1. Introduction

Nanotechnology, a relatively novel technique, offers a broad scope for a smart drug delivery and drug manufacturing (nanomedicine) approach involving the design, synthesis and characterization of materials or molecules and devices that have effective function at nanometer scale. Development of novel nano-sized particulate drug delivery systems (DDS) have shown the profound impact on disease prevention, diagnosis, and treatment as reported after the researches in academic laboratories and pharmaceutical companies all over the world. ^[1]. The term ‘nanogels’ defined as the nanosized particles formed by physically or chemically crosslinked polymer networks that is swell in a good solvent. The term “nanogel” was first introduced to define cross-linked bifunctional networks of a polyion and a nonionic polymer for delivery of polynucleotides. ^[2]. They are soluble in water, but have properties different from linear macromolecules of similar molecular weight. Such structures, along with their bigger analogues ^[3]. Nanogels are typical formulations mainly of the size range of 100 nm, by varying solvent quality and branching the volume fraction can be altered variably to maintain a three dimensional structure. Nanogels have revolutionized the field of gene therapy, since delivery of gene has now become possible within cellular organales for gene silencing therapy systems ^[4]. Nanogels are swollen in nano-sized networks composed of hydrophilic or amphiphilic polymer chains, which can be ionic or non-ionic. Not, only for drug delivery the nanogels is investigated from a longer period of time for making miscellaneous agents like quantum dots, dyes and other diagnostic agents ^[5]. The significance of nano-sized microgel and hydrogel has arisen due to specific delivery system anticipation. Wide variety of polymer systems and the easy alteration of their physico-chemical characteristics have given advantage for versatile form of nanogel formulations ^[6].

2. Routes of Administration of Nanogels [2]

• Oral

• Pulmonary

• Nasal

• Parenteral

• Intra-Ocular

• Topical.

3. Properties of Nanogels

Nanogel based drug delivery system is highly biocompatible and biodegradable due to this characteristics it is highly promising field now a days.

The most beneficial feature of nanogels is their rapid swelling/de-swelling characteristics. Nanogels are soft nanomaterials ^[2]. Swelling of nanogels in aqueous environment is controlled by both nanogel structure chemical nature of polymer chains, degree of cross-linking, charge density for polyelectrolyte gels and environmental parameters for polyelectrolyte gels - pH, ionic strength and chemical nature of low molecular mass ions for thermo-responsive gels – temperature. It is well recognized that a balance between the osmotic pressure and the polymer elasticity determines physical dimensions of a hydrogel particle ^[7].

The properties of higher drug loading capacity of nanogels depend on the functional group present in the polymeric unit. These functional groups have a tremendous effect on drug carrying and drug-releasing properties, and some functional groups have the potential to conjugate with drugs/antibodies for targeting applications. These pendent functional groups of polymeric chains contribute toward establishing hydrogen bonding or vander Waals forces of interactions within the gel network and thus facilitate the drug-carrying efficiency. Moreover, the presence of functional groups at interface with drug/protein molecules is also responsible for higher loading ^[2].

Nanogels typically range in size of 10-100 nm in and hence are effective in avoiding the rapid renal exclusion but are small enough to avoid the uptake by the reticuloendothelial system ^[8]. Good permeation capabilities due to extreme small size. More specifically, it can cross the blood brain barrier (BBB) ^[2]. Size is a key factor in the biodistribution of long-circulating nanoparticles on the basis of physiological parameters such as hepatic filtration, tissue extravasation, tissue diffusion, and kidney excretion ^[9].

Nanogels are able to solubilize hydrophobic drugs and diagnostic agents in their core or networks of gel ^[2]. In addition hydrophobic molecules can be solubilized into hydrophobic domains presented in some nanogels. For example, prostaglandin E2 was solubilized in nanogels of cholesterol-modified pullulan. Doxorubicin was also loaded in amphiphilic cross-linked nanogels based on Pluronic F127 or poly[oligo(ethylene oxide)-methyl methacrylate]. Notably, in most cases loading due to hydrophobic interactions alone results in relatively low loading capacities ^[9].

Nanogels could be prepared without employing energy or harsh conditions such as sonication or homogenization, which is critical for encapsulating biomacromolecules ^[2].

Nanogels or polymeric micellar nanogel systems have better stability over the surfactant micelles and exhibit lower critical micelle concentrations, slower rates of dissociation, and longer retention of loaded drugs ^[2].

This type of drug delivery system usually does not produce any immunological responses ^[2].

Both type of drugs (hydrophilic and hydrophobic drugs and charged solutes) can be given through nanogel. Such properties of nanogel are significantly influenced by temperature, presence of hydrophilic/hydrophobic groups in the polymeric networks, the cross-linking density of the gels, surfactant concentration, and type of cross-links present in the polymer networks ^[2].

4. Advantages of Nanogels [10,11]

• Highly biocompatible (due to high water content and hence behave like natural tissue) and therefore immunological responses

• Biodegradable, that makes these nanocarriers nontoxic

• High drug loading capacity

• Easily escape entrapment by reticuloendothelial system

• By tuning crosslinking densities drug release can be regulated

• Better permeation via biological membranes due to extremely small size

• Can incorporate both hydrophilic and hydrophobic drugs and charged solutes

• Excellent transport characteristics

• Ability to reach the smallest capillary vessels, due to their tiny volume, and to penetrate the tissues either through the paracellular or the transcellular pathways.

5. Disadvantages of Nanogels [12,13]

• Expensive technique to completely remove the solvents and surfactants at the end of preparation process

• Surfactant or monomer traces may remain and can impart adverse effects

• Some fraction of particles are in the micrometer range

• Scale up is not easy due to mean size and weight.

6. Classification of Nanogels

Nanogels are more commonly classified into two major ways. The first classification is based on their responsive behaviour, which can be either stimuli-responsive or non-responsive. In the case of non-responsive microgels, they simply swell as a result of absorbing water.

1. Stimuli-responsive nanogels swell or deswell upon exposure to environmental changes such as temperature, pH, magnetic field, and ionic strength.

2. Multi-responsive nanogels are responsive to more than one environmental stimulus. The second classification is based on the type of linkages present in the network chains of gel structure, polymeric gels (including nanogel) are subdivided into two main categories.

Hybrid nanogels are defined as a composite of nanogel particles dispersed in organic or inorganic matrices ^[14]. Group of studies have demonstrated nanogel formation in an aqueous medium by self assembly or aggregation of polymer amphiphiles, such as pullulan-poly(N-isopropylacrylamid) (PNIPAM), hydrophobized polysaccharides, and hydrophobized pullulan ^[2]. Pullulan is extensively used in food, cosmetic and pharmaceutical industries because it is easily modifiable chemically, non-toxic, non-immunogenic, non-mutagenic, and non-carcinogenic ^[15]. The merits of pullulan are that it is biocompatible, biodegradable, blood compatible and non-immunogenic ^[16]. It can be chemically modified to various derivatives to endow amphiphilic property. Another advantage of Pullulan is that it binds strongly to asialoglycoprotein receptor and is internalized via receptor-mediated endocytosis. This group has investigated cholesterol-bearing pullulan (CHP) Nanogels ^[17].

These nanogels have the ability to form complexes with various proteins, drugs, and DNA; and it is even possible to coat surfaces of liposomes, particles, and solid surfaces including Cells. These hybrid nanogels are also capable of delivering insulin and anticancer drugs more effectively. CHP is composed of pullulan backbone and cholesterol branches. The CHP molecules self aggregate to form mono-dispersed stable nanogels through the association of hydrophobic groups that provide physical crosslinking points ^[2]. As shown in Figure 1.

Download as

• PPT
  PowerPoint Slide
• PNG
  Larger image(png format)

Veiw figureFigures index

•  NEW
  View larger figure in new window

View next figure

Figure 1. Schematic representation of CHP nanogel preparation by physical cross-linking (self-assembly)

Polymeric micelles are nanosized particles with a typical core–shell structure where the core can solubilise the hydrophobic drug and the corona stabilizes the interface between the core and the outside medium ^[18]. Polymer micellar nanogels can be obtained by the supramolecular self-assembly of amphiphilic block or graft copolymers in aqueous solutions. Since the use of block polymer micelles as drug-carrying vehicles was proposed in 1980s, micellar drug delivery systems (DDSs), which are aimed to deliver drugs at predetermined rates and predefined periods of time, have attracted increasing research attention ^[19].

They possess unique core-shell morphological structures, where a hydrophobic block segment in the form of a core is surrounded by hydrophilic polymer blocks as a shell (corona) that stabilizes the entire micelle. The core of micelles provides enough space for accommodating various drug or biomacromolecules by physical entrapment. Furthermore, the hydrophilic blocks may form hydrogen bonds with the aqueous media that lead to a perfect shell formation around the core of micelle ^[20]. Therefore, the drug molecules in the hydrophobic core are protected from hydrolysis and enzymatic degradation. Researchers successfully developed highly versatile Y-shaped micelles of poly(oleic acid-Y-N-isopropylacrylamide) for drug delivery application. In this study, the delivery of prednisone acetate above its lower critical solution temperature (LCST) was demonstrated. A representation of micelle formation ^[2]. As shown in Figure 2.

Download as

• PPT
  PowerPoint Slide
• PNG
  Larger image(png format)

Veiw figureFigures index

•  NEW
  View larger figure in new window
• PREV
  View previous figure

View next figure

Figure 2. Y-shaped copolymer self-assembly to give micelle structures

When liposomes are mixed with the succinylated poly (glycidol); these liposomes can be efficiently deliver calcein to the cytoplasm by fusion the chain below pH 5.5. Liposomes which are the thermo and pH responsive nanogel like as poly (N isopropylacrylamide) are being investigated for transdermal drug delivery ^[5]. Liposomes are simple microscopic vesicles in which lipid bilayer structure is present with an aqueous volume entirely enclosed by a membrane, composed of lipid molecules. There are number of components present in liposomes, with phospholipid and cholesterol being the main ingredients ^[21]. In particular, liposomes have been used as carriers for many kinds of molecules such as anti-cancer, anti-bacterial, anti-fungal and anti-viral agents, and bioactive macromolecules ^[22].

Chemical gels are comprised of permanent chemical linkages (covalent bonds) throughout the gel networks. The properties of cross-linked gel system depend on the chemical linkages and functional groups present in the gel networks ^[2]. Chemically crosslinked hydrogels are synthesized by chain growth polymerization, addition and condensation polymerization and gamma and electron beam polymerization. Chain-growth polymerization includes free radical polymerization, controlled free radical polymerization, anionic and cationic polymerization. It is done by three process viz., initiation, propagation, and termination. After initiation, a free radical active site is generated which adds monomers in a chain link-like fashion ^[23]. The crosslinking agent is explained by the e.g. by using the disulfide cross linking in the preparation of nanogel (20 – 200 nm) the pendant thiol groups are achieved “environmentally friendly chemistry.” ^[5].

7. Synthesis Techniques of Nanogel

Current approaches used for the preparation of nanogels can be classified into following categories: 7.1. Novel pullulan chemistry modification, ^[24]. 7.2. Novel photochemical approach, ^[25]. 7.3. Novel free radical polymerization process with inverse miniemulsion technique, ^[26]. 7.4. Addition fragmentation transfer (RAFT) process, ^[27]. 7.5. Emulsion photopolymerisation process, ^[28]. 7.6. Chemical modifications ^[29].

8. Drug Loading Techniques in Nanogel

Nanogels are widely used as carriers of therapeutic agents. A successful nanodelivery system should have a high drug-loading capacity, thereby reducing the required amount of carrier. Drugs can be incorporated in nanogels by

Covalent conjugation of biological agents can be achieved using preformed nanogels or during nanogel synthesis ^[2]. For e.g. Acrylic groups are modified with enzymes and copolymerized with acrylamide either in inverse microemulsion or dilute aqueous solution to obtain nanosized hydrogel ^[5].

In cholesterol – modified pullulan nanogels proteins was incorporated by physical entrapment SiRNA in HA nanogels. In nonpolar domains by addition of hydrophobic molecules formed a hydrophobic chain which is present in selected Nanogels ^[5]. For example, prostaglandin E2 was solubilized in nanogels of cholesterol-modified pullulan. In another study, N-hexylcarbamoyl-5-fluorouracil (HCFU) was noncovalently incorporated in cross-linked nanogels of Nisopropylacrylamide (NIPAAm) and N-vinylpyrrolidone (VP) copolymers (PNIPAAm/VP ^[2]. Physical entrapment is mainly determined by the sizes of nanocarrier pores and enzyme molecules. Other approaches are based on the functional groups on the surfaces of enzymes and nanocarriers ^[30].

Biological self-assembly provides illustrations of thermodynamically stable supramolecular arrays that not only have regular architectures but also have intelligent functions ^[31]. The self-assembly phenomenon has been defined as the autonomous, spontaneous, and reversible organization of molecular units into structurally stable and well-defined aggregates in which defects are energetically rejected. It has many beneficial features such as –

• It is cost-effective,

• Versatile and facile,

• The process occurs towards the system’s thermodynamic minima, resulting in stable and robust structures.

Self-assembly occurs toward the system’s thermodynamic minima and through a balance of attractive and repulsive interactions, which are generally weak and non covalent, such as electrostatic, vander waals, and coulomb interactions, hydrophobic forces, and hydrogen bonds ^[32]. Many molecules are self–assembly is characterized by diffusion followed by specific association of molecules through non–covalent interaction, hydrophobic associations or including electrostatics. Individually, such interactions are weak, but dominate the structural and conformational behaviour of the assembly due to the large number of interactions involved ^[33].

While oppositely charged polysaccharides associates readily as a result of electrostatic attractions ^[34]. Interactions with neutral polysachharides lead to be weaker or non – existent, by the modification with chemical it is able to trigger assembly being necessary. The polysaccharides which are highly water soluble, inducing the formation of nanoparticles via hydrophobic interactions. This kind of amphiphilic polymer can be used by three methods.

• Hydrophilic chains grafted to a hydrophobic backbone (grafted polymer).

• Hydrophobic chains grafted to a hydrophilic backbone.

• Or, with alternating hydrophilic & hydrophobic segments (block polymers) ^[5].

Upon contact with an aqueous environment, amphiphilic polymers spontaneously form self-aggregated nanoparticles, via intra- or intermolecular associations between the hydrophobic moieties, primarily to minimize the interfacial free energy. The important feature, from the physicochemical point of view is that the molecule is able to orient itself to expose the hydrophilic regions to the polar environment (normally the aqueous medium) and the hydrophobic segments aggregates in the internal core of the material. The concentration above which the polymeric chains aggregate is called the critical micelle concentration or the critical aggregate concentration ^[2].

Download as

• PPT
  PowerPoint Slide
• PNG
  Larger image(png format)

Veiw figureFigures index

•  NEW
  View larger figure in new window
• PREV
  View previous figure

Figure 3. Schematic representation of intermolecular interactions driving self assembly processes that includes (an electrostatic interactions and (b) hydrophobic association

9. Mechanism of Drug Release from Nanogels

Example: The diffusional release of doxorubicin from stable hydrogel nanoparticles based on pluronic block copolymer ^[2]. Various nanomedicine are follows this mechanism & simple procedure, such as polymeric micelles that have already reached a clinical stage ^[5].

The degradation of these nanogels was shown to trigger the release of encapsulated molecules including rhodamine 6G, a fluorescent dye, and Doxorubicin, an anticancer drug, as well as facilitate the removal of empty vehicles ^[2]. Example: The release of Doxorubicin was significantly increased due to glycol chitosan nanoparticles sensitivity to pH stimuli due to grafting of diethylaminopropyl group ^[4]. Significant mesh size alteration has been seen in dietylaminoethyl methyacrylate cationic nanogel for release of medium size molecules by virtue of pH sensitivity ^[35].

There is an increased interest in developing nanogels that can release biological agents in response to environmental cues at the targeted site of action. For example: disulfide cross-linked POEOMA nanogels biodegraded into water-soluble polymers in the presence of a glutathione tripeptide, which is commonly found in cells ^[36]. Cell membrane-triggered release of negatively charged drugs from complexes with cationic nanogels was also proposed to explain cellular accumulation of an NTPs drug delivered with nanogels ^[2].

In the acidic skin pH the reactive oxygen species scavenging the on & off 8catalytic activity by the platinum nanoparticles containing nanogel and for the reason of protonation of crosslinked poly (2 – (N, N – diethylamino) methacrylate) core and PEG ^[37]. When there is exit low PH the polymers methacrylic acid – ethyl acrylate are insoluble 3D structures, again by increasing the PH ranges acidic groups ionizes due to the polymeric chains repulsions begins and lead to a particular release profile of procaine hydrochloride ^[38].

The control the release kinetics mechanism shown by the drug temozolidine due to swelling action of pH sensitive polyacryrlic acid chains ^[39]. But the release of doxorubicin was significantly increased due to pH sensitive of glycol chitosan nanoparticles, & to grafting of diethylaminopropyl groups ^[5].

Excitation of photosensitizers loaded nanogels leads to production of singlet oxygen and reactive oxygen species which cause oxidation of cellular compartment walls such as endosomal barrier walls which effects release of therapeutics into cytoplasm ^[4]. Polyelectrolyte hydrogels that incorporate biological agents via electrostatic bonds allow for release of biological agents in response to environmental changes. Cis-trans isomerisation of azobenbenzene by photoregulation in azo-dextran nanogel loaded with aspirin as model drug exhibited that E-configuration of azo group lead to better release profile of drug than z-configuration at 365 nm radiation ^[40].

10. Application of Nanogels

Nanogels have been transforming the field of curative medicines. In the short duration since the appearance of the concept, these non-conventional drug delivery systems have served as potential candidates for wide spectrum of applications.

Many polymeric nanogels have been employed for cancer therapy. Incorporating chemotherapeutic drugs into the nanogel not only increases the bioavailability but also enhanced permeability and retention ^[6]. Nanogel are being used to deliver drugs more effectively in cancer chemotherapy. One of the polymeric nanogels for use in patients with breast cancer, which has received FDA approval also, is Genexol-PM ^[41].

A study conducted designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). The results of this study concluded that there is a better efficacy of nanogel based local drug delivery for lupus erythematosus as it targets antigen-presenting cells. This new drug delivery system increases the longevity of the patient and delays, the onset of kidney damage, a common complication of lupus ^[42].

Pain control is one of the top priorities in therapeutics in dental treatment. Improvement of regional administration of local anaesthetics could be achieved by incorporating them into drug delivery systems ^[6]. In a study conducted to develop and evaluate thermo-reversible in situ gelling drug delivery system for periodontal anaesthesia. It was found that Pluronic gel proved to be a promising carrier for effective release of Mepivacaine hydrochloride throughout the dental procedure ^[43]. Nanogels are probably one of the better candidates due to the lesser pain during injection and longer blood circulation time ^[44].

A protein molecules which is in solutions & been used for formation of nanogel has been used to stop bleeding, even in severe gashes. The proteins have mechanism of self – assemble on the nanoscale in to a biodegradable gel ^[5].

3-acetyl-11-keto-β-boswellic acid (AKBA) and AKBA loaded nanoparticles were used to prepare nanogel. Carbopol with the desired viscosity were utilized to prepare the nanogels. AKBA loaded nanoparticles were used to prepared the treatment of inflammation. 3-acetyl-11-keto-β-boswellic acid (AKBA) is the most potent pentacyclic triterpenic acid present in gum of Boswellia serrata for anti-inflammatory activity. The result showed much higher anti-inflammatory activity of AKBA ^[45].

Polyvinyl pyrrolidone – poly (acrylic acid) (PVP/PAAc) nanogel is pH sensitive and prepared by γ – radiation – induced polymerization. It is used to encapsulate pilocarpine in order to maintain an adequate concentration of the pilocarpine at the site of action for prolonged of time ^[46].

Nanogel is a promising system for delivery of oligonucleotides (ODN) to the brain. For treatment of neurodegenerative disorders systemic delivery of oligonucleotides (ODN) to the central nervous system is needed. Macromolecules injected in blood are poorly transported across the blood-brain barrier (BBB) and rapidly cleared from circulation. Nanogels bound or encapsulated with spontaneously negatively charged ODN results in formation of stable aqueous dispersion of polyelectrolyte complex with particle sizes less than 100 nm which can effectively transported across the BBB. The transport efficacy is further increased when the surface of the nanogel is modified with transferrin or insulin ^[47].

“An Injectable Nano-Network that Responds to Glucose and Releases Insulin” has been developed. It contains a mixture of oppositely charged nanoparticles that attract each other. This keeps the gel together and stops the nanoparticles drifting away once in the body. In vivo experiments conducted in diabetic rats in 2012 revealed that insulin-loaded nanogels decreased the blood glucose levels by 51% from the baseline level for almost 2 hours. Significantly, when compared with free insulin the insulin-loaded nanogels could keep blood glucose levels stable and avoided blood sugar variations ^[48].

Nanogel drug delivery systems hold great potential to overcome some of the barriers in delivery. Nanogels are efficiently taken up by nasal mucosa and therefore, may possibly be used as efficient transport and delivery systems for therapeutics through nasal mucosa. The use of nanogels for vaccine delivery via nasal route is a new approach to control the disease progression.

Nanogels are high-viscosity systems containing nanoparticulates (NPs, microcapsules, NEs, etc.) in a polymer network ^[49]. The advantages of nanogel take account of reduced mucociliary clearance due to elevated viscosity, reduction in taste impact due to reduced post-nasal drip towards nasopharynx, reduced irritation due to soothing/emollient excipients and target delivery to mucosa for better absorption ^[50]. In situ gelling agents are incorporated in the formulation of nanogel. These systems are appears as liquids in storage conditions but converted to gels at the site of application. This conversion is triggered by the pH, temperature, presence of any other ionic or biological component etc ^[51].

Vaginal nanogel containing antibacterial drugs have been used to prevent various vaginal infections ^[52]. They can also be used to reduce vaginal irritation, discharge and other sexual problems. Some disadvantages of vaginal nanogel are that they are contraindicated during menstruation and pregnancy. Researchers have found that certain vaginal nanogel having antiretroviral drugs may decrease the risk of HIV infection among women ^[53]. Tenofovir vaginal gel has been investigated in the prophylaxis of HIV. Gelatin nanoparticles of Tenofovir were prepared by two step desolvation method HPMC K15M was used as a bioadhesive polymer as well as a gelling agent ^[54].

11. Conclusion

Nanogels are promising, innovative and smart drug delivery system that can play a vital role by addressing the problems associated with traditional and modern therapeutics such as nonspecific effects and poor stability. Every new research entails to discovery of new polymeric systems and novel mechanistic approaches with promising role in therapies and new innovation on fabrication of nanogel design. Recent developments in nanogel and nanotechnology have provided a bright insight into the applications of nanogel in the management of ocular problems, nasal drug delivery, vaginal drug delivery etc.

References

[1]	Tiwari, S., Singh, S., Tripathi, P. and Dubey C., “A Review Nanogel Drug Delivery System,’’ Asian J Res Pharm Sci, 5 (4). 253-255. 2015.
	In article		View Article
[2]	Sultana, F., Manirujjama., Imran, U., Arafat, M. and Sharmin S., “An Overview of Nanogel Drug Delivery System,’’ Journal of Applied Pharmaceutical Science, 3 (8). S95-S105. 2013.
	In article
[3]	Patel, H. and Patel, J., “Nanogel as a Controlled Drug Delivery System,’’ International Journal of Pharmaceutical Sciences Review and Research, 4 (2). 37-41. 2010.
	In article
[4]	Dorwal, D., “Nanogels as Novel and Versatile Pharmaceuticals,” International Journal of Pharmacy and Pharmaceutical Sciences, 4 (3). 67-74. 2012.
	In article
[5]	Adhikari, B., Sowmya, C., Reddy, C., Haranath, C., Bhattal, H. and Inturi, R., “Recent Advances in Nanogels Drug Delivery System,’’ World Journal of Pharmacy and Pharmaceutical Sciences, 5 (9). 505-530. 2016.
	In article
[6]	Prasad, K., Vijay, G., Jayakumari, N., Dhananjaya, A. and Valliyil, L., “Nanogel as a Smart Vehicle for Local Drug Delivery In Dentistry,’’ Am J Pharm Health Res, 3 (1). 20-30. 2015.
	In article
[7]	Kabanov, A, and Vinogradov, S., “Nanogels as Pharmaceutical Carriers,” Finite Networks of Infinite Capability Public Access, 48 (30). 5418-5429. 2009.
	In article
[8]	Labhasetwar, V., Diandra, L. and Pelecky, L., “Biomedical Applications of Nanotechnology Nanogels,” Chemistry to Drug Delivery, 131-172. 2007.
	In article
[9]	Nair, H., Sung, B., Yadav, V., Kannappan, R., Chaturvedi, M. and Aggarwal, B., “Delivery of Anti-Inflammatory Nutraceuticals by Nanoparticles,” Forthe Prevention and Treatment of Cancer, 80 (12). 1833-1843. 2015.
	In article
[10]	Wani, T., Rashid, M., Kumar, M., Chaudhari, S., Kumar, P. and Mishra, N., “Targeting Aspects of Nanogels an Overview”, International Journal of Pharmaceutical Sciences and Nanotechnology, 7 (4). 2612-2630. 2014.
	In article
[11]	Kapadi, S., Gadhel, L., Talele, S. and Chaudhari, G., “Recent Trend in Nanopharmaceuticals: An Overview’’, World Journal of Pharmaceutical Research, 4 (3). 553-566. 2015.
	In article
[12]	Singh, N., Gill, V. and Gill, P., “Nanogel Based Artificial Chaperone Technology: An Overview”, American Journal of Advanced Drug Delivery, 1 (3). 271-276. 2013.
	In article
[13]	Rossetti, H., Albizzati, D. and Alfano, M., “Decomposition of Formic Acid in a Water Solution Employing the Photo-Fenton Reaction”, Ind Eng Chem Res, 41. 1436-44. 2002.
	In article		View Article
[14]	Akiyoshi, K., Kang, E., Kuromada, S., Sumamoto, J., Principia, T. and Winnik, F., “Controlled Association of Amphiphilic Polymers in Water: Thermosensitive Nanoparticles Formed by Self-Assembly of Hydrophobically Modified Pullulans and Poly (N-Isopropylacrylamides)’’, Macromolecules, 33. 3244-3249. 2000.
	In article		View Article
[15]	Sílvia, A., Ferreira, S., Coutinho, P., Francisco, M. and Gama, M., “Synthesis and Characterization of Self-Assembled Nanogels Made of Pullulan,” Materials, 4. 601-620. 2011.
	In article		View Article
[16]	Rekha, M. and Sharma, C., “Pullulan as a Promising Biomaterial for Biomedical Applications a Perspective Trends Biomater Artif,” Organs, 20. 116-121. 2007.
	In article
[17]	Park, S. and Kun, N., “Self-Organized Nanogels of Polysaccharide Derivatives in Anti-Cancer Drug Delivery,” Journal of Pharmaceutical Investigation, 40 (4). 201-212. 2010.
	In article		View Article
[18]	Gros, L., Ringsdorf, H. and Schupp, H., “Polymeric Antitumor Agents on a Molecular and on a Cellular Level,’’ Chem Angew, 20. 305-325. 1981.
	In article		View Article
[19]	Yong, Y., Cheng, H., Zhang, Z., Wang, C., Zhu, J. and Liang, Y., “Cellular Internalization and In Vivo Tracking of Thermosensitive Luminescent Micelles Based on Luminescent Lanthanide Chelate,’’ American Chemical Society, 1 (2). 125-33. 2008.
	In article
[20]	Li, Y., Zhang, Z., Kim, C., Cheng, H., Cheng, X. and Zhuo, X., “Thermosensitive Y Shaped Micelles of Poly (Oleic Acid Ynisopropylacrylamide) for Drug Delivery,’’ Small, 2. 917-923. 2006.
	In article		View Article  PubMed
[21]	Deepthi, V. and Kavitha, A., “Liposomal Drug Delivery System-A Review,” Rguhs J Pharm Sci, 4 (2). 47-56. 2014.
	In article		View Article
[22]	Kazakov, S. and Levon, K., “Liposome-Nanogel Structures for Future Pharmaceutical Applications,” Current Pharmaceutical Design, 12. 4713-4728. 2006.
	In article		View Article  PubMed
[23]	Maitra, J. and Shukla, V., “Cross-Linking In Hydrogels - A Review,” American Journal of Polymer Science, 4 (2). 25-31. 2014.
	In article
[24]	Alles, N., Soysa, N., Hussain, M., Tomomatsu, N., Saito, H. and Baron, R., “Polysaccharide Nanogel Delivery of a Tnf-Α and Rankl Antagonist Peptide Allows Systemic Prevention of Bone Loss,” Euro J Pharm Sci, 37. 83-88. 2009.
	In article
[25]	Lee, J., Kim, J. and Yoo, H., “DNA Nanogels Composed of Chitosan and Pluronic with Thermo-Sensitive and Photo Crosslinking Properties,’’ Int J Pharm, 373. 93-99. 2009.
	In article		View Article  PubMed
[26]	Jaiswal, M., Banerjee, R., Pradhan, P, and Bahadur, D. “Thermal Behavior of Magnetically Modalized Poly (Nisopropylacrylamide)-Chitosan Based Nanohydrogel,” Colloids Surface, 81 (1). 185-194. 2010.
	In article		View Article  PubMed
[27]	Yan, L. and Tao, W., “One Step Synthesis of Paginated Cationic Nanogel of Polly(N, N’-Dimethyl-Aminoethyl Methacrylate) in Aqueous Solution Via Self Stabilizing Micelle Using an Amphiphilic Macro Raft Agent,” Polymer, 51. 2161-2167. 2010.
	In article		View Article
[28]	Raemdonck, K., Naeye, B., Hogset, A., Demeester, J. and Smedt, S., “Prolonged Gene Silencing by Combining Sirna Nanogel and Photochemical Internalization,” J Controlled Release, 145. 281-88. 2010.
	In article		View Article  PubMed
[29]	Park, W., Park, S. and Na K. “Potential Of Self Organizing Nanogel with Acetylated Chondriotin Sulfate as an Anti-Cancer Drug Carrier,” Colloids Surface, 79. 501-518. 2010.
	In article		View Article  PubMed
[30]	Misson, M., Zhang, H. and Jin, B., “Nanobiocatalyst Advancements and Bioprocessing Applications,” J R Soc Interface, 14. 1-20. 2017.
	In article
[31]	Mailin, M., Hu, Z. and Bo, J., “Nanobiocatalyst Advancements and Bioprocessing Applications,” J R Soc Interface, 1. 48-58. 2014.
	In article
[32]	Sılvia, A., Paulo, J. and Francisco, M., “Self-Assembled Nanogel Made of Mannan: Synthesis and Characterization,” Langmuir, 26 (13). 11413-11420. 2010.
	In article		View Article  PubMed
[33]	Zhang, S., “Emerging Biological Materials Through Molecular Self-Assembly,” Biotechnology Advances, 20 (5) 321-339. 2002.
	In article		View Article
[34]	Rinaudo, M., “Non Covalent- Interactions in Polysaccharide Systems,” Macromolecular Bioscience, 6 (8). 590-610. 2006.
	In article		View Article  PubMed
[35]	Marek, S., Conn, C. and Peppas, N., “Cationic Nanogel Based on Diethylaminoethyl Methacrylate,” Polymer, 51. 1237-1243. 2010.
	In article		View Article  PubMed
[36]	Jung, K., Ray, D., Daniel, J. and Krzysztof, M., “The Development of Microgels Nanogels for Drug Delivery Applications,” Prog Polym Sci, 33. 448-477. 2008.
	In article		View Article
[37]	Oishi, M., Miyagawa, N., Sakura, T. and Nagasaki, Y., “Ph-Responsive Pegylated Nanogel Containing Platinum Nanoparticles Application to On–Off Regulation of Catalytic Activity for Reactive Oxygen Species,” Reactive and Functional Polymers, 67 (7). 662-668. 2007.
	In article		View Article
[38]	Mourey, T., Leon, J., Bennett, J., Bryan, T., Slater, L., and Balke, S., “Characterizing Property Distributions of Polymeric Nanogels by Size-Exclusion Chromatography,” Journal of Chromatography, 1146 (1) 51-60. 2007.
	In article		View Article  PubMed
[39]	Wu, W., Aiello, M., Zhou, T., Berliner A., Banerjee, P. and Zhou, S, “In-Situ Immobilization of Quantum Dots in Polysaccharide-Based Nanogels for Integration of Optical pH-Sensing, Tumor Cell Imaging and Drug Delivery,” Biomaterials, 31 (11) 3023-3031. 2010.
	In article		View Article  PubMed
[40]	Patnaik, S., Sharma, A., Garg, B., Gandhi, R, and Gupta K, “Photoregulation of Drug Release in Azo-Dextran Nanogels,” Int J Pharm, 342 184-193. 2017
	In article		View Article  PubMed
[41]	Vitalis, B., Gupta V., and Tenzin, T, “Application of Nanogels in Reduction of Drug Resistance in Cancer Chemotherapy,” Journal of Chemical and Pharmaceutical Research, 8 (2) 556-561. 2016.
	In article
[42]	Michael, L., Eric, S., Qin, A., Leah, D., Michael, K. and Joe, C., “Nanogel-Based Delivery of Mycophenolic Acid Ameliorates Systemic Lupus Erythematosus in Mice,”The Journal of Clinical Investigation, 123 (4) 1741-1749. 2013.
	In article		View Article  PubMed
[43]	Daithankar, A., and Shiradkar, M., “Thermoreversibal Anesthetic Gel for Periodontal Intra-Pocket Delivery of Mepivacaine Hydrochloride,” Der Pharmacia Lettre, 4 (3) 889-896. 2012.
	In article
[44]	Jeremy, P., Maureen, B. and Michael, K.,“Application of Nanogel Systems in the Administration of Local Anesthetics,” Local and Regional Anesthesia,3 93-100. 2010
	In article
[45]	Goel, A., Ahmad, F., Singh, R. and Singh, G., “Anti-Inflammatory Activity of Nanogel Formulation of 3-Acetyl-11-Keto-Β-Boswellic Acid,” Pharmacologyonline, 311-318. 2009.
	In article
[46]	Abd, E., Swilem, A., Klingner A., Hegazy E. and Hamed A. “Developing the Potential Ophthalmic Applications of Pilocarpine Entrapped into Polyvinylpyrrolidone-Poly (Acrylic Acid) Nano Gel Dispersions Prepared By γ Radiation,” Biomacromolecules, 14 (3) 688-98. 2013.
	In article		View Article  PubMed
[47]	Zhongming, W., Xinge, Z., Honglei, G., Chaoxing, L., and Demin, Y., “An Injectable and Glucose-Sensitive Nanogel for Controlled Insulin Release,” J Mater Chem, 22. 22788-22796. 2012.
	In article		View Article
[48]	Vinogradov, S., Batrakova, E. And Kabanov, A., “Nanogels for Oligonucleotide Delivery to the Brain,” Bioconjug Chem, 15 (1) 50-60. 2004.
	In article		View Article  PubMed
[49]	Mcdonough, J. and Persynnino, J., “Microcapsule-Gel Formulation of Promethazine Hcl for Controlled Nasal Delivery,” A Motion Sickness Medication. J Microencapsul, 24. 109-116. 2007.
	In article		View Article  PubMed
[50]	Kumar, A., Pandey, A. and Jain, S., “Nasal-Nanotechnology,” Revolution for Efficient Therapeutics Deliver, 23 (3). 671-683. 2016.
	In article
[51]	Zheng, C., Xiangrong, S., Feng, S., Zhaoxiang, Y., Shixiang, H. and Zhongqiu, L., “Formulation and Evaluation of in Situ Gelling Systems for Intranasal Administration of Gastrodin,” AAPS Pharm Sci Tech. 12 (4) 1102-1109. 2011
	In article		View Article  PubMed
[52]	Sahoo, C., Nayak, P., Sarangi, D. and Sahoo, T., “Intra Vaginal Drug Delivery System: An Overview,” American Journal of Advanced Drug Delivery, 1 (1). 43-55. 2013.
	In article
[53]	Khan, A. and Saha, C., “A Review on Vaginal Drug Delivery System,” Rguhs J Pharm Sci, 4 (4). 142-147. 2014.
	In article		View Article
[54]	Sreejan, M., Uppadi, S., Manasa, R., Pratyusha, S., Lakshmi, K. and Kumar, S., “Bioadhesive HPMC Gel Containing Gelatin Nanoparticles for Intravaginal Delivery of Tenofovir,” Journal of Applied Pharmaceutical Science, 6 (8). 22-29. 2016.
	In article