A novel 1,2,3-benzotriazolium based ionic liquid monomer for preparation of MMT/poly ionic liquid (PIL) pH-sensitive positive charge nanocomposites

Article abstract of DOI:10.1007/s12039-019-1592-y

Abstract : In this work, a new ionic liquid (IL) with two acidic and vinylic functional groups based on 1,2,3-benzotriazolium cation was synthesized. This IL monomer was intercalated into the montmorillonite (MMT) layers by the ion exchange reaction and subsequently copolymerized with the IL monomer and methacrylic acid in order to obtain positive charge pH-sensitive nanocomposites. The structure of the IL monomer was characterized by FT-IR and ¹H -NMR spectroscopy, and the structure of the nanocomposites was studied and confirmed by the FT-IR, XRD, TGA, SEM, and EDX data. These pH-sensitive nanocarriers were used to load and in vitro release of the anticancer drug, methotrexate (MTX) in pH?= 4 and pH?= 7.4. The results showed that the release is pH dependent and more effective in acidic pH; therefore, these nanocarriers have potential to be used for cancer therapy. Graphical abstract : SYNOPSIS Synthesis and characterization of a new dual functional ionic liquid monomer and use of it to prepare positive charge pH-sensitive nanocomposites for anti-cancer drug delivery application. Results showed that use of only this monomer in the structure of nanocomposite is more effective to the delivery of negatively charged drugs. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-019-1592-y

J. Chem. Sci.
(2019) 131:18
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1592-y
REGULAR ARTICLE
A novel 1,2,3-benzotriazolium based ionic liquid monomer for
preparation of MMT/poly ionic liquid (PIL) pH-sensitive positive
charge nanocomposites
FATEMEH SOGHRA JAHEDa, MOHAMMAD GALEHASSADIa,∗ and
SOODABEH DAVARANb
aDepartment of Chemistry, Faculty of Science, Azarbaijan Shahid Madani University, Tabriz, Iran
bBiotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
E-mail: mg-assadi@azaruniv.ac.ir
MS received 6 October 2018; revised 22 December 2018; accepted 2 January 2019
Abstract. In this work, a new ionic liquid (IL) with two acidic and vinylic functional groups based on 1,2,3-
benzotriazolium cation was synthesized. This IL monomer was intercalated into the montmorillonite (MMT)
layers by the ion exchange reaction and subsequently copolymerized with the IL monomer and methacrylic
acid in order to obtain positive charge pH-sensitive nanocomposites. The structure of the IL monomer was
1
characterized by FT-IR and H-NMR spectroscopy, and the structure of the nanocomposites was studied and
confirmed by the FT-IR, XRD, TGA, SEM, and EDX data. These pH-sensitive nanocarriers were used to load
and in vitro release of the anticancer drug, methotrexate (MTX) in pH=4 and pH=7.4. The results showed
that the release is pH dependent and more effective in acidic pH; therefore, these nanocarriers have potential to
be used for cancer therapy.
Keywords. IL monomer; montmorillonite; nanocomposites; nanocarriers; methotrexate; cancer therapy.
1. Introduction
Nowadays, cancer is a common fatal disease. Due
to the side effects of chemotherapy drugs on healthy
cells, their use in the treatment of cancer produces
major problems.10 Targeted drug release has fewer side
effects, as this technique is supposed to reach a more
accurate target. Nanoparticles are one of the most impor-
tant materials that are used in the anti-cancer DDSs.11
Nanoparticles have unique physicochemical and bio-
logical properties due to their small size. For instance,
they can easily cross the cellular barriers due to their
enhanced reactive area,12 and therefore, are suitable for
use as anti-cancer drug carriers. MMT is one of the natu-
rallynano-sizedswellingclaymineralswhichhasalarge
specific surface area; it exhibits good adsorbing ability,
cation exchange capacity, standout adhesive ability, and
drug-carrying capability. MMT is a common ingredient
like both the filler and active agents in the pharmaceu-
tical products.13 Ghanshyam V. Joshi et al., studied the
timolol maleate (TM) controlled release from the MMT-
TM hybrid.14 Ruxandra Irina Iliescu et al., prepared and
Drug delivery or feedback regulated release systems are
smart materials that carry active substances to the target
site in a given time and concentration, by adjusting the
release rate to the level of a biomarker.1 Sensitiveness
to biomarker signals is achieved by means of synthetic
materials such as functional polymers. Polymers have
unique properties that make them appropriate for drug
delivery applications. Based on their chemical structure,
functionalpolymerscanbedividedintothreecategories:
pH-sensitive, biocompatible, and cationic polymers.2
The pH gradient is one of the first stimuli in the body
that attracted considerable attention, and it has been pre-
dominantly studied in recent biomedical researches. The
pH-sensitive polymers deliver drugs into cells by the
environmental pH changes.3 A large number of drug
delivery systems (DDSs) containing polymers, such as
hydrogels,4,5 liposome,6,7 andMMT/polymernanocom-
posites8,9 have been studied during recent years.
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1592-y) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

18 Page 2 of 9
J. Chem. Sci.
(2019) 131:18
characterizedsomeMMT/antitumordrughybridswhich (TGA) data, under N2 from 50 ◦C to 850 ◦C at the 10 ◦C/min
can be used for oral chemotherapy.15
Considering the importance of drug delivery, the
design of new advanced functional materials for drug
heating ramp. Differential scanning calorimetry (DSC) was
performed with a TA instrument (Perkin-Elmer) at the heating
rate of 10 ◦C/min in the air. X-ray diffraction (XRD) analysis
was carried out by a Bruker AXS model D8 advanced diffrac-
delivery targets is an important task in pharmacother-
tometer. A Philips PU 8620 ultraviolet spectrophotometer was
apy. Ionic liquids (ILs) are known as the salts with low
used to determine the amount of drug released. The FESEM
melting points typically below 100 ◦C. Recently, many
images were registered using the image analysis software pro-
studies have been done on the use of ILs in the pharma-
ducedbyTSCANCo. (Czech), inUniversityofKurdistan, and
the energy-dispersive X-ray spectroscopy (EDX) data were
ceutical industry, including (1) as prodrug ILs,16 (2) as
a solvent for synthesis and purification of pharmaceu-
tical compounds17,18 and for dissolving poorly soluble
drug molecules,19 and (3) DDSs.8,20 ILs are extensively
used in the modification of clay nanoparticles for prepa-
ration of organic-inorganic polymer nanocomposites,
which have both inorganic and organic ingredient prop-
erties in a single material.21 In most of the researches,
IL monomers were intercalated into MMT. Afterwards,
they copolymerized with other suitable monomers such
as the methacrylic acid to obtain pH sensitive nanocom-
posites.22,23
The aim of this study is to synthesize and charac-
terize a novel 1,2,3-benzotriazolium based dual acidic
and vinylic functional IL and using it to prepare an
MMT/poly ionic liquid (PIL) pH-sensitive positive
charge nanocomposite without any need for the other
monomers. Having an acidic group and a positive
charge, this nanocomposite is favorable for the release
of negatively charged drugs.
recorded using a scanning electron microscope (SEM) device
produced by phenom Co., the Netherlands model prox, in
Azarbaijan Shahid Madani University.
2.3 Experimental procedure
2.3a Synthesis of 1-carboxymethyl-1,2,3-benzotria-
zole (CmBt): 1-H-1,2,3-benzotriazole (1 g, 8.34 mmol)
was added to a 100 mL flask containing 25 mL dry THF
as a solvent. Then, TEA (2.34 mL, 8.34 mmol) was added to
it and the mixture was stirred at room temperature. After 2
h, chloroacetic acid (0.8 g, 8.5 mmol) dissolved in 10 mL of
dry THF was added to the mixture dropwise, during 20 min.
The reaction mixture was stirred for 24 h at room temperature.
The product was purified using column chromatography (hex-
ane/ethylacetate, 1:1). The melting point of this compound is
50 ◦C.
2.3b Synthesis of ionic liquid monomers (ILMs):
CmBt (10 mmol), 4-vinylbenzyl chloride (11 mmol), and
inhibitor 2,6-di-tert-butyl-4-methyl phenol (0.1 mmol) were
added to a 50 mL two-necked round bottom flask equipped
with a magnetic stirrer. This mixture was stirred under N2
atmosphere at 55−60 ◦C for 48 h. Then the product was
washed several times by excess dry ethyl acetate to leave
unreacted materials. The obtained pure product (ILM-1,
Scheme 1) was dried under vacuum. The melting point of
ILM-1 is 118 ◦C. Then the ILM-1 (2.43 mmol) was dissolved
in deionized water (40 mL) and NaPF6 salt dissolved in deion-
ized water was added to it drop by drop. The mixture was
stirred at room temperature. After 24 h, the obtained precip-
itate was collected and washed several times with deionized
water to remove the unreacted materials and a chloride anion.
Silver nitrate testing indicated that no chloride ion exists,
hence the product (ILM-2, Scheme 1) was dried over CaCl2
under vacuum. The melting point of this monomer is 99 ◦C.
2. Experimental
2.1 Materials
4-vinylbenzyl chloride (VBC), 2,6-di-tert-butyl-4-methyl
phenol (BHT), methotrexate (MTX), sodium, and HCl 37%,
were purchased from Aldrich (America). Benzotriazole (Bt),
α αꢀ
-azobis(isobutyronitrile) (AIBN),
triethylamine (TEA),
,
dimethylformamide (DMF), tetrahydrofuran (THF), acetoni-
trile, diethyl ether, hexane, ethylacetate, methacrylic acid,
chloroacetic acid, sodium dihydrogen phosphate, potassium
hydrogen phosphate, sodium sulfate, and silica gel (60(0.04–
0.063 mm)), were purchased from Merck (Germany). Mont-
morillonite was purchased from Kunimine industries Co.
(Japan).
2.3c Intercalation of ionic liquid monomer in MMT
(OMMT): Na-MMT (0.5 g) was dispersed in H2O/EtOH
(3:1, 30 mL) by ultra-sonication for 15 min and was stirred
at 60 ◦C for 2 h. Then the reaction temperature was reached
2.2 Characterization techniques
Infrared spectra were recorded with a 4600 Unicam FT-IR 50 ◦C. Afterwards, ILM-1 (1 g) solubilized in H2O/EtOH
1
spectrophotometer. H (400 MHz) NMR (nuclear magnetic (1:1, 10 mL) was added dropwise into the mixture in 30 min.
resonance) spectrum was recorded in dimethyl sulfoxide-d6 Then this suspension was vigorously stirred for 48 h. The
(DMSO-d6) on a Bruker 400 MHz spectrometer at room resultant precipitate was filtered and washed several times
temperature. A TA instrument (Mettler Toledo 851e, Ger- withdistilledwateruntilnochlorideionwasdetectedbysilver
many) was used to record the thermogravimetric analysis nitrate testing. The product was dried under vacuum for 24 h.

J. Chem. Sci.
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18
Scheme 1. Synthesis of dual functional ILM.
2.3d Preparation of the OMMT-PIL nanocomposite: Each obtained
pH-responsive
MTX-loaded
This nanocomposite was prepared by polymerization of the nanocompositewasdispersedin3mLbuffersolutionsnamely
suspension of ILM-2 (0.2 g) and OMMT (0.2 g), in acetoni- simulated gastric fluid and simulated intestinal fluid (SGF,
trile as a solvent in the presence of AIBN (2 mol%), as an SIF) for 5 min and was placed in a separate dialysis bag. Then
initiator at 70 ◦C for 48 h under argon atmosphere. The resul- the bags were located in 10 mL of release media at 37 ◦C.
tant product was centrifuged and washed by dry acetonitrile During the release study, the medium was slowly stirred. At
(3 × 10 mL) and was dried under vacuum.
appropriate times, 3 mL of each solution was collected and
3 mL of the same fresh buffer was added to the release pro-
file. The amount of released MTX was measured by a UV-vis
spectrophotometer at 300 nm. The content of the encapsulated
and released drug was estimated with the following formulas,
respectively:
2.3e Preparation of the OMMT-CO(PIL-MAA)
nanocomposite: This nanocomposite was prepared by
copolymerization of the suspension of ILM-2 (0.1 g), MAA
monomer (0.1 g) and OMMT (0.2 g) (0.5:0.5:1, g/g/g) in ace-
tonitrile as a solvent in the presence of AIBN (2 mol%), as an
initiator at 70 ◦C for 48 h under argon atmosphere. The resul-
tant product was centrifuged and washed by dry acetonitrile
(3 × 10 mL) and was dried under vacuum.
Drug entrapment content (%)
Mass of drug in nanocomposite
=
× 100
(1)
Initial mass of drug
Drug released content (%)
Total amount of drug in release medium
2.3f Drug loading and in vitro release study: In a
solution (5 mL) containing MTX (10 mg), 100 mg of each
nanocomposite was dispersed by using an ultrasonic genera-
tor device for 10 min. Then, the mixture was stirred at room
temperature for 24 h. The MTX loaded nanocomposites were
centrifuged at 12000 rpm for 10 min to remove unloaded
MTX and was dried at room temperature under vacuum. The
supernatants were kept for measurement of drug concentra-
=
× 100 (2)
The amount of drug in nanocomposite
3. Results and Discussion
3.1 Characterization
3.1a IL monomer characterization: The synthesis of
tion which was done by a standard MTX concentration curve. the dual functional ILM is shown in Scheme 1. The

18 Page 4 of 9
J. Chem. Sci.
(2019) 131:18
Figure 1. The FT-IR spectra of ILM-1 (a) and ILM-2 (b).
Figure 2. 1H NMR spectrum of ILM-1.
Figure 3. Synthesis route of nanocomposites.
chemical structure of ILM was characterized by FT-IR,
FT-IR (neat, KBr): ILM-1: Figure 1A, represent the
1HNMR. Figure 1 and Figure 2 show the 1H NMR and characteristic peaks of this monomer: 3497 cm−1 (OH,
FT-IR spectra, respectively.
acid), 3000 cm−1 (C–H, aromatic), 2884, 2946 cm−1

J. Chem. Sci.
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Page 5 of 9
18
Figure 4. FT-IR spectra of (a) Na+-MMT, (b) OMMT, (c) OMMT-PIL, (d) OMMT-CO(PIL-MAA), (e)
OMMT-PIL, (f) MTX&OMMT-PIL.
(C–H, aliphatic), 1720 cm−1 (C=O, acid), 1604 cm−1
(C=C, vinyl), 1408−1513 cm−1 (C=C, aromatic),
1445 cm−1 (triazole).
ILM-2: in the FT-IR spectrum of this monomer (Fig-
ure 1B), in addition to other peaks, the P-F peak at
859 cm−1 confirms the anion exchange reaction.
1H NMR (400 MHz, DMSO-d6, ppm): 10.32 (1H, s,
–COOH), 8.41 (2H, m, Bt), 7.99 (2H, m, Bt), 7.52 (4H,
m, styrene), 6.73 (1H, dd, –CH=CH2, vinyl), 6.30 (2H,
s, N–CH2–COOH), 6.0 (2H, s, N−CH2−ph), 5.8, 5.3
(1H, 1H, d, d, −CH = CH2, vinyl).
3.1b Nanocomposite characterization: The ILM-1
was used to modify MMT that was named as OMMT.
The OMMT-PIL nanocomposite was prepared by poly-
merization of ILM-2, and the OMMT-CO(PIL-MAA)
nanocomposite was prepared by copolymerization of
ILM-2 and MAA in the presence of OMMT (Figure 3).
The chemical structure of the OMMT, OMMT-PIL, and
OMMT-CO(PIL-MAA) nanocomposites were charac-
terized by FT-IR, XRD, SEM, EDS, and TGA analyses.
3.1.2.1 FT-IR
ChemicalstructureofOMMTandnanocompositeswere
Figure 5. The XRD patterns of: (a) MMT, (b) OMMT (c)
OMMT-CO(PIL-MAA) and (d) OMMT-PIL.
studied by the FT-IR spectroscopy. It can be seen in
Figure 4 in all spectra, absorption bands at 524 cm−1,
917 cm−1, and 1044 cm−1 are related to bending vibra- the structural hydroxyl group in the MMT and inter-
tion of Si-O-Al and stretching vibration of Al-Al-OH layer water was observed at 3690 cm−1 and 3454 cm−1,
and Si-O-Si, respectively. The stretching vibration of respectively. In the spectra of Figure 4b, adsorption

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J. Chem. Sci.
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Figure 6. The SEM images of: (a) pristine MMT; (b) IL modified MMT (OMMT); (c) OMMT-PIL
nanocomposite; (d) OMMT-CO(PIL-MAA) nanocomposite.
bonds at 1210 cm−1, 1450 cm−1, 1609 cm−1, 1721 cm−1, decreased, because of the low percentage of the PIL
2923 cm−1, and 3000 cm−1 were attributed to C–O of in the OMMT-CO(PIL-MAA) nanocomposite toward
the acid, triazole, C=C aromatic, C=O of the acid, C– OMMT-PIL.
H aliphatic, and C–H aromatic, which confirmed that
The FT-IR spectra in Figure 4e reveal the new absorp-
organic cation of IL is replaced with sodium cation in tion peaks in 1640 cm−1 and 1520 cm−1 which refer to
the interlayer of MMT. In the spectra of Figure 4c and the stretching vibration of the CO–NH bond and the
Figure 4d, the absorption bond of C=O acidic functional bending vibration of the −NH2 group of MTX, respec-
group at 1721 cm−1 has been stronger as well as all of tively. On the other hand, a decrease in peak intensity
the other peaks, due to polymerization of ILM-2 in the at 1721 cm−1 and 1044 cm−1 is due to the ionic inter-
interlayer and surface of MMT, and FT-IR device can action between the drug and carrier. Therefore, FT-IR
easily identify the functional groups easily. In the spec- results confirm the successful MTX loading on the
tra of Figure 4d, the intensity of the C=C aromatic peak carrier.

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Page 7 of 9
18
Figure 7. EDS analysis for (a) OMMT-PIL nanpcomposite; (b) OMMT-CO(PIL-MAA).
3.1.2.2 XRD
Structural changes of the MMT nanoparticles in the
cation exchange reaction and preparation of organic-
inorganic nanocomposites are determined by variation
in the XRD pattern. The XRD pattern of MMT, OMMT,
and nanocomposites are shown in Figure 5, the Bragg
between 2θ = 2o−12o was recorded. As seen in Fig-
ure 5a, MMT has a peak in 2θ = 9.3o which shifted to
2θ = 6o after modification with ILM-1 (Figure 5b).
According to Bragg’s law, the displacement of the
peak replaces to a lower reflection angle, is due to the
increase of d-spacing of MMT, which confirm the cation
exchange reaction is carried out and sodium cations
have been replaced with ILM-1 cations. The d-spacing
was increased from 9.45 nm in MMT to 14.81 nm in
OMMT. The d-spacing of the OMMT-CO(PIL-MAA)
(d-spacing is 15.5 nm) (Figure 5c) nanocomposite was
not very different from that of OMMT (d-spacing is
14.81 nm). It can be concluded that the polymerization
occurred out of the MMT layers. But the d-spacing of
OMMT-PIL (16.85 nm) (Figure 5d) is higher than that
of OMMT and it can be said that the polymerization
occurred in and outside the MMT layers.
Figure 8. The schematic way of MTX loading in pH=7.4.
(Figure 7b), and OMMT-PIL (Figure 7a), an increase in
C is observed after polymerization.
3.1.2.4 Thermal analysis
The thermogravimetric analysis (TGA/DTG) profiles
of MMT, OMMT, and nanocomposites are shown in
Figure S1 (Supplementary Information). In the TGA
profile of MMT (Figure S1A, Supplementary Informa-
tion), all weight loss is due to evaporation of free water
and water in the interlayer space and loss structural
hydroxyl group. In the OMMT TGA profile (Figure
S1B), the weight loss at 80−200 ◦C is due to evapora-
tion of free water and the weight loss at 200−500 ◦C is
attributed to the organic substance. The structural water
evolved in the region between 600−800 ◦C. The TGA
profile of the OMMT-PIL and OMMT-CO(PIL-MAA)
nanocomposites (Figure S1C and S1D, Supplementary
Information) has three steps below 200 ◦C, 200–450,
and up to 450 ◦C. Combustion of pending and polymer
backbone took place at 200−450 ◦C.
3.1.2.3 SEM and EDS
The SEM photographs were used to determine the sur-
face morphology of the MMT, OMMT and OMMT-PIL
nanocomposites. The images (Figure 6) clearly show the
layered structure of MMT. In the OMMT image (Fig-
ure 6b), the changing in morphology is quite evident.
The image Figure 6c, confirms that the layers of MMT
were filled with polymer and the structure became more
homogenous.
The presence of N, C, P, and F atoms in the nanocom-
posite structures was confirmed by the EDS studies
(Figure 7), which confirm the formation of nanocom-
posites. In the EDS spectrum of OMMT-CO(PIL-MAA)

18 Page 8 of 9
J. Chem. Sci.
(2019) 131:18
Figure 9. MTX release from (a) OMMT-PIL and (b) OMMT-CO(PIL-MAA) at 37 ◦C in different pH=4 and pH=7.4.
3.2 MTX loading
release of the drug happens easily. While in pH=7.4,
MTX has an overall negative charge and it is more
attracted to the nanocomposites by hydrogen bonding
and electrostatic interactions with the positive charge
of the 1,2,3-triazole ring and shows a slower release.
Comparing the percentage of drug release of the two
nanocomposites in pH=4 and pH=7.4, the amount of
release is 99 and 39% for OMMT-PIL and 99 and 61%
for OMMT-CO(PIL-MAA), respectively. This shows
high pH dependence of OMMT-PIL.
Nanocomposites contain MMT nanoparticles and
cationic polymers with the carboxylic acid group. On
the other hand, MTX bears two amine and carboxylic
groups in its structure and has a negative charge in
pH = 7.4.24 In this pH zeta-potential for OMMT-PIL is
−1.1 (Figure S4, Supplementary Information), the neg-
ative charge of the nanocomposite is not large and thus
loading of the drug can be done easily.
Incorporation of the drug in the nanocomposite was
occurred by (a) intercalation in MMT layers by sub-
stitution with water molecules and interaction with a
hydroxyl end group of MMT, (b) electrostatic interac-
tion with cationic segments and carboxylic groups of the
IL polymer and (c) anion exchange of the counter anion
of the cationic polymer by drug molecules. The way of
drug loading in this pH is shown in Figure 8. Efficient
drug entrapment for OMMT-PIL and OMMT-CO(PIL-
MAA) was 89% and 81%, respectively, as estimated by
formula 1. High concentration of the carboxyl group
and positively charged moieties in OMMT-PIL cause
the drug entrapment increase toward OMMT-CO(PIL-
MAA).
4. Conclusions
New dual functional ILM based on 1,2,3-benzotria-
zolium was synthesized and intercalated into MMT
using the ion exchange reaction. Then, the organic-
inorganic nanocomposites (OMMT-PIL) and OMMT-
CO(PIL-MAA) were prepared by incorporating positive
charge and acidic groups in the framework. The anti-
cancer drug (MTX) was successfully loaded on these
nanocomposites and the in vitro release of it in pH=4
and pH=7.4 was investigated. The results showed that
release from both the nanocomposites is completely pH
dependent and is high in acidic pH, while OMMT-PIL
has high pHdependency. On the otherhand, drug entrap-
ment content in OMMT-PIL (89%) is more than that
of OMMT-CO(PIL-MAA) (81%). It can be said that
OMM-PIL can bring drug dosage down due to the high
loading level and regular release of the drug. Also, hav-
ing the antimicrobial compound benzotriazole in the
nanocomposite structure produces a great potential to
use as a substrate in the delivery of anticancer drugs in
chemotherapy.
3.2a In vitro MTX release study: Drug release studies
of both nanocomposites were performed at 37 ◦C for 10
days, in the simulated physiological environment of the
intestine (pH=7.4) and the acidic environment of the
cancer cells (pH=4). Figure 9 shows the release profile.
As can be seen in the diagrams, for both nanocom-
posites, the release is pH dependent and it is more
effective in acidic pH. In this environment, the release
has the highest percentage within ten days. Under
these conditions, the carboxyl groups of medicines and
nanocomposites and amine groups of the drug were pro-
tonated and thus, a repulsive force occurred between the
drug molecules and the nanocomposites and this over-
Supplementary Information (SI)
Some additional data about the characterization of monomers
came to ionic interaction and hydrogen bonding, so the and nanocomposites (TGA thermograms and zeta-potential

J. Chem. Sci.
(2019) 131:18
Page 9 of 9
18
of nanocomposites, the original FT-IR and HNMR spectra of
all synthesized molecules) are available in the supplementary
information. Supplementary Information is available at www.
ias.ac.in/chemsci.
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Circulation 113 535
11. Brannon-PeppasLandBlanchetteJO2012Nanoparticle
and targeted systems for cancer therapy Adv. Drug Deliv.
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12. Wilczewska A Z, Niemirowicz K, Markiewicz K H and
CarH2012NanoparticlesasdrugdeliverysystemsPhar-
macol Rep. 64 1020
13. Yeum J H 2011 Novel poly(vinyl alcohol)/Clay
Nanocomposite Microspheres Via Suspension Polymer-
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Acknowledgements
This work is funded by the Azarbaijan Shahid Madani Uni-
versity.
Compliance with ethical standards
14. Joshi G V, Kevadiya B D, Patel H A, Bajaj H C and Jasra
R V 2009 Montmorillonite as a drug delivery system:
Intercalation and in vitro release of timolol maleate Int.
J. Pharm. 374 53
Conflict of interest. The authors report no declaration of
interest. The authors alone are responsible for the content
and writing of the paper.
15. Iliescu R I, Andronescu E, Voicu G, Ficai A and Covaliu
C I 2011 Hybrid materials based on montmorillonite and
citostatic drugs: Preparation and characterization Appl.
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