Journal of Science: Advanced Materials and Devices 4 (2019) 201e212

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Journal of Science: Advanced Materials and Devices

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

Review Article

Different types of smart nanogel for targeted delivery

Mohammad Amir Qureshi a, *, Fehmeeda Khatoon b
a
Department of Chemistry, School of Basic and Applied Sciences, Lingaya's Vidyapeeth, Faridabad, Haryana, 121002, India
b
Department of Applied Sciences & Humanities, Faculty of Engineering & Technology, Jamia Millia Islamia, New Delhi, 110025, India

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

Article history: Decades of massive works have developed different carriers, lipoproteins, liposomes, ionic liquids, sur-
Received 27 January 2019 factants and nanogels, to enhance the targeted transportation of drugs, to reduce the side effects and to
Received in revised form achieve controllable action on the curative sites. The word ‘nanogels’ is defined as the hydrogel nano-
12 April 2019
particles with tunable size of 1e1000 nm formed by physical or chemical cross linked networks. The
Accepted 16 April 2019
Available online 23 April 2019
conventional challenges of solubility, substandard pharmacokinetics, in-vivo stability and toxicity, are
being overcome by nanogels and other carriers. The reviewed nanogels in this article are purely based on
pH, temperature, magnetic field, light and on combination of them. The discussed information will be
Keywords:
pH sensitive
very helpful to design a targeted delivery vehicle by specifically using photo-sensitive core-shell multi-
Temperature sensitive sensitive nanogels.
Magnetic field sensitive © 2019 The Authors. Publishing services by Elsevier B.V. on behalf of Vietnam National University, Hanoi.
Light sensitive This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Degradable
Nanogels

1. Introduction polymer chains. They may have an adjustable chemical framework

to enable the control over water uptake, mechanical strength and
Decades of massive work developed an array of different carriers biocompatibility. They are capable to show faster responsiveness to
that targeted to enhance the transportation of drugs, to reduce the external stimuli like light exposure, pH, ionic strength, temperature
side effects and to achieve controllable action on the curative sites. and magnetic fields by a change in volume, water uptake, refractive
These carriers comprise of lipoproteins, liposomes, ionic liquids, index, hydrophilicity and hydrophobicity [1e3]. By responding to
surfactants and nanogels etc. It is improbable that one type of these stimuli they are also called smart material. The functionali-
carrier can suit to all clinical desires. The delivery of chemothera- zation can be done through ATRP or by adding other molecule on
peutics faces a lot of difficulties related to solubility, substandard the surface of the nanogel [42e44] to make the nanogel sensitive to
pharmacokinetics, in-vivo stability, toxicity and side effects. So, the desired stimuli. These stimuli can be applied to design nanogels
these conventional challenges of carriers or existing drug delivery as an effective carriers in medical diagnostics [4], bio-sensing and
systems (DDS) are being overcome with the advent of Nanotech- bio-imaging [5,6] and tissue engineering [7]. A flexible DDS should
nology. Nanotechnology originates the necessity for developing the show a few key properties such as: preferable and adaptable par-
nanogel systems which validate their capability to transport the ticle size for the improved permeability and retention effect, easy
drugs in controlled, continuous and targetable way. The word non-covalent incarceration of drug in to the DDS, prevention of
‘nanogels’ is defined as the hydrogel nanoparticles (NPs) with early drug release, release must be triggered by external stimuli,
tunable size range of 1e1000 nm formed by physical or chemical tunable release kinetics, no innate toxicity, grounded and repro-
cross linked networks. Nanogel network enable the incorporation ducible delivery procedure. The properties of stimuli responsive
of drugs, protein, DNA and provide a big surface area for multiva- nanogels can be regained by withdrawing the stimulus. They also
lent bioconjugation. These biomolecules absorb through salt show distinctive properties like: to go across the biological barriers,
bridges, hydrogen bonding and hydrophilic-hydrophobic forces of hydrophilic interior network for drug loading and release, higher
stability for prolonged circulation in the blood and effectively target
the desired site. Being soft nano carriers they have a potential of
flattening themselves on the vascular plane and concurrently
* Corresponding author.
E-mail address: [email protected] (M.A. Qureshi). anchoring on multiple points [8]. Nanogels provide distinctive lead
Peer review under responsibility of Vietnam National University, Hanoi. over polymer-protein and polymer-drug conjugates [9e11], over

https://doi.org/10.1016/j.jsamd.2019.04.004
2468-2179/© 2019 The Authors. Publishing services by Elsevier B.V. on behalf of Vietnam National University, Hanoi. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
202 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212

Abbreviations [mPEG-b-P(LGA/CLG)] poly (ethylene glycol monomethyl

ether)-b-poly (L-glutamic acid-co-g-
ATRP Atom transfer radical polymerization cinnamyl-L-glutamate)
AAc Acrylic acid NGs Nanogels
APCs Antigen Presenting cells NIPAAm n-isopropyl acrylamide
(BMP-2) Bone morphogenic protein-2 NPs Nanoparticles
(BLG-NCA) g-benzyl-L-glutamate-N-carboxyanhydride OEG Oligoethylene glycol
eCOOH Carboxylic ORI Oridonin
CTAB Cetyl trimethylammonium bromide PDS Pyridyldisulfide
CS Chitosan PAA Poly acrylic acid
CDs Cyclodextrins P4VP Poly 4-vinyl pyrrolidone
DPP Distillation precipitation polymerization PVA poly (vinyl alcohol)
DOX 2, 5-dimethoxyamphetamine P2VP Poly 2-vinyl pyrrolidone
DMIAAm Dimethylmaleimide PEO Poly Ethylene Oxide
DMAEMA (dimethylamino) ethyl methacrylate PEGMA Poly (ethylene glycol) methyl ether methacrylate
DTT Dithiothreitol PMAA Polymethyl acrlic acid
DDS Drug delivery system pOEOMA Poly(oligo(ethylene oxide) mono-methyl ether
DNA Deoxy-ribose nucleic acid methacrylate)
DLS Dynamic light scattering PBS Phosphate buffer solution
EDMAA Emulsion polymerization of 2-dimethylamino [P(LGA/CLG-b-PEG-b-P(LGA/CLG))] poly (L-glutamic acid-co-g-
acetate cinnamyl-L-glutamate)-b-
5-FU 5-fluorouracil poly(ethylene glycol)-b-
FITC Fluorescein isothiocyanate poly (L-glutamic acid-co-g-
FATP Fatty acids transport protein cinnamyl-L-glutamate)
(Fe3O4) Ferric oxide [P(L-Asp-alt-PEG)] [poly(aspartic acid-alt-poly) (ethylene
GFs Growth factors glycol)]
GFP Green fluorescent protein PEI Poly ethyleneimine
GSH Glutathione pNIPAAM Poly (N-isopropyl acrylamide)
Gal-CS-g-PNIPAm Galactosylated nanogel of CS-graft-poly (N- pHEMA Poly(2-hydroxyethyl methacrylate)
isopropyl acrylamide) QDs Quantum dots
HPC Hydroxyl propyl cellulose RITC-Dx Rhodamine B isothiocyanate-dextran
IR Infra red R6G Rhodamine 6G
IPN Inter penetrating network RNA Ribose nucleic acid
IONPs Iron oxide nano particles ROP Ring opening polymerization
MAA methyl acrylic acid RAFT Reversible addition-fragmentation chain transfer
MRI magnetic resonance imaging SO4 Sulphate
MCF-7 Breast carcinoma cells TEM Transmission electron microscopy
MG-63 Osterosarcoma cells TMZ Temozolomide
MNPs Magnetic nano particles UV Ultra violate
MTT 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium VCL Vinyl caprolactam
bromide

micelles, vesicles, dendrimers [12e14] and submicron-sized par- pH-sensitive polymers can respond to pH changes either in-vivo or
ticulates [15]. The first reported DDS was of polyethyleneimine and in-vitro. Polymers based on pH synthesize switching nanogels for
poly (ethylene glycol) (PEG) for the delivery of polynucleotides [16]. slow drug release while circulating in the blood and for rapid drug
In addition, the incorporation of quantum dots [17] and magnetic release at the targeted site. Acidic pH of the environment shows
Nano-particles (MNPs) [18] for optical and magnetic imaging of changes in the ionization state of the nanogels for their swelling.
living cells and gold Nano-rods for photodynamic therapy [19] has The pH-dependent swelling response of nanogels can be functional
also been reported. Hydrophilic ionizable carriers form polyionic for loading as well as for the release of bio-molecules.
complexes with biomolecules of opposite charge; are also receiving Specifically structured p(NIPAM-co-AA) nanogels with different
attention as DDS [20]. The main areas reviewed in this article are: NIPAM/AA concentration were prepared by precipitation/dispersion
(i) single stimuli responsive nanogels, (ii) dual stimuli responsive polymerization and evaluated as DDS for DOX-HCl in cancer treat-
nanogels, (iii) core-shell nanogels, (iv) functionalized nanogels, (v) ment. The DLS analysis has shown that nanogels exhibit an excellent
degradable nanogels and (vi) photo sensitive nanogels. distribution at pH 7.4 and 5 at 37
C. The developed nanogels showed
a high efficiency of drug loading due to the electrostatic interaction of
2. Single stimuli responsive nanogels the cationic drug with the anionic nanogels. The nanogels exhibited
minimal delivery of the drug in plasma simulated medium of pH 7.4
2.1. pH responsive nanogels and 0.14 M NaCl concentration at 37
C. The triggered release takes
place in lysosomal simulated medium of pH 5 and 0.14 M NaCl con-
Smartness of the materials is the responsiveness to the external centration at 37
C. The above results of low cytotoxic nanogels has
stimuli. The smart materials are able to sense external stimuli to shown that the developed nanogels were good to carry and to deliver
capitalize them for the synthesis of smart DDS. Nanogels based on the drugs after endocytosis in tumor cells in cancer therapy [21].
 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212 203

In continuation of this section Y. Li et al. reported the discovered when MCF-7 cancer cells were cultured with the ORI-
polypeptide-based pH-responsive nanogels as a potential loaded nanogels. The antitumor efficiency of galactosylated nano-
DDS. These nanogels synthesized by using hydrophilic methoxy gels was high in comparison to non-galactosylated nanogels when
poly(ethylene glycol)-b-poly[N-[N-(2-aminoethyl)-2-aminoethyl]- MCF-7 cells were treated at pH 7.4. In addition to this, nanogels
L-glutamate] (MPEG-b-PNLG) and hydrophobic terephthalaldehyde without ORI exhibited no cytotoxicity. The results also showed that
(TPA) as a cross-linker. pH-sensitive benzoic-imine bond formation drug loaded Gal-CS-g-PNIPAm nanogels could be effectively
takes place during the nanogel synthesis. At pH 7.4, the prepared absorbed by HepG2 cells through the mechanism of galactose-
nanogels were highly stable. The loading of the hydrophobic drug is specific receptor-mediated endocytosis. These liver cancer cells
facilitated by the hydrophobic inner core of the nanogel. The tu- targeted and pH triggered nanogels would be a promising DDS [25].
moral acidic conditions (pH~6.4) break the imine bond to instigate By Jianxun Ding, di-block and tri-block copolymers, including
the degradation of the nanogel structure for a rapid release of DOX. poly (ethylene glycol monomethyl ether)-b-poly (L-glutamic acid-
The DOX-loaded nanogels exhibited higher cytotoxicity than free co-g-cinnamyl-L-) [mPEG-b-P(LGA/CLG)] and poly (L-glutamic acid-
DOX against the breast cancer cell line MDAMB-231. The cell co-g-cinnamyl-L-glutamate)-b-poly(ethylene glycol)-b-poly (L-glu-
viability decreased from 35.13% to 18.29% at drug concentrations of tamic acid-co-g-cinnamyl-L-glutamate) [P(LGA/CLG)-b-PEG-b-
10 and 35 mg/mL, respectively, when cells are incubated with DOX- P(LGA/CLG)], were developed through ring-opening polymeriza-
loaded nanogels. These nanogels were stable in the presence of salt tion (ROP) of g-benzyl-L-glutamate-N-carboxyanhydride (gBLG-
or in dilute conditions. The morphologies were globular. All the NCA) monomer along with PEG-dependent macro initiator. Benzyl
performed analyses were in-vitro [22]. group de-protection and chemical modification takes place with
Cunxian Duan et al., reported that the galactosylated nanogels of cinnamyl alcohol. Di-block and tri-block copolymers with PEG at
CS-graft-poly (N-isopropyl acrylamide) (Gal-CS-g-PNIPAm) can be shells and p(LGA/CLG) at cores spontaneously self-assembled into
used as a DDS of oridonin (ORI) for tumors. Fig. 1 shows the as- micelles of pH 7.4 aqueous solution. Under UV-irradiation at l ¼
sembly of the development of nanogels and their pH dependent 254 nm, blocks of P(LGA/CLG) in the cores were cross-linked by
actions. As illustrated in this scheme, the synthesis involves two photo-dimerization of the cinnamyloxy groups for these nanogels
steps: first is the synthesis of CS-g-PNIPAm and second is the gal- formation. These nanogels were pH-responsive and their effective
actosylation. In the first step, CS-g-PNIPAm is polymerized. The qualities could be adjustable by changing the constituents of block
polymerization proceeded for 3 h under nitrogen. The product was copolymers. The MTT assay showed that the developed nanogels
separated by dialysis against the distilled water for 4 days and were biocompatible to HeLa cells. The analyzed results provide
freeze dried. The Gal-CS-g-PNIPAm synthesized according to the their future prospectives for drug delivery applications [26].
method described by Park [23]. The developed nanogels main- Further in this section, a dual-sensitive (pH/redox) nano-
tained a stable structure at pH 7.4, whereas they became leaky and hydrogels with consistent size dispersal was developed through
porous under slightly acidic conditions. The fact that they became distillation precipitation polymerization (DPP) by using monomer
porous might be due to the increased electrostatic repulsion among (MAA) and BACy as a disulfide-functionalized cross-linker. A model
the protonated amino groups on the nanogels in mildly acidic anti-cancer drug (DOX) was effectively encapsulated up to 42.3 wt%
conditions [24]. A sustainable ORI release was achieved during drug into the nanogels. The collective DOX release from nanogels
transportation in the blood (pH ~7.4), whereas an abrupt release of exhibited <15 wt% of drug at pH 7.4 in 24 h. The drug release was
the active drug could be triggered by the mild acidic pH in the notably increased at pH 5.0 and in reducing environment (over
endosomes and lysosomes (pH ~6.0 to 5.0) of cancer cells. The 3- 91 wt% in 5 h) drug release takes place. Both results exhibited the
(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) actual pH/redox dual-sensitive controlled drug release adaptability
assay showed that ORI-loaded galactosylated nanogels exhibited an of the nanogels. DOX is rapidly released in the presence of growth
increased anticancer activity against HepG2 cells at pH 6.5 and that factor glutathione (GSH) but not in dithiothreitol (DTT). DOX-
the anticancer efficacy is enhanced as the degree of galactose loaded nanogels rapidly enter in to the human glioma (U251MG
substitution is increased. However, a different process was cells) via endocytosis to release the loaded drugs for anti-tumor

Fig. 1. Schematic diagram depicting the concept of Gal-CS-g-PNIPAm nanogels. (Adapted from reference no. [25]).
204 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212

efficacy. They possess excellent biocompatibility and biodegrad- 3. Dual stimuli responsive nanogels
ability, sufficient drug loading capacity, minimal premature drug
release and rapid release at the targeted site of low pH and reducing 3.1. Temperature and pH responsive nanogels
potential, to equip them as an assureable DDS for the delivery of
DOX [27]. Nanogels, in their soft forms, are part of the extensively used
DDS for local and systemic drug delivery. Dual stimuli (pH and
2.2. Temperature responsive nanogels temperature) responsive nanogels can release drugs at the desired
targeted sites. Moreover, such stimuli responsive nano-DDS have
Temperature variations may create changes in the nanogels in- been found to enhance the drug bioavailability. O. Zavgorodnya
ternal network and in its dimensions and interactions with the et al., developed temperature and pH sensitive nanogels of poly(N-
foreign particles, which lead into the controlled release of loaded vinylcaprolactam) P(VCL) with a high encapsulation ability for
biomolecules. Copolymers made up of a hydrophilic backbone of topical drug release. Highly swollalbe P(VCL)n multilayer nanogels
[poly(aspartic acid-alt-poly) (ethylene glycol)] [p(L-Asp-alt-PEG)] are produced by a layer-to-layer hydrogen-bonding assembly of
and hydrophobic side chains of capryl units were developed. The core-shell PVCL-co-AA nanogels with linear PVPON followed by a
above amphiphilic copolymer was nearly ~15 nm in size by self- cross-linking of AA shell with either ethylene diamine (EDA) or
assembling at 20
C. Nanogels exhibit phase-transitions in reply adipic acid dihydrazide (AAD). The developed (nPVCL)5 nanogels
of temperature changes. The adjustable range of temperatures for showed an abrupt reversible swelling up to 9 times of its actual
phase transitions was between 19
C to 55
C by changing the width at pH ¼ 7.5 which indicated that 89 volume % of water was
capryl unit amount. The dehydration of PEG takes place with the inside the nanogel. These nanogels showed a reversible ~3-times
increase of temperature. A slow degradation of nanogels takes increase in thickness with a temperature change from 25
C to
place at 37
C in a phosphate buffer solution (PBS). This slow 50
C at pH~5 (average pH of human skin). The developed nanogels
degradation of the nanogel is needed for the regulation of payload loaded with ~120 mg/cm2 sodium diclofenac provide a sustained
at the site of interest. The persistence of the nanogels in the cir- delivery of the drug onto an artificial skin for up to 24 h at ~32
C
culatory system was ensured by PEG. Therefore, p(LAsp-alt-PEG)- (human skin surface temperature). The cumulative amount of the
capryl nanogels could be potentially used as a DDS for hydropho- drug release at 32
C from the nanogel was 12 times higher than
bic drugs [28]. that at 22
C after 24 h. The confocal microscopy confirmed the
Crosslinked j-carrageenan nanogels with an average size absorption without intermixing of different dyes within the
<100 nm were developed by using reverse micro-emulsions in different compartments of the nanogels for multiple drug delivery.
combination with thermally inciting gelation. The nanogel size This work provides the opportunity for the development of tem-
was adjusted by the amount of j-carrageenan at a constant cetyl perature and pH sensitive multilayer nanogels for the topical drug
trimethylammonium bromide (CTAB) concentration. This size delivery [32].
control reflects the electrostatic interactions between CTAB of Chandrakant Mukesh et al., developed a system by using a
surfactant and sulphate (SO4) groups of J-carrageenan. They are choline-based polymerizable bioionic liquid (bio-IL). The shape of
thermo-sensitive between 37ºC-45
C for a reversible volume the NGs particles was near spherical to oval and the diameter
transition. Thus, temperature sensitive j-carrageenan could con- approximately 75 ± 10 nm. In Fig. 2, Bio-IL upon simultaneous
trol the in-vitro release of loaded drugs. The above results show polymerization and crosslinking, synthesized the nanogel system
that the j-carrageenan nanogel could be used as a temperature which is capable of discharging ~80% 5-fluorouracil (5-FU) at pH
sensitive DDS [29]. 1.2 for 10 days at 37
C. The network did not discharge the sig-
nificant amount of drug at pH 5.0 and 7.4. The prolonged in-vivo
2.3. Magnetic field responsive nanogels drug release profile makes the developed nanogel an important
member in the formulation of pH-responsive DDS stomach-
Nanogels must be able to supply prolonged drug delivery at the targeted DDS [33].
targeted site. A major affair for nanogels is the establishment of a
vectoring delivery at the requisite targeted spot. Not long ago, 3.2. pH and magnetic field responsive nanogels
super-para MNPs have been generally used in cell patterning, blood
purification, targeted drug delivery, clinical imaging and biosensors A series of poly (vinyl pyrrolidone) (PVP) nanogels were
for in-vivo biomarker detection [30]. Intrinsic magnetic properties developed and modified with a control over the size of the
and biocompatibility of MNPs could be used in biomaterials to nanogels (200 nm). The reported DDS in this work can act as a
produce novel nanogels. heat moderator for performing hyperthermia and as a gene de-
Ming Fan et al., reported a strategy for fabricating magnetic livery system (in si-RNA treatment). Fig. 3 is showing the scheme
nanogels through particular nucleo-base pairing (like Watson-Crick of loading of iron oxide nanoparticles (IONPs) in to the pH sen-
base pairing) for the vector delivery of growth factors (GFs). Bio- sitive nanogels. This DDS will be in a packed form while in blood
polymeric nanogels, developed from ferric oxide (Fe3O4), CS and circulation (pH < 7.4), as shown by transmission electron micro-
heparin, showed a quick reply by encapsulating super para- scopy (TEM) image in Fig. 3(c). The slight basic nature of the
magnetic Fe3O4 nano-particles (NPs). The delivery of cell GFs by blood constricts the chains of the nanogel to hamper the release
these magnetic nanogels was confirmed by adsorption and release of IONPs. On the other hand, once the nanogels reached in the
of bone morphogenic protein-2 (BMP-2). The presence of heparin extracellular tumor matrix (pH < 6.5), they would begin to swell
made the nanogel to achieve a high loading efficiency of BMP-2. to release the IONPs because of their slight acidic nature. Fig. 3(d)
The release period of BMP-2 was much less and its delivery un- is showing the removal of IONPs after applying a small magnetic
der physiological environment could be easily managed by the field. The hyperthermia treatment could be therefore performed
applied magnetic field. The in-vitro MTT assay indicated that BMP-2 by the delivery of IONPs [34].
loaded magnetic nanogels exhibited a high efficiency to promote Exploitation of pH-sensitive nanogels takes place to deliver
osteosarcoma cells (MG-63 cells) viabilities under a magnetic field. functional anti-green fluorescent protein (GFP) siRNA and super-
Thus, this biopolymer based nanogels have a great future potential paramagnetic IONPs to HeLaeGFP cells. The siRNA release takes
in cartilage and bone tissue regeneration [31]. place via a pH-mediated endosomal escape. The IONPs first act as
 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212 205

Fig. 2. Showing the sustainable release of 5-FU from nanogels at 37
C in PBS buffer solutions at pH 1.2, at pH 7.4, and at pH 5.0. (Obtained from reference no. [33]).

Fig. 3. (a) Scheme of the loading of magnetic nanoparticles in to the pH-responsive nanogels. Corresponding TEM images of different steps: (b) at pH 6.5 the nanogels were mixed
with the IONPs; (c) after 12 h, the pH was switched back to pH 7.4, such that the IONPs were entrapped within the nanogel network. (d) The application of a small magnetic field
helped to remove most of the free IONPs in solution. (Obtained from reference no. [34]).

magneto-fection agents to increase the cellular absorption and attached Ni-Ag NPs responsive to the pH range of 5.0e7.4. The pH-
then act as probes to trace the release process. The multivalent dependent magnetic response with fluorescent pH sensing, is the
mode of this system can be formulated by combining with pH- special quality of this type of hybrid nanogels. This nanogel can
triggered release, gene down-regulation, magnetic resonance im- adjust itself to the local pH environment and can control the sus-
aging (MRI) tracking and possibly hyperthermia treatment, for ceptibility in response to the applied magnetic field (~0.1 T) which
cancer therapy [35]. resulted in the amassing of this nanogel within the time range from
Optical sensing and drug delivery by using stimuli-guided a few seconds to hours as pH decreased from 7.4 to 5.0. This pH-
magnetic hybrid nanogels could permit the medical diagnostics dependent magnetically responsive nanogel was further fused
and therapy. The application of a pH-sensitive PEG-MAA gel shell with the fluorescent signal transduction and with the drug (5-FU)
onto the magnetic and fluorescent Ni-Ag NPs made the PEG-MAA- delivery functions. This hybrid nanogel enters the intracellular
206 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212

region to light up the mouse melanoma B16F10 cells. The high the pseudo-second-order kinetic model. The Pb2þ maximum
porosity of this nanogel can serve as intelligent pH and magnetic adsorption was 510.2 (mg/g) for PVA@P(90AMPS-co-10NIPAm)
field controlled DDS [36]. (wt.: wt%). The PVA@P(AMPS-co-NIPAm) nanogels were applied
for extracting of Pb(II) in real different environmental water sam-
4. Core-shell nanogels ples successfully with minimum recoveries reaching 95.7% [39].
Temperature and pH sensitive core-shell nanogels contain a
Temperature and pH sensitive core-shell nanogels were pre- smart polymer shell coated on MNPs as an anticancer DDS and a
pared by one-pot soapless emulsion polymerization of NIPAM and cancer cell-specific targeting vehicle. MNPs, synthesized by a co-
2-methacryloyloxy benzoic acid with the aid of a crosslinker (core) precipitation process, were modified from the surface by insti-
using poly (ethylene glycol)-methyl ether methacrylate (PEGDMA) tuting amine groups using 3-aminopropyltriethoxysilane. Dual-
as stabilizer (shell). The size of the nanogels was about 100 nm at sensitive pNIPAm-block-PAA copolymer, prepared by RAFT poly-
using the acid-labile cross-linker 9-divinyl-2,4,8,10-tetraoxaspiro merization, was then bound to the modified MNPs. Additionally,
[5.5]-undecane (DVA). The ionic interaction between the carbox- to fulfill the cancer-specific targeted delivery, folic acid was
ylate groups of the nanogels and the protonated amine groups of attached on the surface of the MNPs. Subsequently, rhodamine B
the drug (DOX) was responsible for the high drug loadings. isothiocyanate was attached to the MNPs to provide a fluorescent
PEGDMA cross-linked nanogels release about 30% of the drug after property for cellular imaging. The exterior polymer shell was
8 h at pH 7.4 and 37
C and about 39% in 12 h at pH 6 and 40
C. DVA encapsulated by a huge amount of DOX and the release of DOX
cross-linked nanogels follow a similar release trend: 23% drug takes place desirably at pH 5.0 and at 37
C. The drug loading and
released in 8 h at pH 7.4 and 37
C and 30% in 24 h. Otherwise, 61% entrapment capability extended as high as from 23.0% to 74.4%. An
is released in 12 h at pH 6 and at 40
C. The rapid release of the drug intracellular-uptake analysis showed the favored uptake of these
from DVA cross-linked nanogels was due to the hydrolysis of the MNPs into the cancer HeLa cells compared to normal fibroblast
nanogels at the acidic environment and the slightly higher tem- L929 cells. From Fig. 4, it follows that the HeLa cell nuclei
perature of the tumor. The empty nanogels were non-toxic for a remained intact when incubated with control MNPs (Fig. 4a).
lung cancer cell line (NCI-H1437), while the drug loaded nanogels There was a significant nuclei fragmentation when incubated with
were efficiently cytotoxic for that cell line. The release behavior of different concentrated DOX-MNPs (Fig. 4bed). It has been re-
DOX by using the DVA crosslinked nanogels represents a remark- ported that DOX interacts with DNA topoisomerase II causing the
able DDS for tumor treatment [37]. accumulation of enzyme-DNA adducts that ultimately lead to
G. Aguirre et al., synthesized a dual-responsive core-shell double-strand breaks and cell death via apoptosis a similar
nanogel based on poly(2-diethylaminoethyl) methacrylate behavior of nuclei fragmentation was noticed in this work when
(PDEAEMA) and p(VCL) as a gene delivery vehicle by batch seeded HeLa cells were treated with DOX-MNPs. The in-vitro analysis
emulsion polymerization. The core is based on PDEAEMA and the exhibited that the DOX-loaded folate-targeted MNPs attained
shell is based on PVCL. The swelling analysis showed that the excellent success for simultaneous targeting and killing of HeLa
developed nanogel was both temperature and pH sensitive. cells. Through a receptor directed endocytosis, they specifically
They form complexes with siRNA very rapidly through an collected and released the DOX on HeLa cells. It is envisioned that
electrostatic interaction. The nanogel/siRNA complexes showed these DOX-loaded MNPs are excellent DDS for cancer cell target-
higher polyanion exchange resistance compared to the PDEAEMA- ing, imaging and for other medical applications [40].
based nanogel/siRNA complexes and indicated that the nanogels of
PVCL- shell based enhanced the stability of the complexes. The in- 5. Functionalized nanogels
vitro siRNA release was controlled by the temperature, pH and
crosslinking density of the PVCL-based shell. These results indicate Functional group modification is one of the stamps for nanogels
that dual-responsive core-shell nanogels could potentially be use- synthesis by atom transfer radical polymerization (ATRP) [41]. The
ful as gene delivery systems [38]. functionality can be importantly exploited to develop functional
K. R. Shoueir et al., coated the core of PVA with a p(2- group active materials for different utilities. The functionality is
acrylamido-2-methyl-1-propane sulfonic acid-co-N-isopropylacr affected by molecular structures that ATRP can control. ATRP is
ylamide) shell to produce well-defined PVA@P(AMPS-co-NIPAM) used for the preparation of well-controlled nanogels that are
core-shell nanogels by using surfactant free emulsion polymeriza- functionally modified with biotin, pyrene, and peptides. Hydroxy-
tion (SFEP). The diameter of the core and the shell was 25 ± 0.5 nm modified poly-OH Poly(oligo(ethylene oxide) mono-methyl ether
and of 5 ± 0.5 nm, respectively. The nanogels were studied in an methacrylate) (POEOMA) was synthesized by AGET ATRP of
adsorption bath for removal of the Pb2þ ions. The dependence of OEOMA starting by 2-hydroxyethyl 2-bromoisobutyrate in water or
Pb2þ adsorption at pH 2 is related to the protonation of eOH, by inverse mini-emulsion of water/cyclohexane at 30.8
C. Biotin-
eCONH and eSO3H of PVA, NIPAM and AMPS of the nanogels, conjugated POEOMA was prepared by the reaction of HOPOEOMA
respectively, where Pb2þ ions must compete for the replacement of with the eCOOH group of biotin through a carbodiimide coupling
Hþ ions at the nanogel surface. At high pH, these functional groups reaction. The avidin-HABA analysis was used to determine the
get ionized accordingly and the adsorption of Pb2þ happens owing amount (11.4 nmol mg1) of biotin in polymers and revealed that
to the negatively charged surface sites of functional groups along the biotin attached POEOMA was still capable to make bonds with
the nanogel chain. The removal reached 97.8%, 90.8% and 83.7% for avidin. GRGDS-attached nanogels have the capability to be used in
AMPS90, AMPS50 and AMPS10 nanogels, respectively. The targeted drug delivery. The study of the synthesis of bi-biotin
increased AMPS content leads to the enhanced ionization of sul- nanogels revealed the use of an injectable system for therapeutic
fonic groups, hence to more expansion of the nanogels chains that applications because a bi-component system results in which the
possess a higher Pb2þ removal. The result showed that the polymer solution could be in one syringe and a solution of avidin in
maximum adsorption of Pb2þ is obtained at pH 5. The spontaneous another syringe. By injecting both, a polymer network or gel would
reaction -DG
with temperature showed that the adsorption of be formed. Dibiotin PSt was prepared by a ATRP reaction with a bi-
Pb2þ was favored at low temperature. The results showed that the functional initiator. This was followed by a reaction with sodium
adsorption equilibrium data well fitted in to the Langmuir azide (NaN3) to produce (N3)2 (diazide) terminated PSt. At last,
adsorption isotherm and the kinetic studies were well described by (N3)2 PSt and acetylene-functionalized biotins were clicked
 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212 207

Fig. 4. Apoptosis study of HeLa cells (a) treated with nanoparticles without DOX (FA-MNPs) and nanoparticles containing DOX (DOXMNPs) (b) 10 mg/mL, (c) 15 mg/mL, and (d) 25 mg/
mL (Obtained from reference no. [40]).

together. In a similar fashion, bi-biotin poly ethylene oxide (PEO) results of OVA release from P(HEMA-co-MAA) nanogels and
was synthesized. Post-polymerization modification of interior end mannan-modified P(HEMA-co-MAA) (MN-modified NPs) nanogels
groups and chain end allowed for the attachment of different can be seen very easily from that figure. At low pH, both unmodified
molecules including pyrene, biotin, and GRGDS and can lead for the and MN-modified nanogels limited the release of OVA. The protein
development of new biomaterials [42]. release rapidly increased after one and half hour when pH of the
Modified pH-responsive p(HEMA-co-MAA) nanogels have been release media increased. P(HEMA-co-MAA) carriers released the
developed and got application as DDS for oral vaccination. From maximum amount of protein after 30 min at pH 7.4. MN-modified
Fig. 5, it follows that the developed nanogels exhibited pH- P(HEMA-co-MAA) carriers exhibited a fast release to 81.65% of the
responsive properties such as: to entrap and to protect the drug total OVA, showing a lower release rate in a second stage and
at low pH and to trigger the pay load release at intestinal pH. The reaching the maximum amount of protein release at three and half

Fig. 5. Showing the delivery process of antigen to antigen presenting cells (APCs) and the release kinetics of antigen from stomach to small intestine of pH 3.0 and 7.4. (obtained
from reference no. [43]).
208 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212

hour. This slow release could be attributed to electrostatic in- notable cytotoxicity nor obstructs cell proliferation, indicating that
teractions between the released protein and the mannan molecules the developed polymers were biocompatible. Decreased zeta po-
on the particles surface. Unmodified p(HEMA-co-MAA) nanogels tentials of star polymers were noticed due to reaction with nega-
showed inherent properties by effective incorporation of macro- tively charged siRNA to the cationic core, whereas the
phages and instigate the appearance of co-stimulatory molecules. hydrodynamic diameter did not vary notably. The desired cellular
Surface modification with carbohydrate molecules resulted in an uptake of siRNA attached star polymers was established by using
increased incorporation of macrophages by enhancing the confocal laser microscope and flow cytometry. The analyzed data
appearance of applicable co-stimulatory molecules (i.e., CD40) at showed the inspiring chances that may be maximized for siRNA
higher levels to those noticed for unmodified nanogels. Broadly, delivery of star polymers with PEG arms and cores possessing
these findings showed that both unmodified and mannan-modified cationic and degradable units [45].
p(HEMA-co-MAA) nanogels are a feasible process for increasing W. Chen et al., see Fig. 6, reported for the first time that
antigen delivery to APCs and, in turn, these delivery platforms may reduction sensitive degradable nanogels are readily formed in situ
enable more effective oral vaccination authority [43]. from water-soluble PEG-P(HEMA-co-AC) diblock copolymers and
In this work, the encapsulation of reactive cyclodextrins (CDs) in cystamine in PBS via nucleophilic ring-opening of cyclic carbonate
aqueous nanogels based on p(VCL) is studied by surfactant-free with amino groups of cystamine for intracellular protein delivery.
precipitation polymerization. CDs were modified with acrylic DLS studies showed that these nanogels, though stable at physio-
groups. The increase of CDs amount in the reaction mixture led to logical conditions, were rapidly dissociated in response to dithio-
the deduction of the final hydrodynamic radius of nanogels from threitol (DTT). The loading efficiency was 98.2% of fluorescein
227 nm to 62 nm. The expansion of vinyl groups per CD molecule isothiocyanate-cytochrome C (FITC-CC). The FITC-CC in-vitro
instigate the synthesis of smaller nanogels (Rh ¼ 22.5 nm) and an release was minimal under physiological conditions but signifi-
observable increase of the cross-linking degree. The developed CD- cantly increased under reductive conditions by 10 mM DTT with
modified nanogels exhibited temperature sensitivity in an aqueous ~96.8% in 22 h. In contrast, the protein release from 1,4-
medium with a volume transition point near 30
C and a better butanediamine cross-linked nanogels remained low under the
colloidal stability. The complexation properties of CDs encapsulated same conditions. MTT assays showed that these nanogels were
in nanogel networks were ratified by titration with phenolphtha- nontoxic to HeLa cells up to 2 mg/mL concentration. CC-loaded
lein. This process permits the calculation of “active” CD units, e.g. nanogels exhibited better apoptotic activity than free CC. These in
able to build inclusion complexes with hydrophobic guest mole- situ formed reduction-sensitive degradable nanogels provide a
cules or drug as a carrier system [44]. novel approach for targeted intracellular protein delivery [46].
Stable biodegradable nanogels cross-linked with disulfide link-
6. Degradable nanogels ages were developed by inverse-miniemulsion ATRP. These nano-
gels consist of POEOMA with pendent oligo-(ethylene glycol), an
Biodegradability of nanogels can be established to answer to analog of linear PEO, and are believed to stop protein adsorption to
external stimuli to give number of utilities as choosy DDS. the nanogels. The nanogels had consistent cross-linked networks,
Responsiveness to stimuli could promote the smooth manageable which can enhance the control over the delivery of loaded bio-
release of loaded drugs from nanogels and confirm the eviction of molecules. The nanogels biodegraded into water-soluble poly-
empty DDS after the drug delivery. Star polymers with PEG arms mers in the presence of glutathione tripeptide. Above 90% of the
and a degradable cationic core were prepared by ATRP of poly- nanogels degraded within 3 h in the presence of 20% glutathione.
(ethylene glycol) methyl ether methacrylate macro-monomer The results shown in Fig. 7(a, b) and obtained from optical fluo-
(PEGMA), 2-(dimethylamino) ethyl methacrylate (DMAEMA), and rescence microscope images and MTT analysis of HeLa cells, pro-
a disulfide dimethacrylate (cross-linker, SS) through an “arm-first” pose that the DOX molecules are encapsulated into the cell and,
tactic. The diameter of the star polymers was about 15 nm and its therefore, could suppress the growth of HeLa cells whereas they are
structure was degraded under redox environment by reacting with nontoxic to normal cells (about 95%). Further, OH-modified nano-
glutathione into individual polymeric chains due to the cleavage of gels were synthesized to show their simple appropriateness to-
the disulfide cross-linker, established by the DLS method. MTT wards bioconjugation with biotin. From Fig. 7(c) it follows that the
analysis outcomes indicate that the inclusion of an increased R6G-encapsulated nanogels were degraded in the presence of
amount of star polymers (100e800 mg/mL) neither generates glutathione. The nanogels incubated with C2C12 cells release R6G

Fig. 6. Shows the synthesis of water soluble PEG-P(HEMA-co-AC) nanogel and in-situ loading of Cystamine protein in to it. Further in this figure a reduction triggered the
dissociation for protein release (Obtained from reference no. [46]).
 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212 209

Fig. 7. Optical fluorescence microscopy images of nanogels loaded (a) without, and with (b) R6G fluorescent dyes before and (c) after degradation in the presence of glutathione in
water. (obtained from reference no. [47]).

molecules which penetrated the cell membranes. HEA was added simultaneous thermo-chemotherapeutic effects for noninvasive
into the nanogels to form eOH group activated nanogels. Biotin- optical imaging. The irradiation enhances the glutathione
conjugated nanogels were mixed with fluorescein isothiocyanate responsive DOX release in a controlled manner. This release
(FITC)-labeled avidin that was assured by optical fluorescence mi- synergizes the therapeutic activity of the nanogel in killing hu-
croscopy. These results would be gettable as a consequence of man lung cancer cell line (A549) with limited toxicity to the
conjugating the nanogels with cell receptors (proteins and anti- normal cell line (MDCK) [49].
bodies). As a result of glutathione-instigated intracellular biodeg- H. Wang et al., developed biocompatible PEG-CS@CDs hybrid
radation, the payloads of the nanogel would be released for nanogels by integrating PEG, CS, and graphitic carbon dots (GCDs)
targeting oncologic cells to induce apoptosis. These nanogels could into a single nanoparticle for two-photon fluorescence (TPF) bio-
be used for targeted DDS for therapeutic applications [47]. imaging, for pH and near-infrared (NIR) light dual-responsive
The drug release kinetics for highly stable nanogels can be fine- drug release and for synergistic therapy. Such nanogels can be
tuned by control over the cross-linking density. The precursor of synthesized from a one-pot surfactant-free precipitation polymer-
polymeric nanogels is based on random copolymer of oligoethylene ization of PEG macro-monomers combined with CS and GCDs in
glycol (OEG) and pyridyldisulfide (PDS) units as side-chain. The water. The immobilization of CDs into the PEG-CS network was
nanogel size can be efficiently controlled from 10 to 200 nm by confirmed by the absorption at 240 nm of hybrid nanogels. The
changing the molecular weight, temperature and the relative ratio embedded GCDs not only serve as a confocal and bio-imaging agent
of co-monomers. The non-covalently encapsulated guest molecules and fluorescent pH-sensing probe but also increase the loading of
can be released in response to glutathione (GSH), a redox trigger, DOX. Confocal images of DU145 cells did not show changes in the
because it has a degradable reducing environment for disulfide fluorescent signal after 30 min of regular irradiation by the exci-
bonds. In-vitro DOX delivery into breast carcinoma cells (MCF-7 tation laser at 405 nm and indicate the good photo-stability of
cells) takes place to show the important role of nanogels in hy- hybrid nanogels for long-term cellular imaging. The pH sensitive
drophobic drug loading and cell-uptake efficiencies. These DDS did drug release analysis at 37
C for four days showed that the drug
not seem to suffer from premature delivery. Overall, these nanogels release amount increases from 20.8% to 49.2% at decreasing the pH
showed significant stability and modifiable controlled release after from 7.4 to 5.0. CS induced the regulated drug release over the pH
cellular uptake [48]. range of 5.0e7.4. It also instigated the surface functionalization of
embedded GCDs for fluorescent pH sensing. The DOX releasing
7. Photo sensitive nanogels analysis in pH 7.4 & 5.0 at 37
C PBS solution with and without NIR
radiation for 5 min from the hybrid nanogels showed that without
Controlled photo-sensitive drug release is a proven tactic to NIR irradiation the DOX release was slow and steadied after 14 h
generate sustained therapeutic effects for a long period. The but after 5 min of NIR irradiation the DOX release speeded up from
combined delivery of photo- and chemo-therapeutic agents is an the normal rate. Such notable increase in drug release rate in less
emerging trend to overcome the drug resistivity in cancer treat- than 5 min exposure to NIR light should be attributed to the local
ment. Z. Khatun et al., synthesized nanogels of photo sensitive heat produced by the efficient photo-thermal conversion of the
graphene and pH sensitive di-sulfide bond linked with hyaluronic fluorescent CDs. The in-vitro analysis showed that the developed
acid. The average size of mono-dispersed nanogel was 120 nm. nanogels have high therapeutic efficacy through the combined
Graphene was a photo-luminescent optical imaging agent to synergistic chemo-photothermal effect [50].
provide heat on NIR laser irradiation. After 48 h, 100% of DOX is H. Kang et al., see Fig. 8 as well, reported a NIR light-responsive
released at pH 5.0 with NIR laser irradiation, a nearly 5-time DDS based on Au-Ag-nanorods (Au-Ag NRs) coated with DNA-
greater release than at pH 7.4. The light from the laser source crosslinked polymeric shells. The DNA complementarity has been
initiates the single oxygen generation from graphene by breaking used to develop a polyacrylamide based system to load DOX into
down the disulfide bonds of hyaluronic acid. The ester linkage the nanogel. The MTT assay analysis showed that DOX (in micro
between graphene and DOX was effectively broken to release the micro-molar amount) possessed high toxicity toward both CEM
drug. The temperature of the nanogel solution increased to about and ramos leukemia cells. The developed nanogels composite
50
C after 30 min of laser irradiation. The animal model images showed very little toxicity, (±2)% to CEM cells and 8 (±3)% to Ramos
demonstrate that the intravenously administered nanogel accu- cells. Consequently, these nanogels can be easily functionalized
mulates in the tumor and that the temperature increases to about with targeting aptamers for specific identification to kill tumor
52
C to release more drugs. The developed nanogel showed cells. Direct 808 nm wavelength laser irradiation for 10 min on to
210 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212

Fig. 8. Showing the development of the nanogel and effect of near infra-red (NIR) radiation on to the cell for drug release. (Obtained from reference no. [51]).

the cells alone had little (>10%) effect on cell viability. In contrast, applied magnetic field which resulted in the amassing of the
cells irradiated with that NIR were killed when incubated with nanogel at the targeted cite. The review article also discussed
DOX-loaded NGs. Moreover, as irradiation time increased a signif- core-shell smart nanogels of different monomers with different
icant death (67 ± 5%) of CEM cells was observed while less than 8% cross-linkers as a delivery vehicle. In these cases nanogels made
was observed from Au-Ag-NG conjugates. During NIR irradiation, a more stable complex with the payload. Incorporation of MNPs
the photo-thermal effect of the Au-Ag NRs leads to a rapid rise in into the smart nanogel makes them responsive to applied
the surrounding temperature that resulted in the release of drug in magnetic fields and these magnetic nanogels are finding
a high amount. Analyses confirmed that these nanogels can be used immense application for gene delivery in hyperthermia, MRI
as DDS for targeted drug delivery with remote control capability by tracking, etc. Functionalization of monomers by ATRP [42] and
NIR light with high spatial/temporal resolution [51]. by precipitation for the synthesis of active nanogels to respond
In continuation of this section, a novel triple-responsive (light, the change in pH [43] and temperature. For biodegradable
pH, redox) nanogel of (PAA-co-spiropyran methacrylate) cross- nanogels the eviction of drug delivery vehicle after unloading of
linked by disulfide-containing N,N-bis(acryloyl)cystamine was payload was also a concerned. The cytotoxicity analysis was also
synthesized. Upon UV light irradiation or at low pH, the hydro- an important discussion for the developed biocompatible
phobic spiropyran (SP) isomerized to the hydrophilic mer- biodegradable nanogels to neither generate notable cytotoxicity
ocyanine (MC) and nanogels became swelled. The isomerized MC nor obstruct cell proliferation. Appropriate reducing agent was
in nanogels could emit intensive green light and even endocy- necessary for the breaking of bond to release the payload. In
tosed into the nucleus of the cancer cells for cell imaging. Upon addition to the above discussion, the light sensitive nanogels are
the addition of reducing agents, the nanogels were disrupted due the new inclusion for the targeted release by irradiation of local
to the oxidative breaking of the disulfide cross-linkers. DOX-HCl area through NIR radiation which makes them temperature
could be encapsulated into the nanogels based on electrostatic sensitive nanogels for the required period. The drug release of
interactions with AA. This anti-cancer drug would be released NIR radiated nanogels was more effective than usual smart
upon the stimulation of light, pH and DTT. The in-vitro cytotox- nanogels [49]. Fig. 9 is the conclusive representation of the
icity analysis indicates that the DOX loaded nanogels effectively stimuli, pH, Temperature, Magnetic field and NIR light, which
could kill the cancer cells and this effect would be enhanced in enhance the drug delivery at targeted cite.
the presence of UV light [52]. The work reported in this article demonstrates the many ways
for designing novel nanogels for targeted delivery. For this pur-
8. Conclusion and future perspective pose, smart nanogels should be designed with the advantages of
high drug loading capacity, prolonged circulation time, stability,
The review article discusses the different types of smart receptor recognition ability and stimuli-sensitive degradation at
nanogels used for the prolonged delivery of protein, DNA, siRNA, the targeted cite to release the drug. In the future, injectable,
anti-cancer agents, growth factor and used as a sensing agent, bioactive and biodegradable photo sensitive smart nanogels
for imaging towards affected cites of tumor and cancer for based on well-established non-cytotoxic materials should be
enabling diagnosis and therapy. The biocompatibility, loading developed and investigated for cartilage and myocardial infarc-
capacity, stability, protection of payload, cytotoxicity and biode- tion. There is a clear scope for the study of premature delivery of
gradability of the nanogels have also been discussed. For these the payload in degradable nanogels because of simultaneously
nanogels, bond making and breaking was the important phe- reducing agents also used with the DDS. How can we limit this
nomenon for the delivery of payloads and for their interaction issue? Work must be done to calculate and minimize the normal
with the targeted cite receptor. The amount of the constituent, cell death during in-vivo studies by NIR irradiation. Other pH
such as galactose in one case [25] and capryl unit in another case sensitive and temperature sensitive monomers can be used to
[28] , resulted in an increase of the efficacy of the work. In more design photo sensitive nanogels for better results. Multi-sensitive
cases, the drug release was favored at low pH because the tumor (photo and magnetic field) nanogels with nano-rods have
pH is also acidic. Moreover, the multi-stimuli responsive nano- developed for triggered delivery but there is much scope for
gels have been found to enhance the drug bioavailability at the carbon nano tube as well. What about the excretion and degra-
targeted cite. These nanogels can adjust themselves to the local dation study of nano rods? The light sensitive nanogels can be
pH and they can control the susceptibility in response to the tested for the removal of heavy elements from the industrial
 M.A. Qureshi, F. Khatoon / Journal of Science: Advanced Materials and Devices 4 (2019) 201e212 211

Fig. 9. Conclusive image of all the responsible stimuli for targeted drug release.

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Mohammad Amir Qureshi sincerely thanks Dr. Shagufta Jabeen that are responsive to intracellular pH change, Angew. Chem. Int. Ed. 115
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