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ChemistrySelect doi.org/10.1002/slct.202001102
z Materials Science inc. Nanomaterials & Polymers
Mesoporous Magnetite Nanoclusters as Efficient
Nanocarriers for Paclitaxel Delivery
Shima and P. Damodaran*[a]
This manuscript report the facile and cost-effective fabrication
of a targeted drug delivery system based on mesoporous
magnetite (Fe3O4) nanoclusters. A simple one-pot solvothermal
method was followed for the synthesis of mesoporous Fe3O4
nanoclusters having average cluster size of ∼ 120 nm. As-
synthesized Fe3O4 nanoclusters exhibited excellent water
dispersibility and superparamagnetism in conjunction with fast
magnetic responsiveness. The anticancer drug, paclitaxel (PTX)
was used as the model drug to investigate the applicability of
as-prepared mesoporous Fe3O4 nanoclusters for drug delivery
applications. Successful loading of PTX into Fe3O4 nanoclusters
was confirmed by Fourier-transform infrared (FT-IR) spectro-
1. Introduction
Magnetic nanoparticles are of great scientific interest in the
field of biomedicine on account of their vast number of
potential applications including targeted drug delivery,[1] mag-
netic resonance imaging (MRI),[2] bio-separation,[3] magnetic
hyperthermia,[4] enzyme[5] and protein immobilization.[6] In
particular, controlled release of drugs using magnetic nano-
materials got considerable attention recently because of their
prospects in cancer treatment.[7] Iron oxide nanoparticles,
especially Fe3O4 nanoparticles are mostly favoured for drug
delivery applications because of their high saturation magnet-
ization, biocompatibility, low cytotoxicity and stability in
physiological environments.[8] Fe3O4 possess high saturation
magnetization value (∼ 92 emu/g) compared to other transition
metal ferrites.[9] Furthermore, Fe3O4 nanoparticles are less prone
to oxidation compared to other iron oxide nanoparticles; the
hematite (α-Fe2O3) and maghemite (γ-Fe2O3). In the last
decades, several synthetic routes such as chemical co-precip-
itation, thermal decomposition, microemulsion, hydrothermal
and solvothermal methods have been followed for the syn-
thesis Fe3O4 nanoparticles with controlled size/size-distribution,
morphology and magnetic properties.[10]
[a] Dr. Shima, P. Damodaran
Department of Chemistry, National Institute of Technology, Tiruchirappal-
li-620 015, Tamil Nadu, India
Fax: + 91-431-2500133
Tel: + 91-9447956884
E-mail: shima@nitt.edu
shimapd@gmail.com
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.202001102
ChemistrySelect 2020, 5, 9261 – 9268
scopy and drug loading capacity was estimated by thermogra-
vimetric analysis (TGA). An efficient loading capacity of 17 %
was achieved for PTX in the present study. The in vitro release
of PTX was higher in acidic pH compared to physiological pH.
As the extracellular pH of cancer cells is more acidic than that
of normal cells, mesoporous Fe3O4 nanocluster-based drug
delivery vehicles can reduce the undesired release of PTX in
blood circulation during the delivery process (at physiological
pH) and can enhance the drug release inside the tumour cells.
The results demonstrate that Fe3O4 nanoclusters developed in
the present study are potential drug delivery systems
In small size range (< 26 nm), Fe3O4 nanoparticles exhibit
superparamagnetic behaviour with zero coercive field and
retentivity making them ideal candidates for targeted drug
delivery applications. Since superparamagnetic nanoparticles
possess zero net magnetization at room temperature, they do
not aggregate readily in suspensions compared to bigger-sized
magnetic nanoparticles. However, such smaller-sized super-
paramagnetic nanoparticles will have low magnetization per
particle. Thus, they will exhibit slow magnetic responsiveness
and manipulability under an external magnetic field. Conse-
quently, relatively large external magnetic field will be required
in order to magnetically separate these nanoparticles and/or to
control their movement in blood and body fluids. The
saturation magnetization value and thereby the magnetic
responsiveness of Fe3O4 nanoparticles can be increased by
increasing the nanoparticle size. However, beyond a critical size
range (> 26 nm for Fe3O4), the nanoparticles will lose the
superparamagnetic characteristics and becomes ferromagnetic
in nature.[11] Ferromagnetic nanoparticles are prone to aggrega-
tion because of their retentivity and strong magnetic dipolar
interactions. Furthermore, such aggregated nanoparticles can-
not form stable dispersions and are not suitable for drug
delivery applications.[12]
Fe3O4 nanoclusters where numerous smaller-sized nano-
crystals bound together are advantageous for biomedical
applications, because the saturation magnetization of such
nanoclusters can be increased in a systematic way while
maintaining the superparamagnetic features.[13] Fe3O4 nano-
cluster having good water solubility and superior saturation
magnetization are mostly favoured for biomedical applications.
Studies have shown that Fe3O4 nanoclusters hold great
potential as contrasting agents for clinical MRI applications.[14–18]
Fe3O4 nanoclusters have been used for DNA extraction and the
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ChemistrySelect doi.org/10.1002/slct.202001102
results reveal that efficiency of DNA extraction is inversely
proportional to particle size in the range of nanoclusters
tested.[19] The radio frequency alternating magnetic field
induced heating studies in Fe3O4 nanoclusters demonstrated
that they are promising candidates for magnetic fluid hyper-
thermia applications.[20] A nanovector composed of the meso-
porous Fe3O4 nanoclusters were conjugated with ternary
polymers for efficient microRNA in-vivo delivery.[21] Fe3O4 nano-
clusters was used to efficiently label mesenchymal stem cells
and the labelling efficiency obtained was much higher than
that of commercial superparamagnetic iron oxide nanopar-
ticles. Studies have also shown that Fe3O4 nanoclusters are
ideal drug delivery vehicles.[22,23]
PTX is a promising anticancer drug which has demonstrated
substantial activity against a variety of tumours.[24] However,
the usage of PTX by traditional intravenous administration
mode is restrained because of its poor water solubility. Direct
administration of PTX lacks tumour targeting ability which will
cause its poor biodistribution and subsequent therapeutic
effects. To overcome above mentioned difficulties, a variety of
potential nanocarriers such as liposomes,[25] emulsions,[26]
micelles,[27] carbon nanotubes,[28] graphene oxide,[29] magnetic[30]
and polymeric nanoparticles[31] have been tried for PTX.
Magnetic nanomaterials are advantageous compared to other
nanomaterial-based drug carriers as they can be guided to
specific target sites using an external magnetic field.[32] This can
lower the quantity of drug required to achieve a specific
concentration in the target area and can also minimize the side
effects by reducing the concentration of the drug at non-target
sites. An ideal magnetic nanocarrier should hold high drug
loading capacity, good colloidal stability and fast magnetic
responsiveness.
Development of facile and cost-effective methods for large-
scale synthesis of superparamagnetic Fe3O4 nanoclusters hav-
ing narrow size distribution, good water dispersibility and
superior saturation magnetization are essential to meet their
requirements for drug delivery applications. Additionally, Fe3O4
nanoclusters having mesoporous structure will be promising
drug carriers since they can allow fast diffusion, adsorption and
subsequent release of drug molecules through their three-
dimensional pores. Fe3O4 nanoclusters being prone to acid
etching, a burst release of entrapped drug will be possible from
them in acidic pH conditions which will be highly advanta-
geous for their targeted therapeutic applications. Towards
these goals, herein, we report gram-scale synthesis of mono-
disperse mesoporous Fe3O4 nanoclusters by a simple and cost-
effective solvothermal method. PTX was used as the model
drug to investigate the efficacy of as-prepared Fe3O4 nano-
clusters for drug delivery applications. Successful loading of
PTX into Fe3O4 nanoclusters was confirmed by FT-IR spectro-
scopy and the drug loading capacity was estimated by TGA.
The drug release behaviour of PTX was studied at two different
pH conditions (pH 7.4 and 5.2). The results reveal that as-
synthesized mesoporous Fe3O4 nanoclusters are promising
nanocarriers for PTX.
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2. Results and Discussion
The Fe3O4 nanoclusters were synthesized by a simple solvother-
mal method by using ferric chloride hexahydrate as iron
precursor, trisodium citrate as the binding ligand and urea as
the homogeneous precipitator. EG has a dual role as the
solvent as well as the reducing agent during Fe3O4 nanocluster
formation. Figure 1 shows the schematic illustration of forma-
tion of Fe3O4 nanoclusters. Solvothermal synthesis of Fe3O4
nanoclusters follows the two-step growth model. In the first
step, smaller primary nanocrystals nucleate in the supersatu-
rated solution and in the second step, as-formed primary
nanocrystals agglomerate into larger secondary nanoclusters.[33]
The TEM images confirm that Fe3O4 nanoclusters are nearly
monodisperse and spherical in shape with an average cluster
size of 120 nm (Figure 2a-2c). The individual Fe3O4 nanoclusters
were made up of several interconnected smaller Fe3O4 nano-
particles with size < 10 nm. High magnification TEM image
(Figure 2c) reveals that the clusters have a loose mesoporous
structure. Such mesoporous nanoclusters will have large sur-
face area and will be ideal material for adsorption of drug
molecules. As shown in Fig 5a, drug molecules such as PTX can
easily penetrate and deposit inside the porous channels of
Fe3O4 nanoclusters. The nitrogen adsorption/desorption iso-
therm studies can provide precise information about the
mesoporous structure of as-prepared Fe3O4 nanoclusters. The
SAED pattern of Fe3O4 nanoclusters show clear Debye-Scherrer
rings corresponding to the cubic spinel structure of magnetite
(Figure 2d).
The XRD pattern of Fe3O4 nanoclusters shows six diffraction
peaks at 30.1°, 35.6°, 43.1°, 53.6°, 57.2° and 62.6° corresponding
to the reflections of (220), (311), (400), (422), (511) and (440)
lattice planes of cubic spinel structure of Fe3O4 in agreement
with JCPDS 19–0629 (Figure 3). The XRD spectra exhibit broad
diffraction peaks confirming the small crystallite size of Fe3O4
nanoclusters. The average crystallite size of Fe3O4 nanoclusters
calculated from the most intense (311) peak using Debye-
Figure 1. Schematic illustration of formation of mesoporous Fe3O4 nano-
clusters by a two-step growth process.
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ChemistrySelect doi.org/10.1002/slct.202001102

Figure 2. The TEM images (a, b & c) and corresponding SAED pattern (d) of Fe3O4 nanoclusters.

Scherrer equation and was found to be ∼ 6 nm. The calculated

primary nanocrystallite size matches with the TEM analysis.
As illustrated in Figure1, Fe3O4 nanoclusters will have
surface bound sodium citrate molecules which can enhance
their dispersibility in water. Figure 4a shows the zeta potential
of Fe3O4 nanocluster dispersion in water at pH 7. The observed
zeta potential value was -36 mV, which confirms that large
number carboxylate functional groups are present on the
surface of Fe3O4 nanoclusters. The presence of abundant
sodium citrate molecules on Fe3O4 nanoclusters will prevent
their aggregation and can provide them good dispersibility in
water. As-synthesized Fe3O4 nanoclusters were easily dispersed
in water with the help of sonication and the suspension
remained stable for hours as shown in Figure 5b. To confirm
the colloidal stability, the hydrodynamic size distribution of
aqueous Fe3O4 cluster dispersion was measured by dynamic
Figure 3. The XRD spectrum of as-synthesized Fe3O4 nanoclusters.
light scattering (DLS). As shown in Figure 4b, the intensity-
weighted size distribution of Fe3O4 nanoclusters exhibited a
single peak with narrow size distribution with a polydispersity
index of 0.16. The DLS result demonstrates that the Fe3O4

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Figure 4. (a) Zeta potential of Fe3O4 nanocluster dispersions in water at pH 7. (b) The size distribution of Fe3O4 nanoclusters measured by DLS.

Figure 5. (a) Schematic illustration showing the binding of sodium citrate and loading of PTX into Fe3O4 nanoclusters. (b) Stability of Fe3O4 nanocluster
dispersion in water.

nanoclusters remained well dispersed in water without any
aggregation. Aggregated nanocluster dispersions will exhibit a
multimodal size distribution.[34] The results confirm that as-
prepared Fe3O4 nanoclusters have good colloidal stability
making them ideal candidate for biomedical applications.
The FT-IR studies provided additional evidence for the
presence of sodium citrate molecules on the surface of as-
synthesized Fe3O4 nanoclusters. The characteristic peaks ob-
served at 1631 and 1415 cm 1 in the FT-IR spectrum of Fe3O4
nanoclusters (Figure 6a) correspond to the symmetric and
antisymmetric stretching vibrations of COO groups of
sodium citrate molecules respectively.[33] The FT-IR spectrum of
nanoclusters also exhibited a peak at 568 cm 1 corresponding
to the stretching vibration of the Fe O bond and a broad
band at 3422 cm 1 corresponding to the O H stretching
vibration of citrate and adsorbed water molecules (Figure 6a).
In order to quantify the amount of sodium citrate present on
Fe3O4 nanoclusters, TGA analysis was done. A major weight loss
was observed in the temperature range of 200–700 °C corre-
sponding to the decomposition of sodium citrate molecules
attached on the surface of the Fe3O4 nanoclusters (Figure 6b).[35]
The calculated mass fraction of the bonded citrate was ∼ 12 %
from the TGA studies.
Figure 7a shows the magnetization hysteresis loops of
Fe3O4 nanoclusters at room temperature. The saturation
magnetization value (MS) of Fe3O4 nanoclusters was found to
be 51 emu/g after correcting the surfactant contribution.
Magnified hysteresis curve in the field range of + 200 Oe to
-200 Oe (Figure 7a inset) confirms that Fe3O4 nanoclusters are
superparamagnetic in nature with zero coercive force and

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Figure 6. (a) The FT-IR and (b) TGA curves of Fe3O4 nanoclusters.

Figure 7. (a) The magnetic hysteresis loops of Fe3O4 nanoclusters. A zoomed view of the low magnetic field region of the hysteresis loop is shown in the inset.
(b) The magnetic separation of Fe3O4 nanoclusters from solution using a magnet and their redispersion by a mild shake.

retentivity. The observed magnetic properties is attributed to
the secondary structures of nanoclusters where individual
clusters are made up of numerous smaller-sized primary
nanocrystals. As evident from TEM analysis (Figure 2c), the size
of primary nanoparticles comprising the Fe3O4 nanoclusters
was smaller (∼ 6 nm) than the critical size for superparamagnet-
ism for Fe3O4 (∼ 26 nm). Superparamagnetic Fe3O4 nanoclusters
are ideal candidates for biomedical applications since they do
not experience strong magnetic dipolar interactions in suspen-
sions.
Optical microscopy studies provided additional evidence
for the excellent magnetic responsiveness of as-synthesized
Fe3O4 nanoclusters. As shown in Figure 8a, Fe3O4 nanoclusters
remained well-dispersed in the absence of magnetic field. In
presence of magnetic field, chain-like structures are formed in
Fe3O4 nanocluster dispersion due to dipole-dipole interactions
between adjacent nanoclusters (Figure8b). Accordingly, the
nanoclusters can be completely extracted from the dispersion
within only 5 s using a magnet as shown in Figure 7b. After
removing the external magnet, the nanoclusters can be easily
redispersed by a mild shake. The results reveal that Fe3O4
nanocluster dispersion exhibit fast magnetic responsiveness
and excellent redispersibility making them potential material
for biomedical applications
To check the practical applicability of Fe3O4 nanoclusters for
drug delivery applications, PTX was loaded on them by a
nanoprecipitation method. The slow evaporation of the solvent
will allow the penetration and deposition of PTX molecules
inside the porous channels of Fe3O4 nanoclusters.[22] Successful
loading of PTX was confirmed by FT-IR analysis and the drug
loading capacity was estimated by TGA analysis. The FT-IR
spectra of PTX show a number of absorption peaks over 1722

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Figure 8. Phase contrast optical microscopy images of Fe3O4 nanocluster dispersion in the absence (a) and in presence (b) of an external magnetic field.

to 700 cm-1 range (Figure 9a). The characteristic absorption

Figure 9. The FT-IR spectra of (a) PTX and (b) PTX-loaded Fe3O4 nanoclusters.
Figure 10. The TGA curves of (a) PTX-loaded Fe3O4 nanoclusters and (b) PTX.
peaks observed at 1722 and 1251 cm-1 correspond to the
symmetric and asymmetric stretching vibration of C=O and C-O
respectively.[23] The FT-IR spectrum of PTX-loaded Fe3O4 nano-
clusters exhibited characteristic peaks of PTX (Figure 9b). The
observed peak at 2938 cm-1 correspond to the symmetric and
asymmetric CH2 stretching vibration and it matches well with
that of PTX. The peaks at 1722 and 1249 cm-1 further confirm
the successful incorporation of PTX into Fe3O4 nanoclusters.
TGA was done in order to quantify the amount of PTX-
loaded into Fe3O4 nanoclusters. Figure 10b and 10a show the
TGA curve of PTX and PTX-loaded Fe3O4 nanoclusters respec-
tively. The initial weight loss observed near 250 0C is attributed
to the evaporation of PTX present on or near the surface of
Fe3O4 nanoclusters.[22] The subsequent weight loss observed
from 300 to 450 0C is attributed to the evaporation of PTX
present inside pores of Fe3O4 nanoclusters. The PTX-loaded
Fe3O4 nanoclusters exhibited a total weight loss of ∼ 29 %. The
mass fraction of the bonded citrate being 12 % (Figure 6b), the
calculated weight loss corresponding to PTX was 17 %. The
results reveal that substantial amount of PTX is present in Fe3O4
nanoclusters.
It is known that the extracellular pH of cancer cells is more
acidic than that of normal cells.[36] The extracellular pH in
normal healthy tissues and blood is ∼ 7.4, while tumour tissues
will have a lower extracellular pH of 4.5 6.5. Thus, the drug
release behaviour of PTX-loaded Fe3O4 nanoclusters was
studied at physiological pH (PBS, pH = 7.4) and in acidic pH
(acetate Buffer, pH = 5.2). A burst drug release was observed at
the initial stage in both the cases. It was found that ∼ 20 % of
loaded-PTX was released from Fe3O4 nanoclusters after 72 h at
pH 7.4 (Figure 11). The drug release rate has significantly
enhanced in acidic conditions (pH = 5.2) and ∼ 46 % of loaded-
PTX was released from Fe3O4 nanoclusters after 72 h. Fe3O4
nanoclusters are prone to acid etching and with increasing
contact time in acidic conditions, they will subsequently
transforms to disassembled nanoclusters.[23] Accordingly, a
burst release of entrapped PTX will be happening from such
disassembled clusters in acidic conditions (pH = 5.2). The pH-

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Figure 11. The release of PTX from Fe3O4 nanoclusters as a function of time
at pH 7.4 and pH 5.3.
responsive drug release behaviour of mesoporous Fe3O4 nano-
clusters observed in the present study will be highly advanta-
geous for their targeted therapeutic applications as the
extracellular pH of cancer cells is more acidic than that of
normal cells. The low drug release rate observed in physio-
logical pH (pH = 7.4) can avoid the undesired release of PTX in
blood circulation during the delivery process. The high drug
release rate observed in acidic pH (pH = 5.2) can enhance their
release inside the tumour tissues. The PTX loading and release
studies demonstrate the efficacy of as-synthesized mesoporous
Fe3O4 nanoclusters for targeted drug delivery applications.
3. Conclusions
In conclusion, mesoporous Fe3O4 nanoclusters having average
cluster size of ∼ 120 nm was synthesized by a simple
solvothermal route and were characterized by using TEM, XRD,
FT-IR, TGA, VSM and DLS techniques. As-synthesized Fe3O4
nanoclusters exhibited excellent water dispersibility and super-
paramagnetism in conjunction with fast magnetic responsive-
ness. The efficacy of Fe3O4 nanoclusters for drug delivery
applications was explored by using model drug PTX. Successful
loading of PTX into Fe3O4 nanoclusters was confirmed by FT-IR
spectroscopy and the drug loading capacity was estimated by
TGA. An efficient loading capacity of 17 % was achieved for PTX
in the present study. The in vitro release of PTX was higher in
acidic pH compared to physiological pH (pH = 7.4). As the
extracellular pH of cancer cells is more acidic than that of
normal cells, mesoporous Fe3O4 nanocluster-based drug deliv-
ery vehicles can reduce the undesired release of PTX in blood
circulation during the delivery process (at physiological pH)
and can enhance the drug release inside the tumour cells.
Mesoporous Fe3O4 nanoclusters developed in the present study
are promising drug delivery systems owing to their mesopo-
rous structure, fast magnetic response, good water dispersibil-
ity and pH-responsive drug release performance.
ChemistrySelect 2020, 5, 9261 – 9268
Supporting Information Summary
Synthesis of Fe3O4 nanoclusters, characterization of Fe3O4
nanoclusters, PTX loading and release studies.
Acknowledgments
Authors would like to thank the SAIF-CUSAT for XRD, SEM and
TEM analysis; SMARTS, MMG, IGCAR for optical microscopy and
zeta potential analysis and SAIF - IIT Madras for VSM analysis.
Author SPD also thanks Department of Science and Technology,
Govt. of India for the INSPIRE Faculty Award and research grant
(DST/INSPIRE/04/2014/001995).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Drug delivery · magnetite · mesoporous ·
nanoclusters · paclitaxel
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Submitted: March 19, 2020
Accepted: July 23, 2020

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