Journal of Science: Advanced Materials and Devices (2019) 201e212 Contents lists available at ScienceDirect 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 b Department of Chemistry, School of Basic and Applied Sciences, Lingaya's Vidyapeeth, Faridabad, Haryana, 121002, India 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: Received 27 January 2019 Received in revised form 12 April 2019 Accepted 16 April 2019 Available online 23 April 2019 Decades of massive works have developed different carriers, lipoproteins, liposomes, ionic liquids, surfactants and nanogels, to enhance the targeted transportation of drugs, to reduce the side effects and to achieve controllable action on the curative sites The word ‘nanogels’ is defined as the hydrogel nanoparticles with tunable size of 1e1000 nm formed by physical or chemical cross linked networks The 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 very helpful to design a targeted delivery vehicle by specifically using photo-sensitive core-shell multisensitive nanogels © 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/) Keywords: pH sensitive Temperature sensitive Magnetic field sensitive Light sensitive Degradable Nanogels Introduction Decades of massive work developed an array of different carriers that targeted to enhance the transportation of drugs, to reduce the side effects and to achieve controllable action on the curative sites These carriers comprise of lipoproteins, liposomes, ionic liquids, surfactants and nanogels etc It is improbable that one type of carrier can suit to all clinical desires The delivery of chemotherapeutics faces a lot of difficulties related to solubility, substandard pharmacokinetics, in-vivo stability, toxicity and side effects So, these conventional challenges of carriers or existing drug delivery systems (DDS) are being overcome with the advent of Nanotechnology Nanotechnology originates the necessity for developing the nanogel systems which validate their capability to transport the drugs in controlled, continuous and targetable way The word ‘nanogels’ is defined as the hydrogel nanoparticles (NPs) with tunable size range of 1e1000 nm formed by physical or chemical cross linked networks Nanogel network enable the incorporation of drugs, protein, DNA and provide a big surface area for multivalent bioconjugation These biomolecules absorb through salt bridges, hydrogen bonding and hydrophilic-hydrophobic forces of * Corresponding author E-mail address: maq248@gmail.com (M.A Qureshi) Peer review under responsibility of Vietnam National University, Hanoi polymer chains They may have an adjustable chemical framework to enable the control over water uptake, mechanical strength and biocompatibility They are capable to show faster responsiveness to external stimuli like light exposure, pH, ionic strength, temperature and magnetic fields by a change in volume, water uptake, refractive index, hydrophilicity and hydrophobicity [1e3] By responding to these stimuli they are also called smart material The functionalization can be done through ATRP or by adding other molecule on the surface of the nanogel [42e44] to make the nanogel sensitive to the desired stimuli These stimuli can be applied to design nanogels as an effective carriers in medical diagnostics [4], bio-sensing and bio-imaging [5,6] and tissue engineering [7] A flexible DDS should show a few key properties such as: preferable and adaptable particle size for the improved permeability and retention effect, easy non-covalent incarceration of drug in to the DDS, prevention of early drug release, release must be triggered by external stimuli, tunable release kinetics, no innate toxicity, grounded and reproducible delivery procedure The properties of stimuli responsive nanogels can be regained by withdrawing the stimulus They also show distinctive properties like: to go across the biological barriers, 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 anchoring on multiple points [8] Nanogels provide distinctive lead 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 (2019) 201e212 Abbreviations ATRP Atom transfer radical polymerization AAc Acrylic acid APCs Antigen Presenting cells (BMP-2) Bone morphogenic protein-2 (BLG-NCA) g-benzyl-L-glutamate-N-carboxyanhydride eCOOH Carboxylic CTAB Cetyl trimethylammonium bromide CS Chitosan CDs Cyclodextrins DPP Distillation precipitation polymerization DOX 2, 5-dimethoxyamphetamine DMIAAm Dimethylmaleimide DMAEMA (dimethylamino) ethyl methacrylate DTT Dithiothreitol DDS Drug delivery system DNA Deoxy-ribose nucleic acid DLS Dynamic light scattering EDMAA Emulsion polymerization of 2-dimethylamino acetate 5-FU 5-fluorouracil FITC Fluorescein isothiocyanate FATP Fatty acids transport protein (Fe3O4) Ferric oxide GFs Growth factors GFP Green fluorescent protein GSH Glutathione Gal-CS-g-PNIPAm Galactosylated nanogel of CS-graft-poly (Nisopropyl acrylamide) HPC Hydroxyl propyl cellulose IR Infra red IPN Inter penetrating network IONPs Iron oxide nano particles MAA methyl acrylic acid MRI magnetic resonance imaging MCF-7 Breast carcinoma cells MG-63 Osterosarcoma cells MNPs Magnetic nano particles MTT 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide micelles, vesicles, dendrimers [12e14] and submicron-sized particulates [15] The first reported DDS was of polyethyleneimine and poly (ethylene glycol) (PEG) for the delivery of polynucleotides [16] In addition, the incorporation of quantum dots [17] and magnetic Nano-particles (MNPs) [18] for optical and magnetic imaging of living cells and gold Nano-rods for photodynamic therapy [19] has also been reported Hydrophilic ionizable carriers form polyionic complexes with biomolecules of opposite charge; are also receiving attention as DDS [20] The main areas reviewed in this article are: (i) single stimuli responsive nanogels, (ii) dual stimuli responsive nanogels, (iii) core-shell nanogels, (iv) functionalized nanogels, (v) degradable nanogels and (vi) photo sensitive nanogels Single stimuli responsive nanogels 2.1 pH responsive nanogels Smartness of the materials is the responsiveness to the external stimuli The smart materials are able to sense external stimuli to capitalize them for the synthesis of smart DDS Nanogels based on [mPEG-b-P(LGA/CLG)] poly (ethylene glycol monomethyl ether)-b-poly (L-glutamic acid-co-gcinnamyl-L-glutamate) NGs Nanogels NIPAAm n-isopropyl acrylamide NPs Nanoparticles OEG Oligoethylene glycol ORI Oridonin PDS Pyridyldisulfide PAA Poly acrylic acid P4VP Poly 4-vinyl pyrrolidone PVA poly (vinyl alcohol) P2VP Poly 2-vinyl pyrrolidone PEO Poly Ethylene Oxide PEGMA Poly (ethylene glycol) methyl ether methacrylate PMAA Polymethyl acrlic acid pOEOMA Poly(oligo(ethylene oxide) mono-methyl ether methacrylate) PBS Phosphate buffer solution [P(LGA/CLG-b-PEG-b-P(LGA/CLG))] poly (L-glutamic acid-co-gcinnamyl-L-glutamate)-bpoly(ethylene glycol)-bpoly (L-glutamic acid-co-gcinnamyl-L-glutamate) [P(L-Asp-alt-PEG)] [poly(aspartic acid-alt-poly) (ethylene glycol)] PEI Poly ethyleneimine pNIPAAM Poly (N-isopropyl acrylamide) pHEMA Poly(2-hydroxyethyl methacrylate) QDs Quantum dots RITC-Dx Rhodamine B isothiocyanate-dextran R6G Rhodamine 6G RNA Ribose nucleic acid ROP Ring opening polymerization RAFT Reversible addition-fragmentation chain transfer SO4 Sulphate TEM Transmission electron microscopy TMZ Temozolomide UV Ultra violate VCL Vinyl caprolactam pH-sensitive polymers can respond to pH changes either in-vivo or in-vitro Polymers based on pH synthesize switching nanogels for slow drug release while circulating in the blood and for rapid drug release at the targeted site Acidic pH of the environment shows changes in the ionization state of the nanogels for their swelling The pH-dependent swelling response of nanogels can be functional for loading as well as for the release of bio-molecules Specifically structured p(NIPAM-co-AA) nanogels with different NIPAM/AA concentration were prepared by precipitation/dispersion polymerization and evaluated as DDS for DOX-HCl in cancer treatment The DLS analysis has shown that nanogels exhibit an excellent distribution at pH 7.4 and at 37 C The developed nanogels showed a high efficiency of drug loading due to the electrostatic interaction of the cationic drug with the anionic nanogels The nanogels exhibited minimal delivery of the drug in plasma simulated medium of pH 7.4 and 0.14 M NaCl concentration at 37 C The triggered release takes place in lysosomal simulated medium of pH and 0.14 M NaCl concentration at 37 C The above results of low cytotoxic nanogels has shown that the developed nanogels were good to carry and to deliver the drugs after endocytosis in tumor cells in cancer therapy [21] M.A Qureshi, F Khatoon / Journal of Science: Advanced Materials and Devices (2019) 201e212 In continuation of this section Y Li et al reported the polypeptide-based pH-responsive nanogels as a potential DDS These nanogels synthesized by using hydrophilic methoxy poly(ethylene glycol)-b-poly[N-[N-(2-aminoethyl)-2-aminoethyl]L-glutamate] (MPEG-b-PNLG) and hydrophobic terephthalaldehyde (TPA) as a cross-linker pH-sensitive benzoic-imine bond formation takes place during the nanogel synthesis At pH 7.4, the prepared nanogels were highly stable The loading of the hydrophobic drug is facilitated by the hydrophobic inner core of the nanogel The tumoral acidic conditions (pH~6.4) break the imine bond to instigate the degradation of the nanogel structure for a rapid release of DOX The DOX-loaded nanogels exhibited higher cytotoxicity than free DOX against the breast cancer cell line MDAMB-231 The cell viability decreased from 35.13% to 18.29% at drug concentrations of 10 and 35 mg/mL, respectively, when cells are incubated with DOXloaded nanogels These nanogels were stable in the presence of salt or in dilute conditions The morphologies were globular All the performed analyses were in-vitro [22] Cunxian Duan et al., reported that the galactosylated nanogels of CS-graft-poly (N-isopropyl acrylamide) (Gal-CS-g-PNIPAm) can be used as a DDS of oridonin (ORI) for tumors Fig shows the assembly of the development of nanogels and their pH dependent actions As illustrated in this scheme, the synthesis involves two steps: first is the synthesis of CS-g-PNIPAm and second is the galactosylation In the first step, CS-g-PNIPAm is polymerized The polymerization proceeded for h under nitrogen The product was separated by dialysis against the distilled water for days and freeze dried The Gal-CS-g-PNIPAm synthesized according to the method described by Park [23] The developed nanogels maintained a stable structure at pH 7.4, whereas they became leaky and porous under slightly acidic conditions The fact that they became porous might be due to the increased electrostatic repulsion among the protonated amino groups on the nanogels in mildly acidic conditions [24] A sustainable ORI release was achieved during drug transportation in the blood (pH ~7.4), whereas an abrupt release of the active drug could be triggered by the mild acidic pH in the endosomes and lysosomes (pH ~6.0 to 5.0) of cancer cells The 3(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed that ORI-loaded galactosylated nanogels exhibited an increased anticancer activity against HepG2 cells at pH 6.5 and that the anticancer efficacy is enhanced as the degree of galactose substitution is increased However, a different process was 203 discovered when MCF-7 cancer cells were cultured with the ORIloaded nanogels The antitumor efficiency of galactosylated nanogels was high in comparison to non-galactosylated nanogels when MCF-7 cells were treated at pH 7.4 In addition to this, nanogels without ORI exhibited no cytotoxicity The results also showed that drug loaded Gal-CS-g-PNIPAm nanogels could be effectively absorbed by HepG2 cells through the mechanism of galactosespecific receptor-mediated endocytosis These liver cancer cells targeted and pH triggered nanogels would be a promising DDS [25] By Jianxun Ding, di-block and tri-block copolymers, including poly (ethylene glycol monomethyl ether)-b-poly (L-glutamic acidco-g-cinnamyl-L-) [mPEG-b-P(LGA/CLG)] and poly (L-glutamic acidco-g-cinnamyl-L-glutamate)-b-poly(ethylene glycol)-b-poly (L-glutamic acid-co-g-cinnamyl-L-glutamate) [P(LGA/CLG)-b-PEG-bP(LGA/CLG)], were developed through ring-opening polymerization (ROP) of g-benzyl-L-glutamate-N-carboxyanhydride (gBLGNCA) monomer along with PEG-dependent macro initiator Benzyl group de-protection and chemical modification takes place with cinnamyl alcohol Di-block and tri-block copolymers with PEG at shells and p(LGA/CLG) at cores spontaneously self-assembled into micelles of pH 7.4 aqueous solution Under UV-irradiation at l ¼ 254 nm, blocks of P(LGA/CLG) in the cores were cross-linked by photo-dimerization of the cinnamyloxy groups for these nanogels formation These nanogels were pH-responsive and their effective qualities could be adjustable by changing the constituents of block copolymers The MTT assay showed that the developed nanogels were biocompatible to HeLa cells The analyzed results provide their future prospectives for drug delivery applications [26] Further in this section, a dual-sensitive (pH/redox) nanohydrogels with consistent size dispersal was developed through distillation precipitation polymerization (DPP) by using monomer (MAA) and BACy as a disulfide-functionalized cross-linker A model anti-cancer drug (DOX) was effectively encapsulated up to 42.3 wt% into the nanogels The collective DOX release from nanogels exhibited