Nanogel—an advanced drug delivery tool: Current and future

Figures & data

Table I. Classification of nanogel according to their structure.

S.No	Type	Schematic structure	Network structure	Example
1	Simple Nanogel		a) Cross-linked b) Semi-interpenetrating polymer(semi-IPN) c) Self-assembled	Artificial chaperone, cholesterol-bearing pullulan (CHP) nanogel (Inomoto et al. 2009). Quantum dot nanogel (Wu et al. 2010). Artificial chaperone cholesterol enzymatically synthesized glycogen (CHSEG) nanogel (Takahashi et al. 2010) .
2	Hollow nanogel		Interpenetrating polymer	Stimuli sensitive/responsive nanogel (Xing et al. 2011).
3	Core—shell nanogels		Cross-linked	Stimuli sensitive/responsive nanogel (Sun et al. 2005).
4	Hairy nanogel		Cross-linked	Stimuli-responsive nanogel (Shen et al. 2011).
5	Multilayer nanogels		Cross-linked	Stimuli sensitive/responsive nanogel (Wong et al. 2009).
6	Functionalized nanogels		Cross-linked	Polyethyleneglycol-b-poly (methacrylic acid) [PEG-b-PMA] with PEG terminal aldehyde functionality (Nukolova et al. 2011).

Figure 1. Synthesis of nanogels by copolymerization in colloidal environments. Copolymerization of monomers [A] and bifunctional cross-linkers [B] in w/o microemulsions stabilized by surfactants [C] produces nanogels which can be then transferred into aqueous media after removal of surfactants and organic solvent.

Figure 2. Inverse micro emulsion process.

Figure 3. Aggregation of hydrophobically modified polymer, cholesterol-pullulan, in the presence of insulin molecules results in nanogels containing entrapped protein.

Figure 4. Schematic presentation of RAFT process.

Figure 5. Synthesis of nanogels by cross-linking of the preformed polymer chains or self-assembled polymeric aggregates. Cross-linking of double-end activated PEG and PEI chains in o/w emulsion followed by evaporation of the organic solvent.

Figure 6. Schematic presentation of emulsion photopolymerisation process.

Figure 7. Schematic presentation of pullulan glucose unit modifications.

Figure 8. Drug release due to change in pH.

Figure 9. Drug release due to thermo-volume responsiveness of nanogels.

Figure 10. Drug release from nanogel due to diffusion.

Table II. Applications of nanogels in the cancer therapy.

Nanogel constitution	Type of nanogel	Drug used	Applications	References
Maleic acid poly- (N-isopropylacrylamide) polymer	Sustained release nanogel/pH-sensitive nanogel	Doxorubicin	Dual-responsive delivery of Doxorubicin hydrochloride has resulted in low release of drug at a normal physiological pH of 7.4 and temperature 37°C, but a significant release at the cellular pH 4 of cancer cells and a temperature of 41°C	Ballal et al. (2013)
Carboxyl group conjugation in nanogel with NaOH used as catalyst	Temperature- and pH-responsive nanogel	Cisplatin	pH thermal dual responsive nanogel mainly used for breast cancer therapy	Peng et al. (2013)
Chitin nanogels	Polymerized nanogel	Doxorubicin	This nanogel used for prostate, breast, lungs, liver cancer	Jayakumar et al. (2012)
Acetylated chondroitin sulfate
	Self-organizing nanogel	Doxorubicin	Used for cancer cell	Park et al. (2010)
Hydroxypropylcellulose-poly(acrylic acid)	pH- and temperature-responsive cadmium (Hayashi et al.) ions quantum dots	Temozolomide	Optical pH sensing, cell imaging, and drug loading of Temozolomide	Wu et al. (2010)
Glycol chitosan grafted with 3-diethylaminopropyl groups	pH-responsive	Doxorubicin	Doxorubicin uptake accelerated	Singka et al. (2010)
Reducible heparin with disulfide linkage	Reducible nanogel	Heparin	Internalization of heparin for apoptotic death of melanoma cells	Bae et al. (2008)
Cross-linked folic acid with pullulan	Self-organized with minimal fabrication nanogel	Doxorubicin	Doxorubicin targeting	Kim et al. (2008)
Poly(N-isopropylacrylamide- co-acrylamide)	In situ gelatinized thermosensitivenanogel	5-Flurouracil	Drug-loading capacity of low-mol.-weight 5-Flourouracil was higher than that of biomacromolecules and bovine serum albumin	Wang et al. (2008)
Cross-linked Polyethyleneimine and PEG/pluronic	Biodegradable nanogel	5’-triphosphorylated ribavirin reduced toxicity
	Biodegradable nanogel	5-Triphosphate	5′Triphosphorylated ribavirin reduced toxicity	Kohli et al. (2007)
Cross-linked branched network of Polyethyleneimine and PEG	Polyplex nanogel	Fludarabine	Elevated activity and reduced cytotoxicity of Fludarabine	Vinogradov et al. (2005)

Table III. Applications of nanogels in gene delivery, enzymology, and protein folding.

Nanogel constitution	Type of nanogel	Applications	References
Amphiphilic polysaccharides nanogel with artificial chaperon	Artificial chaperon	Successfully used for the correct folding of Cyclodextrin with rhodanese in cell-free system. Also applied to prevent aggregation of protein	Sasaki et al. (2011)
Enzymatically synthesized glycogen synthesized with cholesterol group to	Artificial chaperon	Used for the stabilization of thermal enzyme and also in biomedical engineering	Takahashi et al. (2010)
Enzymatically synthesized glycogen (CHESG) which make nanocomplex with cyclodextrin.
Dextran hydroxyethyl methacrylate-co-[2-(methacryloyloxy)-ethyl]trimethylammonium chloride	Nanogels with photochemical internalization	Endosomal escape of siRNA	Raemdonck et al. (2010)
Poly [2-(N, N-diethylaminoethyl) methacrylate] PEGlyated macroRAFT agent.	One-step PEGylated cationic nanogel.	Potential gene therapy	Yan and Tao, (2010)
Hybrid hyaluronan hydrogel encapsulating nanogel as a protein nanocarrier	Sustained released nanogel/artificial chaperon nanogel.	Therapeutic peptides and proteins, such as glucagon-like peptide-1, insulin and erythropoietin, were spontaneously trapped in Hyaluronan gel just by immersing hybrid hydrogels into the drug solutions	Hirakura et al. (2010)
Cholesterol group bearing pullulan with methyl-β-Cyclodextrin made a complex.	Artificial chaperon/sustained release	Nanogels did not affect protein synthesis in the cell-free system, providing correctly folded active proteins	Sasaki et al. (2010)
Di-acrylated pluronic 127 and glycidyl methacrylated chito-oligosacchride	DNA nanogel with photo cross-linking.	Controlled delivery of plasmid DNA	Lee et al. (2009)
Methyl acrylic acid and N,N′-Methylene-bis-(acrylamide)	Super magnetic nanogel functionalized with carboxyl group.	α-Chymotrypsin immobilized on animated Nanogel	Hong et al. (2008)
Thiol functionalized Hyaluronic acid	Target specific degradable nanogel	siRNA delivery to HCT-116 cells	Lee et al. (2007)
Cholesterol group bearing pullulan	Self-assembled nanogel/molecular artificial chaperons	This nanogel was an efficient delivery system for bone anabolic agent and cytokines	Nomura et al. (2003)

Table IV. Nanogel applications in gastrointestinal disorder.

Nanogel constitution	Description	References
Zwitter ionic poly (carboxybetaine methacrylate) (p-CBMA) nanogels conjugated to cyclo [Arg-Gly-Asp-D-Tyr-Lys] (cRGD)	Nanogels targeted to Human Umbilical Vein Endothelial Cells (HUVECs) in a model cell system where pCBMA was found to selectively bind to HUVECs	Cheng et al. (2010)

Table V. Marketed formulation of nanogel.

S.no	Product name	Applications
1	Muc-Off Nano Gel (nanogel bike cleaner concentrate)	It has been specifically formulated to protect disc brake pads and paintwork. It also used removing dirt, sand, traffic film, mud, insects, clay, and oily road grime
2	Skin perfect brightening nanogel	It brightens the skin and gives complete hydration. It repairs, tones, and protects the skin
3	NBF Gingival gel	It is a nano-biofusion technology gel. This gel is absorbed in gingival cellular level and maintained with a nano bioactive protecting film. It is a high-quality gum protector
4	Aqua Multi Effect Nano Gel Cream	It's a moisturizing gel that gives complete hydration for a long time. It also works as anti-wrinkle cream
5	HA nanogel	Excellent alternative to regular toothpaste. Reducing risk of decay and also reduced bad breath
6	Zyflex nanogel	It relaxes the muscles and erase the body pain
7	Oxalginnanogel	It gives deeper action and quicker penetration
8	Sane care nanogel	Reduces accumulated fats on the abdomen, arms, legs, thighs, and double chin
9	Revivagenix Pro Collagen Nano Gel	It is an anti-wrinkle cream, gives complete hydration to the skin for longer time
10	AugenNanogel Eye-care Gel	It is an eye care gel with deep penetration properties

Inomoto N, Osaka N, Suzuki T, Hasegawa U, Ozawa Y, Endo H, et al . 2009. Interaction of nanogel with cyclodextrin or protein: study by dynamic light scattering and small-angle neutron scattering. Polymer. 50:541–546.

 Web of Science ®Google Scholar

Wu W, Aiello M, Zhou T, Berliner A, Banerjee P, Zhou S. 2010. In-situ immobilization of quantum dots in polysaccharide-based nanogels for integration of optical pH-sensing, tumor cell imaging, and drug delivery. Biomaterials. 31:3023–3031.

 PubMed Web of Science ®Google Scholar

Takahashi H, Sawada S-I, Akiyoshi K. 2010. Amphiphilic polysaccharide nanoballs: a new building block for nanogel biomedical engineering and artificial chaperones. ACS Nano. 5:337–345.

 PubMed Web of Science ®Google Scholar

Xing Z, Wang C, Yan J, Zhang L, Li L, Zha L. 2011. Dual stimuli responsive hollow nanogels with IPN structure for temperature controlling drug loading and pH triggering drug release. Soft Matter. 7: 7992–7997.

 Web of Science ®Google Scholar

Sun H, Yu J, Gong P, Xu D, Zhang C, Yao S. 2005. Novel core–shell magnetic nanogels synthesized in an emulsion-free aqueous system under UV irradiation for targeted radiopharmaceutical applications. J Magn Magn Mater. 294:273–280.

 Web of Science ®Google Scholar

Shen W, Chang Y, Liu G, Wang H, Cao A, An Z. 2011. Biocompatible, antifouling, and thermosensitive core− shell nanogels synthesized by RAFT aqueous dispersion polymerization. Macromolecules. 44:2524–2530.

 Web of Science ®Google Scholar

Wong JE, Mu ller CB, DI ez-Pascual AM, Richtering W. 2009. Study of layer-by-layer films on thermoresponsive nanogels using temperature-controlled dual-focus fluorescence correlation spectroscopy. J Phys Chem B. 113:15907–15913.

 PubMed Web of Science ®Google Scholar

Nukolova NV, Oberoi HS, Cohen SM, Kabanov AV, Bronich TK. 2011. Folate-decorated nanogels for targeted therapy of ovarian cancer. Biomaterials. 32:5417–5426.

 PubMed Web of Science ®Google Scholar

Ballal NV, Tweeny A, Baumgartner JC, Ginjupalli K, Saraswathin V. 2013. Effect of maleic acid and ethylenediaminetetraacetic acid on the shear bond strength of RealSeal SE sealer to root canal dentin. Eur J Prosthodont Restor Dent. 21:152–156.

 PubMedGoogle Scholar

Peng J, Qi T, Liao J, Chu B, Yang Q, Li W, et al. 2013. Controlled release of cisplatin from pH-thermal dual responsive nanogels. Biomaterials. 34:8726–8740.

 PubMed Web of Science ®Google Scholar

Jayakumar R, Nair A, Rejinold NS, Maya S, Nair S. 2012. Doxorubicin-loaded pH-responsive chitin nanogels for drug delivery to cancer cells. Carbohydr Polym. 87:2352–2356.

 Web of Science ®Google Scholar

Park W, Park SJ, Na K. 2010. Potential of self-organizing nanogel with acetylated chondroitin sulfate as an anti-cancer drug carrier. Colloids Surf B Biointerfaces. 79:501–508.

 PubMed Web of Science ®Google Scholar

Singka GS, Samah NA, Zulfakar MH, Yurdasiper A, Heard CM. 2010. Enhanced topical delivery and anti-inflammatory activity of methotrexate from an activated nanogel. Eur J Pharm Biopharm. 76:275–281.

 PubMed Web of Science ®Google Scholar

Bae KH, Mok H, Park TG. 2008. Synthesis, characterization, and intracellular delivery of reducible heparin nanogels for apoptotic cell death. Biomaterials. 29:3376–3383.

 PubMed Web of Science ®Google Scholar

Kim S, Park KM, Ko JY, Kwon IC, Cho HG, Kang D, et al. 2008. Minimalism in fabrication of self-organized nanogels holding both anti-cancer drug and targeting moiety. Colloids Surf B Biointerfaces. 63:55–63.

 PubMed Web of Science ®Google Scholar

Wang Q, Xu H, Yang X, Yang Y. 2008. Drug release behavior from in situgelatinized thermosensitive nanogel aqueous dispersions. Int J Pharm. 361:189–193.

 PubMed Web of Science ®Google Scholar

Kohli E, Han HY, Zeman AD, Vinogradov SV. 2007. Formulations of biodegradable Nanogel carriers with 5’-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity. J Control Release. 121:19–27.

 PubMed Web of Science ®Google Scholar

Vinogradov SV, Zeman AD, Batrakova EV, Kabanov AV. 2005. Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs. J Control Release. 107:143–157.

 PubMed Web of Science ®Google Scholar

Sasaki Y, Asayama W, Niwa T, Sawada SI, Ueda T, Taguchi H, Akiyoshi K. 2011. Amphiphilic Polysaccharide Nanogels as Artificial Chaperones in Cell‐Free Protein Synthesis. Macromol Biosci. 11:814–820.

 PubMed Web of Science ®Google Scholar

Raemdonck K, Naeye B, Hogset A, Demeester J, De Smedt SC 2010. Prolonged gene silencing by combining siRNA nanogels and photochemical internalization. J Control Release. 145:281–288.

 PubMed Web of Science ®Google Scholar

Yan L, Tao W. 2010. One-step synthesis of pegylated cationic nanogels of poly ( N, N′-dimethylaminoethyl methacrylate) in aqueous solution via self-stabilizing micelles using an amphiphilic macroRAFT agent. Polymer. 51:2161–2167.

 Web of Science ®Google Scholar

Hirakura T, Yasugi K, Nemoto T, Sato M, Shimoboji T, Aso Y, et al . 2010. Hybrid hyaluronan hydrogel encapsulating nanogel as a protein nanocarrier: new system for sustained delivery of protein with a chaperone-like function. J Control Release. 142:483–489.

 PubMed Web of Science ®Google Scholar

Sasaki Y, Nomura Y, Sawada S-I, Akiyoshi K. 2010. Polysaccharide nanogel–cyclodextrin system as an artificial chaperone for in vitro protein synthesis of green fluorescent protein. Polym J. 42:823–828.

 Web of Science ®Google Scholar

Lee JI, Kim HS, Yoo HS. 2009. DNA nanogels composed of chitosan and Pluronic with thermo-sensitive and photo-crosslinking properties. Int J Pharm. 373:93–99.

 PubMed Web of Science ®Google Scholar

Hong J, Xu D, Gong P, Yu J, Ma H, Yao S. 2008. Covalent-bonded immobilization of enzyme on hydrophilic polymer covering magnetic nanogels. Microporous Mesoporous Mater. 109:470–477.

 Web of Science ®Google Scholar

Lee H, Mok H, Lee S, Oh Y-K, Park TG. 2007. Target-specific intracellular delivery of siRNA using degradable hyaluronic acid nanogels. J Control Release. 119:245–252.

 PubMed Web of Science ®Google Scholar

Nomura Y, Ikeda M, Yamaguchi N, Aoyama Y, Akiyoshi K. 2003. Protein refolding assisted by self-assembled nanogels as novel artificial molecular chaperone. FEBS Lett. 553:271–276.

 PubMed Web of Science ®Google Scholar

Cheng G, Mi L, Cao Z, Xue H, Yu Q, Carr L, Jiang S. 2010. Functionalizable and ultrastable zwitterionic nanogels. Langmuir. 26: 6883–6886.

 PubMed Web of Science ®Google Scholar