DOI: 10.1002/cphc.
201501012 Articles
Smart Approach for In Situ One-Step Encapsulation and
Controlled Delivery of a Chemotherapeutic Drug using
Metal–Organic Framework–Drug Composites in Aqueous
Media
Chandan Adhikari and Anjan Chakraborty*[a]
Controlled release of an anticancer drug, doxorubicin (dox),
from metal–organic framework (MOF)–drug composites is
demonstrated under different external stimuli. 1,3,5-Benzenetri-
carboxylic acid (H3BTC) is used as an organic ligand, and iron
acetate and zinc nitrate are used as metal sources to synthe-
size Fe–BTC and Zn–BTC MOFs, which are known to be bio-
compatible. The in situ formation of MOF–drug composites
demonstrates high drug loading capacity compared to conven-
tional methods. The present methodology is devoid of any
extra steps for loading the drug after synthesis. Moreover, the
drug loading is also independent of pore size of the MOF as
the drug molecules are embedded inside the MOF during their
in situ formation. The drug release was monitored under exter-
1. Introduction
Metal–organic frameworks (MOFs), because of their robustness,
tunable structure, high functionality, high surface area, wide
range of pore size, and high porosity, have attracted research-
ers from different branches of science during recent years and
MOFs are used for important applications in various fields.[1, 2]
MOFs have been used in the different fields of science and in
research areas including gas storage, catalysis, gas sensing,
contrast agents, and gas separation.[3–11] In addition to these
applications, recently MOFs have been used in biomedical ap-
plications for their amphiphilic nature, easily adjustable func-
tional groups in the framework, possible fine tuning of the
pore size, and so forth, and several reports describe the load-
ing and delivery of different drugs.[12–22] Although MOFs have
been known for more than four decades, it is only in the last
15 years that scientists have paid great attention to them.[23]
A large number of MOFs have been synthesized in recent
years according to conventional methodologies, for example,
solvothermal, hydrothermal, mechanochemical and electro-
chemical methods.[24–35] These processes have the advantage of
yielding highly crystalline structures, but suffer from the use of
[a] C. Adhikari, Dr. A. Chakraborty
Discipline of Chemistry
Indian Institute of Technology Indore
Indore, Madhya Pradesh (India)
E-mail: anjanc@iiti.ac.in
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cphc.201501012.
ChemPhysChem 2016, 17, 1070 – 1077
nal stimuli including change to acidic pH and the presence of
biocompatible liposomes for a period of more than 72 h.
Steady-state fluorescence spectroscopy is used to monitor the
drug release as a function of time and confocal laser scanning
microscopy is used to unravel the post-release fate of doxoru-
bicin in the presence of liposomes. It is found that drug release
rate is higher for the Zn–BTC–dox composite than for the Fe–
BTC–dox composite. This is attributed to the stronger binding
between dox and Fe-BTC than that between dox and Zn–BTC.
This study highlights a novel approach for the preparation of
MOF–drug composites in an aqueous medium for future bio-
medical applications.
high temperatures, toxic solvents, longer reaction times (in
most cases days to weeks), difficulty in scaled-up synthesis
and, of course, need to use sophisticated instruments. The
toxic solvents used in conventional methods need to be re-
moved carefully before any biomedical applications. To the
best of our knowledge, there are only a few reports to date
that describe the synthesis of MOFs at room temperature.[36–39]
However, those room-temperature MOF preparations have the
drawbacks that they use several highly toxic solvents including
N,N-dimethylformamide, N,N-diethylformamide, and chloro-
form, and require nearly 2–7 days to react.[36–39] These methods
are neither environmentally friendly nor economically viable,
thus limiting their industrial applications. Therefore, if a synthe-
sis is achieved just by using only metal ions and organic li-
gands in reasonably good yield, and at room temperature in
one step without using toxic solvents, then many of the prob-
lems associated with the synthesis of MOFs would be solved.
Although iron- and zinc-based biodegradable MOFs were
synthesized previously using polycarboxylate ligands, they
emerged from the use of the conventional methodologies de-
scribed earlier.[14, 40–45] Even the hydrothermal methodology for
the synthesis of iron- and zinc-based biodegradable MOFs
using water as a solvent suffers from the need for high tem-
peratures, long reaction times and difficulties in scaled-up syn-
thesis, which limits their industrial application.[25] By keeping in
mind the high impact of these iron- and zinc-based biocom-
patible MOFs in medicinal chemistry, as well as industrial as-
1070 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Articles
pects, we hereby report a novel approach for the synthesis of
two important biocompatible MOFs at room temperature
using water as a solvent. The use of water removes the possi-
bility of many kinds of toxicity related to solvents and renders
this method greener than previous methods. The room tem-
perature, scaled-up synthesis marks it as more economical and
affords opportunities for industrial applications. Thus, the nov-
elty of our methodology lies in the simple preparation and
short reaction times at room temperature, with the prospect
of easy scale-up. In Table 1, we summarize the advantages of
our method compared to conventional methods.

Table 1. Comparison of the conventional methods of MOF synthesis with

those developed in this work.

Conventional methods[24–35] Method used in this manuscript

1) Need high temperatures
(100–200 8C)
2) Uses toxic organic solvents
3) Work-up is needed (sometimes
this work-up is complex in nature)
4) Need more time
(in general 2–7 days)
5) Need pressurized sealed
conditions
6) Yields are 60–80 %
7) Highly crystalline product
8) Difficulty in scale up
1) Room temperature reaction
2) Only water was used
3) No work-up, only centrifugation
is needed to collect the product
4) Only 3–8 h Scheme 1. Structures of doxorubicin and the lipids with which the lipo-
somes used in this study were made.
5) No need for special conditions
or equipment
6) 70–80 % yield
7) No crystallinity, amorphous in
nature
8) Easily scalable

In addition to their synthesis, we also describe the use of

these MOFs as carriers of a widely used anticancer drug, doxo-
rubicin (dox, Scheme 1). Although MOFs have been used for
the encapsulation of different drugs, it is still a major challenge
to encapsulate significant amounts of larger-sized drug mole-
cules inside MOFs as post-synthetic drug loading is highly de-
pendent on the pore size of the MOF. Here, we propose a new
synthetic route to prepare MOF–drug composites in situ
during the synthesis of the MOF in an aqueous medium
(Scheme 2). This method removes the need for any extra steps
for drug encapsulation after synthesis, and drug loading is in-
dependent of the pore size of the MOF. The methodology also
enables high drug loading (in the case of Zn–BTC, the drug
loading is … 83 % and in the case of Fe–BTC, drug loading is
… 92 %; H3BTC = 1,3,5-benzenetricarboxylic acid).
Scheme 2. Preparation of Fe–BTC and Zn–BTC MOFs at room temperature
Here, we demonstrated the controlled release of dox from
using water as a solvent. The structures of the MOFs depicted here are not
MOFs by using different external stimuli. The encapsulation of the exact single-crystal structure.
doxorubicin and other anticancer drugs such as topotecan, bu-
sulfan, and others, inside MOFs has been studied recently and
the stability of MOF–dox has been studied at physiological In this study, we investigated the effect of pH change on
pH.[46–51] There are several reports that describe successful en- drug release. We also investigated the efficiency of MOF–dox
capsulation and release of different small molecules (e.g. caf- composites as drug delivery systems upon contact with lipo-
feine) from MOFs under the control of different triggering somes, which mimic the cell membranes. The fate of dox in
agents.[15, 52–57] Our group recently studied encapsulation and the presence of liposomes was determined by using confocal
controlled release of dox from zeolitic imidazole frameworks laser scanning microscopy (CLSM) imaging. We were able to
under different external stimuli.[58] encapsulate and control the release of the drug using a com-

ChemPhysChem 2016, 17, 1070 – 1077 www.chemphyschem.org 1071 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

pletely green route, that is, in situ synthesis of MOF–dox com-
posites in an aqueous medium. We hope the results from this
study help the future development of on-demand drug deliv-
ery systems and afford opportunities for the industrial applica-
tion of MOFs.
Experimental Section
Materials
Doxorubicin, iron acetate dihydrate, zinc nitrate hexahydrate, 1,3,5-
benzenetricarboxylic acid, mesoporous silica, 1,2-dimyristoyl-sn-
glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-
phosphoglycerol (DMPG), sodium dihydrogen phosphate, and diso-
dium hydrogen phosphate were purchased from Sigma–Aldrich
(see Scheme 1 for the structure of lipids and dox). All the reagents
were used without further purification.
Preparation of Zn–BTC MOF
Zinc nitrate hexahydrate (5 g, 16.81 mmol) was placed in a round-
bottom flask and dissolved in water (50 mL). In another flask, 1,3,5-
benzenetricarboxylic acid (H3BTC, 1.6 g, 7.614 mmol) was dispersed
in water (50 mL) with sonication for 15 min. Then, the H3BTC sus-
pension was added to the zinc nitrate solution with continuous
stirring. Stirring was continued for 8 h at room temperature to
obtain the optimum yield. Then, the product was collected by cen-
trifugation, washed with water and dried in an oven at 100 8C
before being used in further experiments (yield: 72 %).
Preparation of Fe–BTC MOF
Iron(II) acetate dihydrate (5 g, 28.90 mmol) was added to a round-
bottom flask and dissolved in water (50 mL). In another flask,
H3BTC (1.6 g, 7.614 mmol) was dispersed in water (50 mL) with
sonication for 15 min. Then, the H3BTC suspension was added to
the iron acetate solution with continuous stirring. Stirring was con-
tinued for 3 h at room temperature to obtain the optimum yield.
Then, the product was collected by centrifugation, washed with
water and dried in an oven at 100 8C before being used in further
experiments (yield: 83 %).
In Situ Doxorubicin Loading in Fe–BTC MOF
Dox was added to water (50 mL) to give a concentration of
0.1 mg mL¢1. Next, iron(II) acetate dihydrate (5 g, 28.90 mmol) was
added and fully dissolved by stirring for 15 min. In another flask,
H3BTC (1.6 g., 7.614 mmol) was dispersed in water (50 mL) with
sonication for 15 min. Then, the H3BTC suspension was added to
the dox/iron acetate solution with continuous stirring. Stirring was
continued for 3 h. The product was collected by centrifugation,
washed several times with water and dried in an oven at 100 8C
before being used in further experiments (yield: 82 %).
In Situ Doxorubicin Loading in Zn–BTC MOF
Dox was added to water (50 mL) to give a concentration of
0.1 mg mL¢1. Next, zinc nitrate hexahydrate (5 g, 16.81 mmol) was
added and fully dissolved by stirring for 15 min. In another flask,
H3BTC (1.6 g., 7.614 mmol) was dispersed in water (50 mL) with
sonication for 15 min. Then, the H3BTC suspension was added to
ChemPhysChem 2016, 17, 1070 – 1077 www.chemphyschem.org 1072
Articles
the dox/zinc nitrate solution with continuous stirring. Stirring was
continued for 8 h at room temperature. The product was collected
by centrifugation, washed several times with water and dried in an
oven at 100 8C before being used in further experiments (yield:
70 %).
Calculation of Encapsulation Efficiency
The encapsulation efficiency (EE) of dox in both MOFs was calculat-
ed by using a standard equation [Eq. (1)].[47] The EE for Fe–BTC was
found to be 92 %, whereas the EE for Zn–BTC was 83 %. The EEs
were comparable to other values reported in the literature.[47] The
higher EE of Fe–BTC compared to Zn–BTC can be explained based
on the binding efficiency of dox to the MOFs.
encapsulated drug ½mg¤
EE ½%¤ ¼   100 ð1Þ
drug solution ½mg¤
Preparation of Liposomes
Liposomes were prepared according to a previously reported pro-
tocol.[59] In brief, an aqueous buffer solution (pH 7.4) was added to
a round-bottom flask and the temperature was kept above the
phase-transition temperature of the lipids. Then, the required
amounts of lipids were dissolved in ethanol (less than 1 % v/v) and
the lipid solution was rapidly injected into the buffer solution at
above the phase-transition temperature.
In Vitro Drug Release Study under Acidic pH
In vitro drug release was studied using fluorescence spectroscopy.
A known amount of solid MOF–dox composite was immersed into
a phosphate buffer solution (pH … 4.0) and the supernatant was
collected over a certain interval of time. The fluorescence emission
of the supernatant was measured periodically. The gradual increase
in fluorescence intensity gave a clear indication that the drug mol-
ecules were released from the MOF–drug composite.
In Vitro Drug Release Study in the Presence of Liposomes
Solid MOF–drug composite was immersed into a liposome prepa-
ration composed of DMPG/DMPC (1:9) and the fluorescence inten-
sity of the supernatant was measured periodically to monitor the
drug release. The uptake of drug molecules by liposomes was also
shown by CLSM.
Instrumentation
We characterized MOFs and MOF–dox composites by powder
X-ray diffraction, scanning electron microscopy and infrared spec-
troscopy. Powder X-ray diffraction was performed in an automated
multipurpose Rigaku SmartLab X-ray diffractometer. The X-ray gen-
erator was a 3 kW sealed tube X-ray generator (maximum voltage
60 kV, maximum current 50 mA, with a Cu target). Field-emission
scanning electron microscopy (FE-SEM) studies were conducted on
a Zeiss Supra 55 electron microscope. Steady-state absorption
spectra were recorded on a Varian Cary 100 UV/Vis spectrometer.
IR spectra were measured on a Tensor 27 FTIR spectrometer
(Bruker). Thermogravimetric analysis (TGA) was performed on
a TGA/DSC1 instrument from Mettler Toledo (Switzerland) under ni-
trogen flow at a heating rate of 5 8C per minute. The drug released
Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

was monitored by steady-state fluorescence spectroscopy using
a Horiba Jobin Yvon Fluoromax-4p FM-100 spectrofluorimeter. The
samples were excited at 480 nm. For the time-resolved studies, we
used a picosecond time-correlated single-photon counting (TCSPC)
system from IBH (model Fluorocube-01-NL). The experimental
setup for TCSPC has been described elsewhere.[60, 61] The samples
were excited at 480 nm using a picosecond diode laser and the
decays were collected at 600 nm. The repetition rate was 5 MHz.
The signals were collected at magic-angle (54.708) polarization
using a photomultiplier tube (TBX-07C) as the detector. The full
width at half-maximum of the decay function was around 140 ps.
Uptake of drugs by liposomes were studied by CLSM on an Olym-
pus IX83 microscope (multiple Ar laser, XY LSM). The wavelength
of the excitation laser was 488 nm. The morphologies of the MOFs
were also studied by CLSM and bright-field imaging.
2. Results and Discussion
After the synthesis, we characterized the MOFs and MOF–drug
composites by SEM. The images show that the morphology re-
mains the same for both MOF and MOF–drug composite
(Figure 1).
Both MOFs were stained with the well-known dye rhodami-
ne B for the CLSM and bright-field studies. The excitation
wavelength was set at 559 nm and the emission was collected
at 625 nm. Figure 1 e and f show the CLSM and bright-field
images, respectively, for the Zn–BTC MOF, and Figure 1 g and h
are the CLSM and the bright-field images, respectively, for the
Fe–BTC MOF. The images are in good agreement with the SEM
images. From CLSM, bright-field and SEM studies, it is clear
that the size of the MOFs are close to one micrometer.
Figure 1. SEM images of a) Zn–BTC, b) Zn–BTC–dox, c) Fe–BTC, and d) Fe–
BTC–dox (scale bars = 1 mm). e) CLSM and f) bright-field image of Zn–BTC.
g) CLSM and h) bright-field image of Fe–BTC.
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Articles
To monitor the in situ loading of the drug and its release
from the MOFs, we used UV/Vis and fluorescence spectroscopy.
To confirm that dox was embedded inside the MOF, we mea-
sured absorption and emission spectra for both the initial dox
solution in water (diluted fivefold as the initial concentration
was high) and supernatant after the reaction. Figure 2 a shows
the UV/Vis spectra for dox in an aqueous medium and after
forming composites with MOFs. It is clear from Figure 2 a that
after formation of the composite, the absorption of dox was
diminished almost to zero for Fe–BTC MOF. This indicates that
most of the dox molecules are embedded in Fe–BTC. Con-
versely, in the case of Zn–BTC–dox, a few dox molecules re-
mained in solution and thus showed a weak absorption at
490 nm. Figure 2 b shows the fluorescence spectra for dox in
aqueous medium (diluted fivefold) and after forming compo-
sites with MOFs. The data also indicates that after the drug is
embedded in Fe–BTC, there is no free dox remaining in the su-
pernatant and hence there is no emission at 590 nm for the su-
pernatant. However, in the case of Zn–BTC–dox, even after
composite formation takes place, few dox molecules remain in
solution, which showed weak emission at 590 nm. The result
implies that Fe–BTC has a stronger binding affinity [EE around
92 % using Eq. (1)] for dox as compared to Zn–BTC [EE around
83 %].
The FTIR spectroscopy of the powders of Fe–BTC, Zn–BTC
and Fe–BTC–dox and Zn–BTC–dox composites are shown in
Figure 1 c. The bands centered at 1550 and 1422 cm¢1 corre-
spond to the C=O and C¢O stretching frequencies, respective-
ly, for the free carboxylate groups of H3BTC. The bands cen-
tered at 1610 and 1380 cm¢1 correspond to C=O and C¢O
group of carboxylic acid after coordination to the metal
center.[62, 63] The bands centered at 1324, 1390, 1615, 1720,
2525, and 3000–3500 cm¢1 (broad band) correspond to ether
C¢O and carboxylic acid C¢O, C=C, C=O and O¢H, and O¢H of
dox, respectively.
TGA was performed to gain information about the thermal
stability of the MOFs and drug-embedded MOFs. Figure 3 a
shows that Fe–BTC and Zn-BTC MOFs are stable up to 300 and
285 8C, respectively. The higher thermal stability of Fe–BTC
over Zn–BTC can be explained by the electronic configuration
of the metal ions. Metal complexes with d10 electronic configu-
ration, such as Zn2 + , are less stable than complexes with d6
configuration such as Fe2 + due to the ligand-field stabilization
energy. Drug-embedded MOFs show the same thermal stability
as blank MOFs. At the beginning, for both the MOF–dox com-
posites, the small weight loss (around 10 %) at 150 8C takes
place due to the thermal decomposition of dox. A sharp
weight loss (75 %) was observed for both the MOF after 350 8C.
This weight loss indicates thermal decomposition of the MOF
into its corresponding metal oxide in that temperature range.
Figure 3 b shows the powder X-ray diffraction (PXRD) pattern
of synthesized MOFs and MOF–drug composites. The sharp
peak of the PXRD pattern indicates a uniform size distribution
of the particles. The PXRD pattern of pure Fe–BTC and Zn–BTC
match with those reported previously.[62, 63] Figure 3 b also
shows that there was no change in the PXRD pattern of MOFs
after forming composites with drug molecules. We did not
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Figure 2. a) Absorption spectra for dox in water (diluted fivefold), dox-embedded Fe–BTC MOF and dox-embedded Zn–BTC MOF. b) Fluorescence emission
spectra of dox, dox-embedded Fe–BTC MOF and dox-embedded Zn-BTC MOF. d) IR spectra of Fe–BTC, dox-embedded Fe–BTC MOF, Zn–BTC, and dox-embed-
ded Zn–BTC MOF; d) expanded IR spectra of Fe–BTC–dox and Zn–BTC–dox.

Figure 3. a) TGA curves for blank MOFs and dox-embedded MOFs. b) PXRD patterns of blank MOFs and dox-embedded MOFs. The emission spectra of dox in
phosphate buffer (pH … 4.0) at varying times from 0–72 h for c) Fe–BTC–dox and d) Zn–BTC–dox. Inset: plots of intensity versus time are shown. Exponential
fitting of % drug release versus time under acidic conditions for e) Zn–BTC–dox and f) Fe–BTC–dox.

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choose a rigorous structural characterization of the MOFs as
the structures of both MOFs have been studied extensively by
other groups and single-crystal structures are available in the
literature.[40, 63]
So, the MOFs prepared in the current methodology were
well characterized by PXRD, TGA, IR and SEM, CLSM and
bright-field spectroscopy. From the UV/Vis, fluorescence, IR,
TGA and PXRD data it is clear that MOFs were formed and that
drug molecules were embedded inside MOF successfully.
After the characterization, we shifted our focus to the re-
lease of drugs under the stimulus of changes in pH. We chose
pH … 4 and 5 (data not shown) for our study as cancer cells are
acidic (pH 4–6) in nature.[64, 65] To investigate drug release, the
solid MOF–drug composites (500 mg) were immersed in phos-
phate-buffer solution (pH … 4.0, 10 mL) and the release of drug
molecules was monitored by fluorescence emission of the su-
pernatants. The drug release was monitored for a period of
72 h. Figure 3 c and d shows that there is a monotonic incre-
ment in fluorescence intensity at 590 nm as time increases.
This gradual increase in intensity with time implies the release
of drug molecules from the framework. At acidic pH the car-
boxylate anions are protonated and the coordination between
carboxylic acid group and metal center breaks down, which re-
sults in disruption of the MOF leading to drug release. Fig-
ure 3 c shows that release of drug was complete by a period of
72 h in the case of Fe–BTC–dox, whereas Zn–BTC–dox took
60 h to completely release its drug. The percentage of drug re-
lease was estimated using Equation (2):
F t ¢F t¼0
%release ¼
F ¢F t¼0
t¼1
where F0 is the fluorescence intensity at zero time, Ft is the
fluorescence intensity at time t and Ft = 1 is the maximum in-
tensity if all dox molecules are released from the composite.
The rate constant was obtained by fitting to a single-expo-
nential rate equation following first-order kinetics [Eq. (3)]:
Figure 4. The emission spectra of doxorubicin in the presence of liposomes at times varied from 0–72 h. a) Fe–BTC–dox, b) Zn–BTC–dox.
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Articles
f ¼ að1 ¢ expð¢kt ÞÞ ð3Þ
where k is the rate constant of release and a is the pre-expo-
nential factor, which is a measure of the extent of the release
of contents (Figure 3 e and f).
Thus, the fitting yielded rate constants of around 0.03 and
0.01 h¢1 for Zn–BTC and Fe–BTC MOF, respectively. The lower
rate constant for Fe–BTC might be due to the stronger binding
ability of dox with the Fe–BTC MOF than with the Zn–BTC
MOF, as indicated by UV/Vis and fluorescence results. There-
fore, the drug molecules are released from the Zn–BTC frame-
work at a faster rate than Fe–BTC framework.
After pH stimuli, we investigated the effect of biomimetic
systems such as liposomes on MOF–dox composites as lipo-
somes are known to mimic cell membranes and are considered
to be a true biomimetic system. We used negatively charged
liposomes composed of two lipids (DMPC/DMPG, 8:2). As the
pKa of dox is 8.2, it remains mostly positively charged under
the experimental conditions (pH … 7.4) used.[46] Therefore, it is
likely that dox will bind strongly with the negatively charged
liposomes. To establish this fact, we studied the interaction of
dox with bare liposomes (see Figure S1 and Table S1 in the
Supporting Information). Figure 4 a and b shows the release of
drugs upon contact with liposomes. It is clear from Figure 4 a
and b that there is an almost 1.6-fold increase in fluorescence
intensity in the case of Fe–BTC–dox and the increment was
2.8-fold in the case of Zn–BTC–dox. This is also attributed to
the stronger binding affinity of Fe–BTC with dox compared to
Zn–BTC. Notably, the intensity at zero time in the presence of
ð2Þ liposomes is much higher compared to that in buffer solution.
This fact indicates that in the presence of liposomes, dox mole-
cules absorbed on the surface of the MOFs immediately re-
lease from the composites due to electrostatic interactions
with the liposomes.
The post-release fate of dox upon addition of liposomes to
MOF–dox composites was also studied by CLSM. CLSM images
(Figure 5) reveal that there was no emission from blank lipo-
1075 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Figure 5. CLSM images of a) blank liposomes, b) MOF–dox-liposomes,
c) zoomed image of liposomes after uptake of dox.
somes. As liposome is added to MOF–dox composites, the
drug release takes place and an intense signal was obtained
from solution. Furthermore, it is revealed that the drug mole-
cules appear to be in the core of the liposome and were uni-
formly distributed in the bulk as a result of release from MOF–
dox composites. This confirmed the successful uptake of dox
molecules into liposomes.
3. Conclusions
In conclusion, we report a simple, environmentally benign
method for the synthesis of two highly biocompatible MOFs
and drug-embedded MOFs in a one-step, room temperature
reaction. The drug-embedded MOFs were found to release the
drug in the presence of a biomimetic system such as lipo-
somes. This is the first time that liposomes have been used to
release dox from a dox-embedded MOF. We also demonstrated
the successful release of the drug from MOF–drug composites
using low-acidity conditions over a period of three days for the
first time. The novelty of the present work is in its facile and in-
dustrially amenable synthesis of the MOFs and drug-embed-
ded MOFs and in the slow delivery of dox using external stim-
uli. We hope this study will afford new opportunities in the
field of biomaterials science in the near future.
Acknowledgements
The authors would like to thank Sophisticated Instrument Centre
(SIC), IIT Indore for providing the facilities and infrastructure. We
are grateful to the powder X-ray diffraction (P-XRD) facility at the
SIC, IIT Indore. C.A. acknowledges financial support from IIT
Indore.
Keywords: doxorubicin · drug delivery · liposomes · metal–
organic frameworks · pH
[1] N. W. Ockwig, O. Delgado-Friedrichs, M. O’Keeffe, O. M. Yaghi, Acc.
Chem. Res. 2005, 38, 176 – 182.
[2] M. Eddaoudi, D. B. Moler, H. Li, B. Chen, T. M. Reineke, M. O’Keeffe, O. M.
Yaghi, Acc. Chem. Res. 2001, 34, 319 – 330.
ChemPhysChem 2016, 17, 1070 – 1077 www.chemphyschem.org
Articles
[3] J. L. Rowsell, O. M. Yaghi, Angew. Chem. Int. Ed. 2005, 44, 4670 – 4679;
Angew. Chem. 2005, 117, 4748 – 4758.
[4] M. Dincă, J. R. Long, Angew. Chem. Int. Ed. 2008, 47, 6766 – 6779; Angew.
Chem. 2008, 120, 6870 – 6884.
[5] J. Zhuang, C.-H. Kuo, L.-Y. Chou, D.-Y. Liu, E. Weerapana, C.-K. Tsung, ACS
Nano 2014, 8, 2812 – 2819.
[6] B. Chen, S. Ma, E. J. Hurtado, E. B. Lobkovsky, C. Liang, H. Zhu, S. Dai,
Inorg. Chem. 2007, 46, 8705 – 8709.
[7] B. Chen, S. Xiang, G. Qian, Acc. Chem. Res. 2010, 43, 1115 – 1124.
[8] H.-L. Jiang, Y. Tatsu, Z.-H. Lu, Q. Xu, J. Am. Chem. Soc. 2010, 132, 5586 –
5587.
[9] H.-L. Jiang, Q. Xu, Chem. Commun. 2011, 47, 3351 – 3370.
[10] J. Lee, O. K. Farha, J. Roberts, K. A. Scheidt, S. T. Nguyen, J. T. Hupp,
Chem. Soc. Rev. 2009, 38, 1450 – 1459.
[11] C.-H. Kuo, Y. Tang, L.-Y. Chou, B. T. Sneed, C. N. Brodsky, Z. Zhao, C.-K.
Tsung, J. Am. Chem. Soc. 2012, 134, 14345 – 14348.
[12] J. Della Rocca, D. Liu, W. Lin, Acc. Chem. Res. 2011, 44, 957 – 968.
[13] P. Horcajada, T. Chalati, C. Serre, B. Gillet, C. Sebrie, T. Baati, J. F. Eubank,
D. Heurtaux, P. Clayette, C. Kreuz, Nat. Mater. 2010, 9, 172 – 178.
[14] P. Horcajada, C. Serre, M. Vallet-Reg†, M. Sebban, F. Taulelle, G. F¦rey,
Angew. Chem. Int. Ed. 2006, 45, 5974 – 5978; Angew. Chem. 2006, 118,
6120 – 6124.
[15] J. An, S. J. Geib, N. L. Rosi, J. Am. Chem. Soc. 2009, 131, 8376 – 8377.
[16] N. Li¦dana, A. Galve, C. Rubio, C. T¦llez, J. Coronas, ACS Appl. Mater. In-
terfaces 2012, 4, 5016 – 5021.
[17] I. Imaz, J. Hernando, D. Ruiz-Molina, D. Maspoch, Angew. Chem. Int. Ed.
2009, 48, 2325 – 2329; Angew. Chem. 2009, 121, 2361 – 2365.
[18] I. Imaz, M. Rubio-Mart†nez, L. Garc†a-Fern‚ndez, F. Garc†a, D. Ruiz-Molina,
J. Hernando, V. Puntes, D. Maspoch, Chem. Commun. 2010, 46, 4737 –
4739.
[19] S. Devautour-Vinot, C. Martineau, S. Diaby, M. Ben-Yahia, S. Miller, C.
Serre, J. Phys. Chem. C 2013, 117, 11694 – 11704.
[20] D. Cunha, C. Gaudin, I. Colinet, P. Horcajada, G. Maurin, C. Serre, J.
Mater. Chem. B 2013, 1, 1101 – 1108.
[21] R. Babarao, J. Jiang, J. Phys. Chem. C 2009, 113, 18287 – 18291.
[22] S. Devautour-Vinot, G. Maurin, C. Serre, P. Horcajada, D. Paula da Cunha,
V. Guillerm, E. de Souza Costa, F. Taulelle, C. Martineau, Chem. Mater.
2012, 24, 2168 – 2177.
[23] H. Li, M. Eddaoudi, M. O’Keeffe, O. M. Yaghi, Nature 1999, 402, 276 – 279.
[24] S. J. James, Chem. Soc. Rev. 2003, 32, 276 – 288.
[25] A. U. Czaja, N. Trukhan, U. Mìller, Chem. Soc. Rev. 2009, 38, 1284 – 1293.
[26] J. R. Long, O. M. Yaghi, Chem. Soc. Rev. 2009, 38, 1213 – 1214.
[27] Z. Wang, S. M. Cohen, Chem. Soc. Rev. 2009, 38, 1315 – 1329.
[28] M. Eddaoudi, J. Kim, N. Rosi, D. Vodak, J. Wachter, M. O’Keeffe, O. M.
Yaghi, Science 2002, 295, 469 – 472.
[29] K. Schlichte, T. Kratzke, S. Kaskel, Microporous Mesoporous Mater. 2004,
73, 81 – 88.
[30] A. Pichon, A. Lazuen-Garay, S. L. James, CrystEngComm 2006, 8, 211 –
214.
[31] J. A. Rood, B. C. Noll, K. W. Henderson, Inorg. Chem. 2006, 45, 5521 –
5528.
[32] O. M. Yaghi, H. Li, J. Am. Chem. Soc. 1995, 117, 10401 – 10402.
[33] J. L. C. Rowsell, O. M. Yaghi, Microporous Mesoporous Mater. 2004, 73,
3 – 14.
[34] O. M. Yaghi, M. O’Keeffe, N. W. Ockwig, H. K. Chae, M. Eddaoudi, J. Kim,
Nature 2003, 423, 705 – 714.
[35] A. Czaja, E. Leung, N. Trukhan, U. Mìller in Metal-Organic Frameworks:
Applications from Catalysis to Gas Storage (Ed.: D. Farrusseng), Wiley-
VCH, Weinheim, 2011, pp. 337 – 352.
[36] J. R. Hunt, O. M. Yaghi, Tetrahedron 2008, 64, 8553 – 8557.
[37] M. Gerardo, I. Oliver, Y. Maxim, J. Gunnar, J. P¦rez-Ram†rez, CrystEng-
Comm 2013, 15, 9885 – 9892.
[38] J. L. Zhuang, D. Ceglarek, S. Pethuraj, A. Terfort, Adv. Funct. Mater. 2011,
21, 1442 – 1447.
[39] L. Huang, H. Wang, J. Chen, Z. Wang, J. Sun, D. Zhao, Y. Yan, Micropo-
rous Mesoporous Mater. 2003, 58, 105 – 114.
[40] P. Horcajada, S. Surble, C. Serre, D.-Y. Hong, Y.-K. Seo, J.-S. Chang, J.-M.
Greneche, I. Margiolaki, G. Ferey, Chem. Commun. 2007, 2820 – 2822.
[41] V. Agostoni, R. Anand, S. Monti, S. Hall, G. Maurin, P. Horcajada, C. Serre,
K. Bouchemal, R. Gref, J. Mater. Chem. B 2013, 1, 4231 – 4242.
1076 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

[42] A. G. M‚rquez, A. Demessence, A. E. Platero-Prats, D. Heurtaux, P. Horca-
jada, C. Serre, J. S. Chang, G. Ferey, V. A. de la PeÇa-O’Shea, C. BoissiÀre,
Eur. J. Inorg. Chem. 2012, 32, 5165 – 5174.
[43] Y.-K. Seo, J. W. Yoon, J. S. Lee, U.-H. Lee, Y. K. Hwang, C.-H. Jun, P. Horca-
jada, C. Serre, J.-S. Chang, Microporous Mesoporous Mater. 2012, 157,
137 – 145.
[44] L. Xu, E.-Y. Choi, Y.-U. Kwon, Inorg. Chem. Commun. 2008, 11, 1190 –
1193.
[45] L. Luo, K. Chen, Q. Liu, Y. Lu, T. Okamura, G. C. Lv, Y. Zhao, W. Y. Sun,
Cryst. Growth Des. 2013, 13, 2312 – 2321.
[46] R. Anand, F. Borghi, F. Manoli, I. Manet, V. Agostoni, P. Reschiglian, R.
Gref, S. Monti, J. Phys. Chem. B 2014, 118, 8532 – 8539.
[47] M. R. di Nunzio, V. Agostoni, B. Cohen, R. Gref, A. Douhal, J. Med. Chem.
2014, 57, 411 – 420.
[48] T. Chalati, P. Horcajada, P. Couvreur, C. Serre, M. Ben Yahia, G. Maurin, R.
Gref, Nanomedicine 2011, 6, 1683 – 1695.
[49] A. C. McKinlay, R. E. Morris, P. Horcajada, G. Ferey, R. Gref, C. Couvreur, C.
Serre, Angew. Chem. Int. Ed. 2010, 49, 6260 – 6266; Angew. Chem. 2010,
122, 6400 – 6406.
[50] R. Canioni, C. Roch-Marchal, F. S¦cheresse, P. Horcajada, C. Serre, M.
Hardi-Dan, G. F¦rey, J. M. GrenÀche, F. Lefebvre, J. Chang, Y. Hwang, O.
Lebedev, S. Turnerf, G. Van Tendeloo, J. Mater. Chem. 2011, 21, 1226 –
1233.
[51] V. Agostoni, T. Chalati, P. Horcajada, H. Willaime, R. Anand, N. Semira-
moth, T. Baati, S. Hall, G. Maurin, H. Chacun, K. Bouchemal, C. Martineau,
F. Taulelle, P. Couvreur, C. Rogez-Kreuz, P. Clayette, S. Monti, C. Serre, R.
Gref, Adv. Healthcare Mater. 2013, 2, 1630 – 1637.
[52] D. Cunha, M. B. Yahia, S. Hall, S. R. Miller, H. Chevreau, E. Elkam, G.
Maurin, P. Horcajada, C. Serre, Chem. Mater. 2013, 25, 2767 – 2776.
ChemPhysChem 2016, 17, 1070 – 1077 www.chemphyschem.org 1077
Articles
[53] Q. Hu, J. Yu, M. Liu, A. Liu, Z. Dou, Y. Yang, J. Med. Chem. 2014, 57,
5679 – 5685.
[54] L.-N. Duan, Q. – Q. Dang, C.-Y. Han, X.-M. Zhang, Dalton Trans. 2015, 44,
1800 – 1804.
[55] N. Li¦dana, A. Galve, C. Rubio, C. T¦llez, J. Coronas, ACS Appl. Mater. In-
terfaces 2012, 9, 5016 – 5021.
[56] L. Nuria, L. Pablo, G. Alejandro, T. Carlos, C. Joaqu†n, J. Mater. Chem. B
2014, 2, 1144 – 1151.
[57] P. Lorena, P. Gr¦gory, A. Steven, C. Joaqu†n, Org. Biomol. Chem. 2015, 13,
1724 – 1731.
[58] C. Adhikari, A. Das, A. Chakraborty, Mol. Pharm. 2015, 12, 3158 – 3166.
[59] R. Thakur, A. Das, A. Chakraborty, J. Photochem. Photobiol. B 2014, 130,
122 – 131.
[60] R. Thakur, A. Das, A. Chakraborty, Phys. Chem. Chem. Phys. 2012, 14,
15369 – 15378.
[61] C. Adhikari, A. Das, A. Chakraborty, ChemPhysChem 2015, 16, 866 – 871.
[62] M. Tong, D. Liu, Q. Yang, S. Devautour-Vinot, G. Maurinb, C. Zhonga, J.
Mater. Chem. A 2013, 1, 8534 – 8537.
[63] X. Huang, Y. Chen, Z. Lin, X. Ren, Y. Song, Z. Xu, X. Dong, X. Li, C. Hu, B.
Wang, Chem. Commun. 2014, 50, 2624 – 2627.
[64] N. W. Read, K. Sugden, Crit. Rev. Ther. Drug Carrier Syst. 1998, 4, 221 –
263.
[65] T. T. Kararli, Biopharm. Drug Dispos. 1995, 16, 351 – 380.
Manuscript received: November 9, 2015
Accepted Article published: January 11, 2016
Final Article published: February 16, 2016
Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim