recent advances in nanogels drug delivery systems

www.wjpps.com Vol 5, Issue 9, 2016.

505

Adhikari et al. World Journal of Pharmacy and Pharmaceutical Sciences

RECENT ADVANCES IN NANOGELS DRUG DELIVERY SYSTEMS

Bishnu Adhikari*1, Cherukuri Sowmya

1, Chappidi Suryaprakash Reddy

1,

Chinthaginjala Haranath1, Hari Prasad Bhatta

1, Raghavendra Naidu Inturi

1

Department of pharmaceutics, Centre for Pharmaceutical Research (CPR), Raghavendra

Institute of Pharmaceutical Education & Research (RIPER), Anantapur, Andhra Pradesh,

India – 515721.

ABSTRACT

Nanogel drug delivery has remained as one of the most challenging

task for pharmaceutical scientists at this 21st century. From the last 3

decades ocular drug delivery research accelerated advanced towards

developing a novel, safe, patient compliant formulation and drug

delivery devices/ techniques which may suppress these barriers and

maintain drug level in tissues. Controlled and sustained delivery of

ophthalmic drugs have a major focus area in the field of

pharmaceutical drug delivery with emergence of new, more potent

drugs and biological response modifiers that may also have very short

biological half-life. The major objective of controlled and sustained

delivery is to provide and maintain adequate concentration of drugs at

the site of action. Anterior segment drug delivery advances are

treatment by the conventional topical solutions with permeation and

viscosity enhancers. On the other hand, for the posterior ocular drug

delivery, research has been immensely focused towards development of drug releasing

devices & treatment for chronic vitreo-retinal diseases. Polymers with nanogel proposed are

reported to be devoid of any irritant effect on cornea, iris, conjunctiva and thus appear to be a

suitable inert carrier for ophthalmic drug delivery. Nanogels based materials have high drug

loading capacity, biocompatibility and biodegradability which are the key points to design &

drug delivery system effectively. Recently different types of nanogel along with the synthetic

procedure & mechanism of drug release from nanogel carrier are mainly focused. An

intensive study of clinical trial in future will confirm nanogel as a suitable carrier for drug.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.041

Volume 5, Issue 9, 505-530 Review Article ISSN 2278 – 4357

*Corresponding Author

Bishnu Adhikari

Department of

pharmaceutics, Centre for

Pharmaceutical Research

(CPR), Raghavendra

Institute of

Pharmaceutical Education

& Research (RIPER),

Anantapur, Andhra

Pradesh, India – 515721.

Article Received on

21 June 2016,

Revised on 12 July 2016,

Accepted on 03 Aug 2016,

DOI: 10.20959/wjpps20169-7539


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KEYWORDS: Nanogel, polymers, controlled and sustained release, bioavailability, novel

drug delivery systems.

INTRODUCTION

A nanoparticle which is composed of a hydrogel with a cross linked hydrophilic polymer

network is known as “Nanogel”. Nanogel which is physically or chemically cross linked and

most often composed of synthetic polymers or biopolymers. Nanogels are swollen in nano-

sized networks composed of hydrophilic or amphiphilic polymer chains, which can be ionic

or non-ionic. Nanogels are developed as a carrier for drug which can design to spontaneously

absorb biologically active molecules through formation of salt bonds, hydrogen bonds or

hydrophobic interactions.[1-2]

The pores in nanogels can be filled with small molecules or macromolecules and usually the

size of nanogels in the one to hundreds nanometers in diameter. The nanogel contains the

some properties like as swelling, degradation and chemical functionality can be controlled.[3-

4]

Fig.1: Schematic drug release model from nanogel

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.[5-8]

The

major significance of nanogels has been arisen due to specific delivery system expectation,

wide variety of polymer systems and the ease of change of the physical-chemical properties.

Current studies at the clinical level shown promising value of nanogel.[9-10]


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Nanogels are used in the field of gene therapy, since delivery of gene now become possible

within cellular organelles for gene silencing the system.[3]

In nanogel, by using varying

solvent quality & branching the volume fraction can be altered variability to maintain a three

dimensional structure.[11]

ADVANTAGES OF NANOGELS.[12]

The advantages of nanogels are as follows:

a) It can be applied to both hydrophilic & hydrophobic drugs and charged solutes.

b) Good for specific target and transport characteristics.

c) Permeation capabilities are good due to extremely small size.

d) It is biodegradable and highly biocompatible.

e) It has non immunological responses and invasion by reticuloendothelial system is

prevented.

f) Reticuloendothelials are invasion in nature which can be prevented by nanogel.

g) Target or site specific delivery to be achieved.

h) Helps in enhancing oral and brain bioavailability of low molecular weight drugs and

biomacromolecules.

DISADVANTAGES OF NANOGELS[12-14]

a) Solvent and surfactant is not easily removed at the end of preparation, so it may be some

more expensive.

b) Traces amount of surfactant or monomer; there are chances to increase toxicity.

CLASSIFICATION OF NANOGELS

Basically, nanogels are classified into three types.

A) Based upon the polymers.

B) Based on their responsive behavior.

C) Based on their linkages present in the network chains of gel structure.

A. Based upon the polymers

Chitosan- based nanogel

Chitosan, α (1-4)-2 amino-2-deoxy β-D-glucan, is a polysaccharide which is a deacetylated

form of chitin and present in crustacean shells. Chitosan is found in 19th

century, but it has

been used as a polymers from last two decades and used as material for biomedical and drug


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delivery application.[15]

The physicochemical and biological properties of chitosan impart the

drug delivery and specifically the carrier for macromolecules.[16]

The polymer chitosan having the positive charge and easily hydro-soluble in nature of these

properties permit to interact with negatively charged polymers and have contact with

polyanions in aqueous environment. The force present between these types of ions is known

as interactive forces and resulting in sol-gel transitions stages.[17]

Chitosan has the property of

adhering to the mucosal surface within the body. It has a capacity to open tight junctions

between epithelial cell, by this the biocompatibility is increasing and toxicity is decreased.

Poly (vinyl alcohol) – based nanogel

PVA plays vital role for nanogel studies. It has the crosslinking characteristics which have

been carried out using physical and chemical Methods. Physical methods such as eg:

(freezing/ thawing) methods and chemical methods such as eg: crosslinking agents, electron

beam, γ- irradiation). Eventhough crosslinking method is difficult but it is useful for various

applications in medical and pharmaceuticals fields.[18]

Unlike structured composites involving PVA has been interested in the field of nanogel.

Biodegradable polymers having short polylactone chains grafted to PVA or change

sulfobutyl- PVA were prepared and used as a novel class of water soluble comb- like

polymers. These types of polymers directly undergoes and assembling to produce the nanogel

a stable complexes with a number of protein such as human serum albumin, tetanus toxoid

and cytochrom c.[19]

Alginate – based nanogel

A new drug carrier made up of sodium alginate is proposed by Rajaonarivony et al in the year

of 1993 (20)

. These prepared alginate nanoparticles with a wide range of particle sizes (250 –

850 nm), by using the sodium alginate and calcium chloride and followed by poly – lysine. In

this study the concentration of both polymer and opposite ion solutions were less than those

regularly used for gel formation. Now a day the numbers of studies involving alginate- based

nanoparticles are increasing, using the therapeutic agents such as insulin, antitubercular and

antifungal drugs, and prominent increases in the field of gene delivery. The antitubercular

chemotherapy is increases the bioavailability by using the alginate nanoparticles and of all

drug encapsulated in alginate nanoparticles were significantly higher than those with free

drugs.[21]


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Poly (vinyl pyrrolidone) – based nanogel

Polyvinyl based hydrogel nanoparticle with final diameter is less than 100 nm, using the

aqueous core was reverse micellar described by Baharali et al.[22]

These reverse micellar are

highly monodispersed, the droplet sizes can be well- controlled and size can be modulated by

controlling the size of the reverse micellar droplets.[23]

Poly – N – Isopropylacrylamide – based nanogel:

Dextran containing hydrogel have been developed by G.Huang et al.[24]

In this study,

covalently crosslinking are formed by the PNIPAM – co – allylamine nanoparticles network.

These are the more stable and stated that the more bioavailability. Thermoresponsive core –

shell PNIPAM nanoparticles via seeding and feeding precipitation polymerization is

described by Gan & Lyon[25]

They describe the kinetic and thermodynamic behavior between

the core and shell of polymers.

B) Based On Their Responsive Behaviour[26]

a) Stimuli – responsive

In this type of nanogel, it may be swell or deswell. It depends upon exposure to

environmental changes such as temperatures, PH, magnetic field and ionic strength. The

nanogels which have the multi – responsive character it have more than one environmental

stimulus.

b) Non – responsive

These have a characteristic like absorbing of water and swelling.

C) Based on their linkages in the network chains

Based on their linkage it have a capacity like to form a gel structure, polymeric gels

(including nanogel) and these divided as follows:

Physical Cross-linked Gels

These types of gels are also known as pseudo gels. They are formed by weaker linkages

through vander waals forces, hydrogen bonding, hydrophobic or electron static interactions. It

is very sensitive gels and depends on polymer composition, temperatrure, ionic strength or

the medium, concentration of polymer and the cross – linking agent. A nanogel can easily

formed by the combination of amphiphilic block copolymers and complexation of oppositely

charged polymeric chains.


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Chemically Cross-linked Gels

These types of gels are permanently linkages through the covalent bonds. It have the

properties like crosslinked gel system and depend on the functional group present in the gel

networks. Different types of chemical linking have the properties of synthesized different

types of nanogels. By the polymerization of vinyl monomers in the presence of

multifunctional cross-linkers the hydrophilic polymers and hydrophilic – hydrophobic

copolymers are obtained. These types of crosslinking points allow altering the total

physicochemical properties of the gel system. The crosslinking agent is explained by the

(Labhasetwar et al., 2007) 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.” (Aliyer et al., 2005).

Liposome Modified Nanogels

When liposomes are mixed with the succinylated poly (glycidol)s; these liposomes can be

efficiently deliver calcein to the cytoplasm by fusion the chain below ph 5.5 .(kono et al;,)

Liposomes which are the thermo and PH responsive nanogel like as poly (N

isopropylacrylamide) are being investigated for transdermal drug delivery. (Labhasetwar et

al,.).[27]

Hybrid Nanogels

When the nanogel particles dispersed in organic and inorganic matrices is known as hybrid

nanogels. These types nanogel formation takes place in an aqueous medium by self assembly

or aggregation of polymer amphiphiles, such as pullullan – PNIPAM, hydrophobized

polysaccharides, and hydrophobized pullan.[28-29]

These types of nanogel have the ability to form complexes with various proteins, drugs and

DNA; and it is even possible to coat surface of liposomes and solid surface including cells.

These types of hybrid nanogel are formed physical cross linkings and capable to deliver the

insulin and anti-cancer drugs more effectively.[30-31]

SYNTHESIS OF NANOGELS

Synthesis of Nanogels by Free Radical Polymerization (FRP)

The monomers present in the compound play a vital role, which may be hydrophilic or water

soluble monomers either difunctional or multifunctional crosslinkers have been mostly used.

Different methods by this free radical polymerization (FRP) are as follows;


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Dispersion Polymerization

In this method an organic solvent act as continuous phase and capable to soluble the

monomers, polymeric stabilizers and initiators. Initially, the polymerization reaction takes

place in a homogenous reaction mixtures but the formed polymers is insoluble in continuous

medium, and finally the formation of stable dispersion by the aid of colloid stabilizers

hydrophilic monodisperse micro-sized particles of PHEMA were also prepared by dispersion

polymerization in the presence of PEO – b – poly (1,1,2,2 – tetrahydroperfluorodecyl

acrylate) diblock copolymer as a stabilizer in super critical carbon dioxide and methacryloyl

– terminated PMMA in a 55/45 (wt/wt) mixture of 2 – butanol / tolune. Another method also

the dispersion of drugs and magnetic nanoparticles were physically in corporate or

chemically attached to microgels. These types of forming gels are more effective a drug

delivery carriers & for DNA application.[32]

Inverse (mini) Emulsion Polymerization

This type of polymerization is also known as w/o polymerization in which aqueous droplets

(including water – soluble monomers) stably dispersed in a oil soluble surfactant in a

continuous organic medium. By the help of mechanical stirring for inverse emulsion and by

sonification the stable dispersion of polymerization is formed. By addition of radical

initiators, polymerization occurs within the aqueous droplets producing colloidal particles.

Inverse Micro emulsion Polymerization

If the inverse (mini) emulsion polymerization is formed the stable macroemulsion, at below

the critical micellar concentration (CMC), then inverse micro emulsion also can produce by

addition of emulsifier above the critical threshold and thermodynamically stable. This process

also has same disperse and continuous phase like as inverse miniemulsion but producing

stable hydrophilic and water soluble colloidal nanoparticles having a diameter of less than 50

– 100nm. Inverse microemulsion polymerization was invented for the synthesis of stable

nanogels. By using dextran as a water soluble macromolecular carbohydrate drug with poly

(vinyl pyrrolidone) was prepared by (Gaur et al., 2000; Bharali et al., 2003).[23,33]

Precipitation Polymerization

Initially, this type of polymerization takes place in the homogenous mixture. If the polymers

are not swellable in the medium then the use of crosslinker is necessary to crosslink the

polymer chains for separation of particles. The present crosslinked often has an irregular

shape with a high polydispersity. By using the precipitation polymerization (Peppas et al.,)


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synthesize nanospheres by using poly (methacrylic acid – g – ethylene glycol) (P (MAA – g –

EG)), delivery of proteins. They also disclosed that the increasing the cross – linker

concentration during polymerization decreased the equilibrium swelling of the nanospheres.

(Robinson and Peppas, et al., 2002).

Heterogenous Controlled / Living Radical Polymerization

Now a day, the controlled radical polymerization method has been preparation of well

controlled polymer – protein/Peptide bioconjugates. There are many methods of CRP but the

atom transfer radical polymerization (SFRP), and reversible addition fragmentation chain

transfer (RAFT) polymerization.[34]

Photolithographic techniques

This method reveals the 3D hydrogel particles and nanogel or microgel rings for drug

delivery. This method requires the stamps or replica mold for the release of gels.[32]

Fig.2 : Representation diagram of five steps involved in photolithography.

This method consists of the 5 steps. The first step is the UV crosslink able polymer is used,

which possess low surface energy, as a substrate is released on the pre – backed photo resist

coated water. In the second step the silicon water is molded by the polymer and exposed it to

the intense UV light. In the third step, the thin interconnecting film layers are uncovered by


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removing the quartz template. In the fourth step, the remaining thin layer is removed by a

plasma containing oxygen that oxidizes it. In last step the buffer solution of the dissolution

the fabricated particles are directly collected (sasaki & Akiyoshi., 2010).

Micromolding Method

In this method, the cells were suspended in a hydrogel precursor solution consisting of either

methacrylated hyaluronic acid (MeHA) or photoinitiator in water. This method also similar to

photolithographic but it can minimize cost. These are photocrosslinked and mixture was

deposited on to plasma – cleaned hydrophilic PDMs patterns & exposure to UV – light. After

it the cell – laden microgels were removed, hydrated and then harvested. It can also mold in

different shapes like as square prisms, disks, and strings.

Fabrication of Bipolymers

Naturally occurring polymers such as chitosan, hyaluronan and dextran are based on

biopolymers. By using this polymer various preparation methods are developed. Such

as:Water – in – oil heterogenous emulsion, aqueous homogenous gelation, spray drying

method and chemical cross linking of dextran. (jung et al., 2008).

Reverse Micellar Method

In this method involve a w/o dispersion, however a relatively large amount of oil – soluble

surfactant is used to form thermodynamically stable micellar solution. The final size of the

resultant micellar droplets ranges from 10 – 100 nm.

Fig.3: Diagram of the reverse micellar method for the nanogel preparation

Membrane Emulsification

In these method, the dispersed phase which is passed through the membrane i.e. glass or

ceramic. In which the membrane contains uniform pore size. On the surface of membrane the


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emulsion droplets are formed under the specific condition and afterwards the continuous

phase which is flowing across the membrane, these formed emulsion droplets or microgels

are recovered (Nakashima et al., 2000). The formation microgel emulsion takes place in the

different form like as, water – in – oil (w/o), oil – in – water (o/w), oil – in – water – in – oil

(o/w/o) and water – in – oil – in – water (w/o/w). (oh et al., 2008 b). The size of the droplets

is sepends upon the pore present in membrane, velocity of continuous phase and pressure of

transmembrane.

Fig.4: Schematic figure of the membrane emulsification technique. Fig from (Miyazaki

prefectural industrial technology center)

HOLOCENE METHODOLOGIES FOR NANOGEL SYNTHESIS

Novel Photochemical Approach

This technology has the advantage to gene delivery. By this technique we produce the ferric

oxide nanoparticles nanogel for MRI application by coating oxide with N – (2 – aminoethyl)

methylacrylamide and N,N – methylene bis acrylamide treated with UV radiation at 388 nm

for 10 minutes and recovering the product after washing with water.[7]

Like this way

diacrylated pluronic and glycidyl methylacrylated chitooligosaccharide were loaded with

plasmid DNA at different ratio’s and were photo irradiated with long wave length UV light at

365 nm, the photo initiator was igracure added to the mixture for cross linking.[35]

Novel Pullulan Chemistry Modification

When mixture of cholesterol isocynate in dimethyl sulfoxide & pyridine then synthesis of

cholesterol based pullulan nanogel takes place. This preparation was freeze dried and in


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aqueous form it form a nanogel which was complexed with w – 9 peptide for drugs delivery

for the osteological disorders, here pullulan was substituted with 1.4 cholesterol moieties per

100 anhydrous glucoside units. Pullulan is known as good protein carrier so, that it is used in

the nanogel drug delivery.[36]

Fig.5: Diagram of pullulan glucose unit modification

Cis – trans isomerization of azobenzene by photoregulation in azo – dextran nanogel loaded

with aspirin as model drug shows that E – configuration of azo – group lead to better release

profile of drug than Z – configuration at 365 nm radiation.[37]

Reversible Addition Fragmentation Transfer (RAFT) Process

This method is taken for the single step of synthesis for PEGlyated. Poly (N,N –

dimethylamino methyl methacrylate) nanogel by using amphiphilic macroRaft agent

trithiocarbonate with hydrophobic dodecyl chain i.e. (500 – 800 nm) size by supporting the

polymerization. By this method only in one step reduced the radii of nanogel i.e. 10 nm.[38–39]

Procedure to obtain nanogel is as follows

Dodecanethanoil and tetrabutyal ammonium bromide mixed and N2 passed at 10 0c

temperature.

Then carbon di – sulfide and acetone added drop wise.

After then, chloroform and sodium hydroxide added

30 minutes later yellow ppt. obtained

Ppt. dissolves in isopropanol and crystallized in hexane, Raft agent obtained.

PEG reacted with RAFT in dichloroethane

Polymerization in polymer with aqueous dispersion with RAFT agent to obtain nanogel.


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Chemical Modification

Acetylation of chondriotin sulfate can easily release doxorubicin in HeLa cells over a three

week period for the anticancer purposes. From this we can understood chemical modification

of polymers controlled the release of drugs from the nanogels.[40]

By using quaternary group

to form the nanogel complexes by consisting of poly 2 – (N,N – diethylaminoethyl)

methacrylate increases SiRna binding capacity which provides the treatment of cancer &

gene delivery.[41]

The drug methotrexate also can be controlled release by using the polymer N –

isopropylacrylamide and butyl acrylate saturated with sodium carbonate and it leads the

delayed of absorption.[42]

By using of heparin in pluronic nanogels containing RNase it

showed better heparin RNase conjugation and hence the enzyme was internalized with

ease.[43]

Grafting of 3 – diethylaminopropyl to glycol – chitosan nanogel leads to

deaggregation of product at lower PH, doxorubicin release pattern has been investigated.[44]

DRUG LOADING TECHNIQUE IN NANOGELS

Nanogel drugs delivery systems can be successful technique by a high drug loading capacity

and by reducing the amount of carriers. Various methods are as follows:

Covalent Conjugation

In the biological agents by using covalent conjugation can achieved nanogels. For eg. Acrylic

groups are modified with enzymes and copolymerized with acrylamide either in inverse

microemulsion or dilute aqueous solution to obtain nanosized hydrogel. (yan et al, 2006,

2007).

Physical Entrapment

In cholesterol – modified pullulan nanogels proteins was incorporated by physical entrapment

(28) and SiRNA in HA nanogels.[11]

In nonpolar domains by addition of hydrophobic

molecules formed a hydrophobic chain which is present in selected nanogels. Eg; in the

cholesterol – modified pullulan the prostaglandin E2 is easily solubilized. (Kato et al., 2007)

Another eg ; N – hexyl carbamoyl – 5 – fluorocil (HCFU) was noncovalently incorporated in

cross – linked nanogels of N – isopropylacrylamide (NIPAAM) & N – vinylpyrrolidone (VP)

copolymers. (soni et al., 2006) Doxorubicin was also loaded in amphiphilic cross – linked

nanogels based on pluronic F127 (Missirlis et al., 2003) Due to the hydrophobic interaction in


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the most of the cases the loading of drug molecules with the nanogel result in relatively low

degrees (not more than 10%).

Self Assembly

When the autonomous organization of components are aggregates in to structurally well –

defined then it is known as self assembly (Goncalves et al., 2010).

It has advantage such as,

Minima thermodynamics in which resulting in stable & robust structures.

Versatile & facile,

It is cost – effective.

Many molecules are self – assembly is characterized by diffusion followed by specific

association of molecules through non – covalent interaction, hydrophobic associations or

including electrostatics.

Fig.6: Diagram of intermolecular interactions driving self – assembly processes that

includes (a) electrostatic interactions (b) hydrophobic association. (F. sultana et al.,

2013).

Due to large number of interaction involved it has weak and dominates the structural and

conformational behavior of the assembly. (Zhang, 2002).[44]

While oppositely charged polysaccharides associates readily as a result of electrostatic

attaractions (Rinaudo, 2006).[45]

Interactions with neutral polysachharides lead to be weaker


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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).

Amphiphilic polymers when contact with aqueous environment then spontaneously form self

– aggregated nanoparticle via intra or intermolecular association between the hydrophobic

moieties, primarily to minimize the interfacial free energy. The important feature, from the

physicochemical point of view is that the hydrophobic portion aggregates in the internal core

and the hydrophilic region to the polar or aqueous medium. The concentration above which

the polymeric chains are aggregates is known as critical micelle concentration or critical

aggregates concentration.

MECHANISM OF DRUG RELEASE FROM NANOGELS

1) Thermosensitive & Volume Transition Mechanism

The polymer which has thermosensitive characteristics like as poly (N –

isopropylacrylamide) leads to initially shrinkages in gel volume and efflux of indomethacin

drug due to maintenance of temperature above lower critical solution temperature (LST).[46]

In the rats the polymer (N – isopropylacrylamide – co – acrylamide) with 5 – fluorouracil is

advantageous due to low temperature & release at body temp.[47]

The superficial modification

of polyethyleneimine nanogels by pluronic, it has the thermoresponsive characteristics with

regard to size and successfully used a gene delivery systems[48]

By the physical destruction of

cellular network, it is expand up to 1 µm in nanogel size by thermally trigerred volume of

nanogels of poly alkylene oxides.[49]

By the modification of temperature of nanogels like as poly (N – isopropylacrylamide) and

chitosan in which the lower critical solution temperature could be modified by changing ratio

of polymers and used in the hyperthermic cancer treatments.[50]


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Fig.7: Schematic drug release due to thermo – volume transition of nanogels

2) Photochemical Internalization & photoisomerization

Singlet oxygen & reactive oxygen is produced by the excitation of photosensitizers loaded

nanogels & cause oxidation of cellular compartment walls such as endosomal barrier walls

which effects release of therapeutics in to cytoplasm easily, otherwise hindered by

intracellular compartment.[51]

Fig.8: Illustrative of drug release due to endosomal rupture caused by photo sensitizers

loaded


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By using photoregulation in the azobenzene the Cis – trans isomerization can seen in which

azo dextran loaded nanogel 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.[34]

3) Diffusion Mechanism

Doxorubicin follows the diffusional release and which is stable hydrogel nanoparticles based

on puronic block copolymer. (Missirlis et al., 2006) Various nanomedicine are follows this

mechanism & simple procedure, such as polymeric micelles that have already reached a

clinical stage (Kabanov & Alakhor, 2002).

4) PH responsive Mechanism

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.[9]

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.[11]

Fig.9: schematic drug release from nanogel due to PH responsive polymer chain

repulsion.


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The control the release kinetics mechanism shown by the drug temozolidine due to swelling

action of PH sensitive polyacryrlic acid chains.[6]

But the release of doxorubicin was

significantly increase due to PH sensitive of glycol chitosan nanoparticles, & to grafting of

diethylaminopropyl groups.[43]

Fig.10: schematic drug release due to protonation of amine shell and destabilization of

nanogel due to PH changes.

5) Displacement by Ions present in the Environment

Maximum research work is developing nanogel that can release biological agents in response

to environmental cues at the specific site of action. Eg Water soluble polymers like as

POEOMA nanogels are biodegraded in aqueous in the presence of glutathione tripeptide,

which is commonly found in cells (oh et al., 2007).

Cationic nanogels when triggered with negatively charged drug in cell – membrane from

complelexes and explain cellular accumulation of drug delivered with nanogel. (Vinogradov.,

2006).[52]

APPLICATION OF NANOGELS

Nanogel in Opthalmic

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


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maintain an adequate concentration of the pilocarpine at the site of action for prolonged of

time.[53]

Nanogel in Stopping Bleeding

A protein molecules which is in solutuion & 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.[54]

Nanogel as NSAIDS

Carbopol and Hydroxypropylmethyl cellulose (HPMC) with the desired viscosity used to

prepare the nanogels. Same like another polymer chitosan & poly –(Lactide – co – glycolic

acid) used to prepare bilayered nanoparticles and surface was modified with oleic acid.

For eg Two anti – inflammatory drugs spantide II & ketoprofen drugs are effective against

allergic contact dermatitis and psoriatic plaque were prepared in nanogel and applied

topically. The results shows that nanogel increases the absorption through percutaneous of

these two drugs deeper skin layers for the treatment of various skin inflammatory

disorders.[55]

Nanogel In Autoimmune Diseases

Cyclodextrin easily solubilized the loading liposomes with mycophenolic acid, oligomers of

lactic acid – poly (ethylene glycol) that were terminated with an acrylate end group and

Irgacure 2959 photoinitiator. After it is exposed to ultraviolet light to produce

photopolymerization of the PEG oligomers. Nanogel is having greater systemic accumulation

due to their intrinsic abilities and bind to immune cells in vivo than free fluorescent tracer and

permit high localized concentration of mycophenolic acid. By this types of drug delivery

system there will increase patient compliance & delays the onset of kidney damage and

common complication of lupus.[56]

Nanogel in Cancer

Nanogel in cancer is used for the specific targeted drug delivery with low toxicities with high

therapeutic efficacy.


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Based on the Mechanism of Action

1) PH responsive mechanism

Glycol chitosan grafted with 3 – diethyl aminopropyl group & used Doxorubicin uptake

accelerated.[43]

2) Thermosensitive & Volume Transition Mechanism

Pluronic polyethyleneimine / DNA complex which is used in thermoresponsive endosomal

rupture by nanogel and drug release.(50) Crosslinking of oligo (L –lactic acid) – poly

(ethylene oxide) – poly (propylene oxide) – poly (ethylene oxide) – poly (lactic acid) grxafted

poly (l – lysine) these all are used in the traumatic cell death due to physical stress and good

source for loading anticancer drugs.[49]

Poly (N – isopropylacrylamide – co – acrylamide) is a insitu gelatinized thermosensitive

nanogel used for drug loading capacity of low molecular weight of 5 – Flourouracil was

higher than that of bimacromolecules, bovine serum albumin.[47]

Poly (N –

isopropylacrylamide) and chitosan is a thermosensitive magnetically modalized nanogel &

used in hyperthermia cancer treatment and targeted drug deliverey.[50]

Hydroxypropyl cellulose – poly (acrylic acid) and cholesterol bearing pullulan modified with

amino group is a nanogel quantum dot hybrid PH and temperature responsive cadmium II

ions quantum dots which is used for probe for imaging[5]

, optical PH sensing, cell imaging

and drug loading of temozolomide.[6]

3) Based on Sustained Release

Cholesterol bearing pullulan nanogels is controlled by sustained release nanogel and used for

recombinant murine interleukine – 12 sustained tumour immunotherapy.[60]

Reducible

heparin with disulfide linkages nanogel is used for internalization of heparin for apoptoric

death of melanoma cells.[58]

4) Based Upon the Self Assembly

Heparin pluronic which is a self assembling nanogel and used in RNase A enzyme delivery

internalized in cells.[42]

Polymer with cross linked poly (2 – (N,N – diethylamino)

methacrylate) core & PEG is a quarternized, amine and size dependent nanogel which is used

for efficient SiRNA delivery.[40]


524


Acetylated chondroitin sulfate is self organizing nanogel and used for Doxorubicin loaded.[39]

Acrylate group modified cholesterol bearing pullulan is nanosized cationic hydrogel which is

used enhancing oral and brain Bioavailability of oligo nucleotides.[59]

Based on Gene Delivery

Controlled delivery of plasmid DNA by using the polymer Di – acrylated pluronic 127 and

glycidyl methacrylated chitoolgosaccharides and making Photocrosslinking nanogel.[36]

Potential in gene therapy by using the polymer poly (2 – (N,N – diethylaminoethyl)

methacrylate) PEGlyted macroRAFT agent for making one step PEGlylated cationic

nanogel.[38]

Used in Endosomal escape of SiRNA by using the polymer Dextran hydroxyl ethyl

methacrylate – co – (2 – methacryloyloxy) – ethyl) trimethyl ammonium chloride for making

nanogels with photochemical internalization.[53]

SiRNA delivery to HCT – 116 cells by using

the polymer thiol functionalized hyaluronic acid for making specific target and degradable

nanogel.

Based on Protein

Treatment of alzehimer’s disease by inhibiting aggregation of amyloid β – protein by using

cholesterol bearing amino group modified for making artificial chaperone nanogel.[60]

Based on the Enzymes

α – chymotrypsin immobilized on aminated nanogel by using methylacrylic acid and N,N –

methylene – bis – (acrylamide) for making supermagnetic nanogel functionalized with

carboxyl group.[61]

Assisted protein refolding of carbonic anhydrase and citrate synthase during GdmCL

denaturation by using cholesterol bearing pullan for making self assembled artificial

molecular chaperone.[62]

CURRENT STATUS AND FUTURE PERSPECTIVE OF NANOGELS

The recombinant murine interleukin – 12 (IL – 12) encapsulated in CHP nanogels, via

incubation at room temperature and injected in mice with subcutaneous fibrosarcoma leads

delayed release & retardation the growth of tumor.[63]


525


Nanogels have been primarily used for cancer therapy. Cholesteryl pullulan nanogel has

shown in clinical trials for delivery of peptidase. The cholesteryl – HER – 2 vaccine was

administered to nine patients with 300 µg with booster doses twice a week. From this shown

that skin sensitivity at the site of S.C injection & CD4+ & CD8

+ T- cell shows the better

therapeutic efficacy.[39]

cholesterol pullulan nanogels show the reduce the cytoxicity to the

nervous system cells and increase the binding capacity to AB oligomer in treating

Alzheimer’s disease.[62–64]

Recently the new development of controlled diabetes by optical sensitive insulin loaded silver

nanoparticle nanogel of poly ( 4 – vinyl phenyl boronic acid – co – 2 – (dimethylamino) ethyl

acrylate) have been designed.[64]

Now a days nanogel is conjugated with antibiotics for the specific drug delivery and

conducted at the single cell level.[53]

In future the mechanism of blood brain barrier and cytosolic destination over and endosomal

or nuclear are necessary to study for the specific and targeting drug delivery.

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recent advances in nanogels drug delivery systems

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