction was
78% (based on final product). Then the obtained powders were
washed with DMF and stored in this solvent for 2 days (the solvent
was refreshed two times each day). This process was repeated with
methanol instead of DMF. In the end, the product was heated at 80
°C for 1 day for activation.
2.3. Drug Loading. First, 50 mg of activated MIL-101(Fe) was
suspended in 50 mL of a concentrated solution of CCM (2.65
mg.mL−1) in ethanol and stirred for 48 h in the dark. After 48 h, the
solution was centrifuged, and the obtained products were washed with
ethanol three times. The amount of drug loading was obtained based
on the reported method in previous literature.16a,19 The obtained
MIL-101(Fe)@CCM was separated and dried in the air at room
temperature. To determine the amount of drug loading in the MOF, 3
mg of MIL-101(Fe)@CCM was digested in 0.75 mL of HCl (2 M)
and diluted to 30 mL with ethanol. Measurements were done by UV−
vis spectrophotometer based on the absorbance of the solution at 425
nm. A calibration curve of CCM in ethanol was used for obtaining
DLC (drug loading content) and DLE (drug loading efficiency)
(Figure S1).
2.4. In Vitro Drug-Release Studies. First, 2 mg of MIL-101(Fe)
@CCM (dry sample) was suspended in 40 mL of phosphate-buffered
solution (PBS) + 1% v/v Tween 80 as media and placed in the shaker
(with speed of 80 rpm) to determine drug release profile. Tween 80
was used as stabilizer and solubilizer of CCM because CCM is not
stable in PBS. At a predetermined time, 1 mL of the solution was
removed and replaced with 1 mL of fresh preheated PBS + 1% v/v
Tween 80 to maintain constant conditions. The withdrawn solution
was analyzed with UV−vis spectrophotometer to obtain the
concentration of released drug based on the calibration curve of
CCM in PBS+ 1% v/v Tween 80. The obtained results were reported
as an average from two repeated experiments. Then, the percent
accumulative drug release was calculated as a function of time.
Equations for the calculation of corrected drug concentration20 are
listed in the Supporting Information. These calculations were done at
two pHs (7.4 and 5).
2.5. Cytotoxicity Assay. The toxicity of MIL-101(Fe), CCM, and
MIL-101(Fe)@CCM on HeLa and HEK 293 cell lines was
investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-
bromide (MTT) assay. Briefly, the HeLa and HEK 293 cells with a
density of 104 cells/well were seeded in 96-well plates and incubated
overnight. Various concentrations of MIL-101(Fe)@CCM, CCM,
and MIL-101(Fe) in DMEM were prepared and supplemented with
10% FBS. These solutions were added to 5 wells containing the
seeded cells. In the following 24 h, the medium was exchanged with
100 μL of a 0.5 mg mL−1 MTT solution (Sigma, USA). After 4 h,
formazan crystals were dissolved in 100 μL of isopropanol (Merck,
Germany) by incubation at 37 °C for 15 min. The absorbance of each
well was evaluated by a multiwell microplate reader (Statfax 2100,
USA) at 545 nm then normalized to the control test.
2.6. Cellular Uptake Studies. Because of the intrinsic green
fluorescence of CCM, the cellular uptake of MIL-101(Fe)@CCM was
investigated by fluorescence microscopy. For this analysis, HeLa cells,
with a density of 104 cells per well, were seeded in 6-well culture
plates and incubated in DMEM for 24 h. After this time, the culture
medium was replaced by a solution of CCM in fresh DMEM with a
concentration of 20 μg/mL. After 48 h, the medium was removed and
cells washed with PBS (pH 7.4). The cells were fixed with 800 μL of
4% formaldehyde and washed with PBS again. Then samples were
measured by fluorescence microscopy.
2.7. Kinetic Study. Mathematical models are useful tools to study
the optimal design of new pharmaceutical formulations, evaluate drug
release processes, and understand drug release mechanism.21 Some
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Inorganic Chemistry pubs.acs.org/IC Article

main-release kinetic models were applied to the data obtained in the

drug release studies to predict the release process. The zero-order,
first-order, Higuchi, Hixson−Crowell, and Korsmeyer−Peppas are
well-known mathematical models that were used in many kinds of
literature.22 In this study, kinetic models were investigated to achieve
a better understanding of the drug release mechanism. These models
with their formula are available in Table S1.

3. RESULTS AND DISCUSSIONS

3.1. Synthesis and Characterization of MIL-101and
MIL-101(Fe)@CCM. MIL-101(Fe) was prepared in DMF
solution at a molar ratio of Fe3+/BDC2− = 1:1 under reflux
condition. MIL-101(Fe), activated MOF, and MIL-101(Fe)@
CCM are represented in Figure 1.

Figure 2. PXRD of simulated pattern of MIL-101(Cr), activated MIL-

101(Fe), and MIL-101(Fe)@CCM.

Figure 1. Photograph of MIL-101(Fe) before and after activation and

MIL-101(Fe)@CCM.

The FT-IR spectra of MIL-101(Fe), activated MIL-101(Fe),

MIL-101@CCM, and pure curcumin are shown in Figure S2.
A peak at 1657 cm−1 (represented with a red rectangle) is
attributed to a CO group of DMF molecule that is omitted
after activation with methanol exchange and heating in the
oven.23 There are some characteristic peaks in curcumin
spectra that also appeared in MIL-101(Fe)@CCM that
represent the existence of CCM in the structure. These
peaks are listed in Table S2 and shown in Figure S2 with green
dots.
Other evidence of CCM presence in MIL-101(Fe) is 1H
NMR (Figure S3). There are some characteristic peaks in the
spectrum of MIL-101(Fe)@CCM in the region of 6.5−7.5
ppm and at 3.78 ppm that are attributed to CCM24 (peak at
2.5 ppm is assigned to DMSO-d6). The presence of these peaks Figure 3. Nitrogen adsorption−desorption isotherm of MIL-101(Fe)
indicates that curcumin was present in MIL-101(Fe)@CCM. before and after CCM loading.
Powder X-ray diffraction (PXRD) patterns of activated MIL-
101(Fe) and MIL-101(Fe)@CCM are shown in Figure 2.
Both patterns are matched to the simulated PXRD pattern of
MIL-101(Cr). This result confirmed the successful synthesis,
activation, and drug loading of MIL-101(Fe), and this pattern
suggests that activation of MIL-101(Fe) and CCM incorpo-
ration did not affect the MIL-101(Fe) crystal structure.
The results obtained from nitrogen sorption measurements
showed reduced the BET surface area of MIL-101(Fe) after
the drug loading process. The BET surface area of MIL-
101(Fe) after activation was 1419.9 m2/g, but after drug
loading, this amount was reduced to 84.09 m2/g. Moreover,
the total pore volume decreased from 1.06 to 0.64 cm3 g−1).
This reduced surface area and changed N2 isotherm (Figure 3)
represents CCM loading in the pores of MIL-101(Fe).
The ZP (zeta potential), also known as electrokinetic
potential, is defined as the amount of potential at the slipping/
shear plane of moving colloidal particles under an electric field.
The electric potential of the surface of particles is defined as
“the amount of work that needs to be done to bring a unit Figure 4. Zeta potential of MIL-101(Fe) before and after CCM
loading.
positive charge from infinity to the surface without any
acceleration.”25 ZP measurements in Figure 4 indicated a
positive zeta potential of +8.3 mV for MIL-101(Fe)@CCM,
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Figure 5. SEM images of (A) MIL-101(Fe) before, (B) after CCM loading, and (C) TEM image of MIL-101(Fe)@CCM.

which is lower than MIL-101 (+28.6 mV). On the basis of the According to previous literature,19a,27 curcumin could
previously reported literature,26 this reason can be attributed to coordinate with the central metal in the diketo form. In this
the interaction of the electrons in the β-diketones of CCM study, some evidence confirms that there are some interactions
with metal ions in the external surface of MOF. Therefore, the between the open metal sites in MIL-101(Fe) and CCM. The
zeta potential of MIL-101(Fe) is decreased after the SBU of MIL-101(Fe) is composed of a carboxylate-bridged,
incorporation of CCM to form MIL-101(Fe) @CCM. This oxo-centered, trinuclear Fe3+ complex (Figure 6). This SBU
result represents that beside encapsulation of drug into the
pores of the MIL-101 (Fe) that leads to a decrease in surface
area and pore volume of the MOF the surface adsorption of
curcumin has also been effective in drug loading content.
The SEM images before and after drug loading are shown in
Figure 5a,b. SEM image of MIL-101(Fe)@CCM (Figure 5b)
with agglomerated nanostructures is different from MIL-
101(Fe) with a nanostructured surface. A comparison between
these images also approved the surface adsorption of CCM in
addition to its internal loading. Also, the TEM image of MIL-
101(Fe) after drug loading (Figure 5c) clearly supported the Figure 6. SBU of MIL-101(Fe).
nanosize of MIL-101(Fe)@CCM and surface adsorption of
CCM. consists of removable coordinated H2O molecules. After
3.2. Drug Loading and Release Study. The amount of activation, coordinative unsaturated sites (CUSs) or open-
drug loading was obtained based on the calibration curve of metal sites are formed.28 These CUSs are capable to
CCM in ethanol with UV−vis spectrophotometer in λ = 425 coordinate to CCM.
nm that is due to π−π* transitions (eqs 1 and 2 in the The FT-IR spectrum in Figure S2 shows two bands at 1496
Supporting Information). According to calculations, DLC and and 1424 cm−1 that indicate the presence both of the free
DLE are 56.3 and 48.7%, respectively. carbonyl group of the diketone and enol form in CCM.
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Figure 7. Cumulative drug release profile in two pH of 7.4 and 5.

Scheme 1. Proposed Mechanism for Higher Release of CCM at Acidic pH

Figure 8. (A) In vitro biocompatibility of MIL-101(Fe) (with concentrations of 400, 200, 100, 50, 25, and 12.5 μg/mL), CCM with concentrations
of: 250, 125, 62, 31, 16, and 8 μg/mL), and MIL-101(Fe)@CCM (with concentrations of: 444, 222, 111, 55.5, 27.75, and 13.875 μg/mL) against
HeLa cell lines for 48 h. Selectin of concentrations was based on the amount of drug loading on MIL-101(Fe). (B) In vitro biocompatibility of
MIL-101(Fe)@CCM against HeLa and HEK cell lines at various concentrations for 48 h.

However, after the drug loading step, the peak at the lower
wavelength (1424 cm−1, shown with a red circle in Figure S2)
that is attributed to the enol form has been omitted. Also, the
broad peak (that contributed to enolic OH, shown with a red
circle in Figure S2) in the range of 3200−3500 cm−1 is absent
after drug loading. Therefore, it concluded that CCM in MIL-
101(Fe)@CCM is in the diketo form. On the basis of ZP
results that showed reduced potential after CCM loading, it is
concluded that beside drugs loaded in the pores of MIL-
101(Fe) that was confirmed with reduced BET surface area
and pore volume, there are some drugs adsorbed on the surface
E https://dx.doi.org/10.1021/acs.inorgchem.9b02756
of the MIL-101(Fe). These drugs probably have some
interactions with metal ions27,29 that lead to the slow release
of CCM and high drug loading content.
Another reason to support the coordination between metal
and CCM is 1H NMR analysis is reported previously by Tiwari
and co-workers.19a The 1H NMR spectrum of curcumin
displayed peaks at δ 6.06 ppm in DMSO + DCl solutions
(Figure S4) that are related to methine protons and confirmed
the presence of enol form of curcumin. This peak was absent in
the MIL-101(Fe)@CCM spectrum. It could be related to the
interactions between Fe and the diketo form of curcumin.
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Inorganic Chemistry pubs.acs.org/IC
Table 1. Results Obtained from Investigation of Different Models in Terms of R2
pH zero-order first-order Higuchi model
7.4 R2 = 0.864 R2 = 0.9019 R2= 0.9783
5 R2= 0.8393 R2 = 0.9364 2
R = 0.9716
In the following, the in vitro drug release profile of MIL-
101(Fe)@CCM was investigated (based on the calibration
curve of CCM in PBS + 1% v/v Tween 80 and eqs 3−5 in the
Supporting Information) at pHs of 7.4 and 5, and its results are
shown in Figure 7. As shown in this picture, MIL-101(Fe)@
CCM presented a prolonged drug release profile, only 26 ± 2%
of CCM, even after 22 days in normal PBS (pH 7.4). This
amount was higher in acidic pH, and the amount of cumulative
drug release was reached to 64.7 ± 2.9% at that time. Also, the
photograph in the inset of Figure 7 clearly shows the color
difference at the two pHs. This slow release can prove the
attractive interaction between CCM in the diketo form with
the metal ion of MIL-101(Fe).
This pH-stimulus release feature of MIL-101(Fe) can reduce
premature drug release in normal cells and enhance drug
release in the acidic microenvironments of tumors cells. This
feature will be beneficial for cancer treatment.
The observed higher release of curcumin in acidic pH might
be attributed to the protonation of CCM at lower pH.30 CCM
can react with excess protons in solution. It is proved in
published literature in 2014 that the diketo oxygen atoms can
act as a proton sponge. It means that the added protons lead to
a stable six-membered ring formation.31 Therefore, acidic pH
can trigger the release of CCM. The proposed mechanism for
the higher release of CCM in the acidic condition is
represented in Scheme 1.
3.3. In Vitro Cytotoxicity by the MTT. The cytotoxicity
of MIL-101(Fe)@CCM, CCM, and MIL-101(Fe) were
investigated by carrying out MTT tests on HeLa and HEK
293 cell line. The obtained results (with seven repetitions) are
shown in Figure 8A,B. Based on the obtained results in Figure
8A, MIL-101(Fe) has no apparent cytotoxicity in the HeLa cell
line even up to high concentrations (400 μg/mL). However,
MIL-101(Fe)@CCM exhibited a cell growth inhibition effect
on HeLa cells with an IC50 72.6 μg/mL. A noticeable point in
this figure is the greater effect of free CCM than MIL-101(Fe)
@CCM. This result is predictable. This in vitro analysis was
done after 48 h, but MIL-101(Fe) needs 22 days to release its
entire drug load. In another word, based on the data obtained
in Figure 8, at 48 h only 27 and 10% of all drug load can be
released at pH 5 and 7.4, respectively. An important point in
DDS is the amount of cytotoxicity to normal cells. Therefore,
MIL-101(Fe)@CCM was tested on HeLa (as cancer cell
model) and HEK 293 (as normal cell model) and the results
are shown in Figure 8B. As this picture indicates, the MIL-
101(Fe)@CCM has no cytotoxicity to HEK 293 in low
concentration. Even at high concentrations, its cytotoxicity is
very small in comparison with that in the HeLa cell line.
3.4. Kinetic Models. The results obtained from the drug
release profiles were fitted to some well-known kinetic models
that are briefly explained below.
3.4.1. Zero-Order Model. The zero-order kinetics model
represents that the release of an active agent is only a function
of time with a constant rate and is independent of the time or
concentration. The data obtained from drug release inves-
tigation were fitted into this model by plotting a cumulative
drug release (%) against time. In this model M0, Mt and k are
F https://dx.doi.org/10.1021/acs.inorgchem.9b02756
Article
Korsmeyer−Peppas Hixson−Crowell
R2 = 0.9729 n = 0.28 R2 = 0.921
R2 = 0.9957 n = 0.41 R2 = 0.9094
the initial amounts of the drug, the amount of drug released at
time t, and the zero-order rate constant.
3.4.2. First-Order Model. The first-order model represents
that the drug release from a formulation depends upon two
factors; I) time and II) initial concentration of the drug.
Because of the dependence of the amount of drug released to
the amount of remaining drug in the matrix, the amount of
active released tends to decrease in function of time. Log of the
cumulative remaining drug (%) against time was used for
fitting data obtained into this model. k1 in the formula in Table
S1 represents the first-order rate constant.
3.4.3. Higuchi Model. This model is based on some
hypotheses: (I) The initial drug concentration in the matrix is
much higher than the solubility of the drug. (II) The diffusion
is unidirectional. In other words, drug diffusion takes place
only in one dimension, and the edge effect is negligible. (III)
The drug particles are smaller than the system thickness. (IV)
The matrix swelling or dissolution are negligible. (V) The drug
diffusivity is constant. (VI) The sink conditions are attained in
the release environment. The Higuchi model indicates that the
rate of drug release is based on the diffusion process according
to Fick’s law. This model represents that the concentration of
active agent is proportional to the square root of time. KH in
this model is the release constant of Higuchi.
3.4.4. Hixson−Crowell Model. Hixson and Crowell in 1931
discovered that a group of particles’ regular area is proportional
to the cube root of its volume. On the basis of this finding, they
proposed an equation that is listed in Table S1. The drug
release from particles in this model is described keeping in
view the volume and area of the particle. In the Hixson−
Crowell formula, Mt/M∞, and kHC are the fractional drug
release and Hixson−Crowell rate constant, respectively. In the
Hixson−Crowell model, the dissolution velocity and not
diffusion limit the drug release, which can occur through the
polymeric matrix. Data from the release study of the drug were
fitted into Hixson−Crowell model by plotting cube root of
percent of drug remaining against time.
3.4.5. Korsmeyer−Peppas Model. This model could be
used to predict the drug release mechanism from a polymeric
system. This equation was applied to the data by plotting the
log of the cumulative drug release (%) against the log of time.
Mt/M∞, kKP, and n represent the fractional drug release, the
Korsmeyer−Peppas rate constant, and release exponent,
respectively. The size of n characterizes the mechanism of
the drug release (Table S3). To find out the size of n, Mt/M∞
< 0.6 should only be used.
In the Fickian model (n = 0.5), the drug release is governed
by diffusion. A value of n = 1 represents the model is non-
Fickian, and the drug release rate corresponds to zero-order
release kinetics. In this case, the swelling or relaxation of
polymeric chains is the driving force for the drug release
process. When 0.5 < n < 1, the model is non-Fickian or
anomalous transport. In this case, the drug release mechanism
is governed by diffusion and swelling. Finally, the Super Case II
model is characterized by n > 1, constituting an extreme form
of drug transport. Tension and breaking of the polymer
occur.21,22,22c,32
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Inorganic Chemistry pubs.acs.org/IC Article

The results obtained from the investigation of the in vitro Table 2. List of Reported MOFs for Load and Release of
drug release profile with different mathematical models CCM
(Figures S5 and S6) are listed in Table 1. In acidic pH, the
MIL CCM loading time stimulus ref
correlation coefficient (R2) is higher for the Korsmeyer−
Peppas model, and at normal pH, this value is approximately The DLC and DLE were
ZIF-8 12.7% and 88.2%, respec- 100 (h) pH 16a
the same for the Higushi and Korsmeyer−Peppas models and tively.
slightly higher in the Higuchi model. As mentioned above, the The DLC and DLE were
MOF- pH and
Higuchi model indicates that the rate of drug release is based 11.8 and 78.7%, respec- 24 (h) 26
Zr(DTBA) GSHa
tively
on the diffusion process, according to Fick’s law. Moreover, the
The drug loading capacity
mount of n in acidic pH represents the quasi-Fickian diffusion ZIF-8
was 3.42%.
72 (h) pH 19a
mechanism. According to these results, it could be suggested The bulk loading of CCM
Ca-BDC 350 (min) pH 27
that the diffusion is main driving force for the drug release was about 0.14 g·g−1.
from MIL-101(Fe) at both pHs. PDA-MSN@ZIF
The loading capacity was
8/DOX + ∼32 (h) pH 34
The stability of the MIL-101(Fe)@CCM in PBS at pH 5 778 μg mg−1.
CUR
was investigated in PBS + 1% v/v Tween 80 for 7 days at 37 The DLC and DLE were
°C. After this time, the PXRD analysis was done (Figure S7). MCH NPsb 33.0% and 94.3%, respec- ∼72 h pH 29
On the basis of the obtained results, most of the main peaks tively.
are unchanged (represented with green color). These results CCM@ZIF-8/ The capacity of the encap-
∼180 h pH 19b
HAc sulated CCM was 4.24%.
indicate the stability of MIL-101(Fe) in the PBS solution after Fe3O4@Bio-
a week and confirm the proposed mechanism of drug release CCM was the organic linker. ∼50 h pH 35
MOF
obtained from kinetic study. However, based on the reported MIL-101(Fe)@ DLC and DLE are 56.3 and
528 (h) pH
this
literatures, beside the importance of the stability of drug CCM 48.7%, respectively. work
a
carriers in medical applications, a carrier with a degree of Glutathione. bCoating MC NPs (curcumin-loaded MIL-100) with
instability leads to avoiding accumulation of endogenous. For HA-PDA (PDA-modified). cHyaluronic acid (HA)-coated ZIF-8
example, it is expected that a carrier of anticancer drug, save its nanocomposite.
structure before reache to the tumor site. On the basis of
earlier reports, MIL-101(Cr) degraded after 7 days (in coordination of CCM to open metal sites on MIL-101(Fe)
simulated body fluid (SBF) at 37 °C).33 The stability of external surface. Coordinated CCM on the surface of MIL-
MIL-101(Fe)@CCM in PBS/Tween 80 at pH 5 at 37 °C was 101(Fe) presents the slow release of CCM from the pores of
investigated, and the PXRD pattern is shown in Figure S7. MIL-101(Fe). At acidic pH, because of the proposed
This pattern shows acceptable stability after a week. After mechanism (Scheme 1), the release of CCM adsorbed on
this time the MIL-101(Fe)@CCM starts to lose its crystal the external surface of MIL-101(Fe) was faster than that at
structure. Therefore, based on the results obtained in this study normal pH. Then the stored CCM in the pores of MIL-
it could be concluded that MIL-101(Fe)@CCM keeps its 101(Fe) releases more easily than at normal pH.
structure intact and that diffusion is a main driving force for On the basis of this comparison, it is clear that MIL-101(Fe)
the drug release process. MIL-101(Fe) is able to control has an appropriate potential for load and release of CCM. The
release for 22 days. Finally, after this long time, based on the reported data revealed the ability of this MOF for achieving
PXRD patterns, MIL-101(Fe) starts to lose the crystal suitable DDS with a pH-stimulus-controlled release manner.
structure that is suitable for avoiding endogenous accumulation
in the body. The SEM image of MIL-101(Fe)@CCM after 4. CONCLUSION
drug release (22 days) at pH 7.4 and 5 are shown in Figure S8 In this study, MIL-101 (Fe) was used for load and sustained
shows the nanosized structure with similar morphology to release of CCM as an anticancer drug. Obtained data from
fresh MIL-101(Fe)@CCM. drug release investigation in two pH (7.4 and 5) were fitted
The results obtained from the investigation of cellular with some mathematical models to understand the drug release
uptake of MIL-101(Fe)@CCM by fluorescence microscopy mechanism. This kind of MOF was chosen because of the low
are shown in Figure 9. Green fluorescence is detected which toxicity of its components, high surface area, large pore size,
indicates the endocytosis ability of MIL 101(Fe)@CCM that is and simple preparation. The results confirmed the ability of
related to its nanosized structure. MIL-101(Fe) for high loading of CCM (56.3 wt %) as an
There are some reports about the application of MOFs for anticancer drug with pH stimulus release behavior (more drug
load and release of CCM. In Table 2, MIL-101(Fe) is release in lower pH) over prolong time (22 days). On the basis
compared with other kinds of literature in the viewpoint of two of observed changes in IR, SEM, TEM, 1H NMR, and ZP
factors: drug release time and drug loading ability. It seems results before and after the drug loading process, the reasons
that the effective factor for its excellent CCM release time is for high loading and prolonged drug release time in
comparison with other reports can be attributed to the large
pore size of MIL-101(Fe) and combination of encapsulation of
drug molecules in the pores of MIL-101(Fe) and surface
adsorption of CCM on the open metal sites of this MOF. The
mathematical models showed that drug release data at pH 7.4
and 5 are best fitted by Higuchi (R2 = 0.9783) and
Korsmeyer−Peppas (R2 = 0.9957) models, respectively.
Figure 9. Fluorescence images of (A) MIL-101(Fe)@CCM (green These results imply that diffusion is main driving force for
fluorescence), (B) cell nucleus (blue fluorescence, stained by Hoechst CCM release from MIL-101(Fe)@CCM. MTT test on HEK
33342), and (C) the overlay image (scale bars = 10 μm). 293 cell line, as healthy cells model, indicates low cytotoxicity
G https://dx.doi.org/10.1021/acs.inorgchem.9b02756
Inorg. Chem. XXXX, XXX, XXX−XXX
Inorganic Chemistry
of MIL-101(Fe)@CCM. A combination of high drug loading
content, sustained-release behavior, and sensitivity to pH
conditions (higher drug release at a pH similar to cancer cells)
can provide new opportunities to achieve more effective
treatment for cancer in the future.
■
ASSOCIATED CONTENT
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.9b02756.
Structure of curcumin, calibration curve, Table of IR
peaks, kinetic models and their mathematical formula,
1
H NMR spectra, PXRD patterns, calculations of drug
loadin and release, curves of the application of drug
release data on mathematical models, and SEM images
(PDF)
■ AUTHOR INFORMATION
Corresponding Author
Kamran Akhbari − School of Chemistry, College of Science,
University of Tehran, Tehran, Iran; orcid.org/0000-0002-
4574-683X; Phone: +98 21 61113734; Email: akhbari.k@
khayam.ut.ac.ir; Fax: +98 21 66495291
Author
Roya Karimi Alavijeh − School of Chemistry, College of Science,
University of Tehran, Tehran, Iran
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.9b02756
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Support of this investigation by the Iran National Science
Foundation (INSF) under grant number 98002623 is
gratefully acknowledged. The authors also would like to
acknowledge the financial support of the University of Tehran
for this research under grant number 01/1/389845 for
supporting this investigation.
■
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