Document Type : Review Paper
1 Department of Physics, University of Zabol, Zabol, Iran
2 Young Researchers Society, Shahid Bahonar University of Kerman, Department of Chemistry, Kerman, Iran
3 Young Researchers Society, Zabol university of medical sciences, Zabol, Iran
4 Department of Chemistry, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
Nanotechnology is nowadays currently applied in various research tendencies as drug nanocarrier systems (DNS) , medical imaging , cancer therapy , diagnostic tests  and so on for the remedy of diversity cancers to improve medical diagnosis methods. Nanocarriers can control the drug release into the cell compared with the bulk drug delivery systems . In addition, they can circulate within the blood circulation system after the injection as well as the ability to deliver the drug to target . This aspect of nanomaterials is particularly useful in the cancertherapy so that accurate design of nanocarrier systems is a special factor in the targeted treatment of this disease according to the increased permeability and inhibition [7-8]. In the drug delivery systems (DDS), the patient’s cells are attacked by the attachment of ligands or antibodies . With this in mind, nano-gel particles which are polymer-based material with adjusting properties are applied for various applications in the drug delivery . Nanogels are the networked polymeric particles with a dimension less than 100 nm which they create the hydrophilic polymer similar to hydrogels . The nanogels have been introduced as biocompatible nanocarriers in the biomedicine and biotechnology sciences to date . On the other hand, nano-gels are used in the various fields such as sensors , biomedicine , in vivo imaging detectors , water purification , catalyst , and bioactive scaffolds production , but they have the most effect on DNS because of their capability to carry drug and significant sustainability . In the nanogels, the bioactive molecules can absorb a lot of water based on properties of their fluid transfer which nanogel size is significantly less than the pore size of the bioactive molecules [20-22]. The hydrogel nanoparticles are chemically (covalently bonded) or physically bonded together  (without covalent bonding) and also they have a high capability to convert to the initial structure through the hydrogen, electrostatic, and hydrophobic interactions . Chaco et.al synthesized the nano-gels from the chemical network of polyethylene glycol (PEG) so that they applied the polyethylene imine (PEI) ligand to release the oligo-nucleotide anesthetic drug . In a conducted study by Akiyoshi et al  focus on the self- organized amphiphilic polymers, the physical networked nanogels were prepared by using polysaccharides containing the cholesterol in water as a nanocarrier for the DDS . Undoubtedly, cancer is one of the challenging issues to study of nanogels. Although for a long time, these systems have been used to synthesis methods not only for DDS, but also for other systems such as quantum dots , MRI (Magnetic Resonance Imaging) contrast agents , and other diagnostic cases. The designing the different polymeric systems has been led to formulate nano-gels with unique physical and chemical characteristics (Fig. 1) . Also in the Table 1, kinds of nanogels, properties and their applications are presented . As a result, nowadays the researchers have focused on the design the nanogels as the effective nanoplatforms to encapsulate the bioactive substances with specific chemical properties such as cytokines , nucleic acids  and so on for cancer treatments and autoimmune diseases .
SYNTHESIS METHODS OF NANO-GELS
In this section, preparation methods of nano-gels are divided into three procedures: 1) self-assembly of active amphiphilic polymers;  2) emulsion;  and 3) Nano-template .
Self-assembly of active amphiphilic polymers
In this method, amphiphilic polymers are made so that the recognized active groups located on the base polymer structure. These polymers have the potency to surfactant self-assembly (micelle) in an aqueous medium so that the nanogels will be prepared after the process of networking as well as fixing of micelles. Generally, networking of micelles is done based on the chemical mechanism, which is related to the synthetic copolymer structure completely [36-38]. The construction of nano-gels in this pathway and also some examples related to the synthesis of nanogels according to the chemical method are presented following. For instance, in the polymerization process by adding a primer, the gelation process can be done with disulfide (S-S) bonds . The synthesis of nanogels based on the replacement of the thiol with the lipoic acid-dextran structure is an example related to the mentioned method (Fig. 2) . In this process, lipoic acid is attached to dextran, which process of attaching occurs by self-assembly in the aqueous medium. Then, the drug is loaded within nanoparticles and the drug-loaded nanogels are formed by the user of the dithiothreitol (DTT) subsequently . It is important to mention that in the current process, the degrading enzymes leads to break the S-S bond and resulting in the drug release occurs instantaneously (Fig. 3) . Woolley et al have reported a variety of methods for the creation of nanogels using amine groups [41-43], activated esters , carboxylic acids , and isocyanates  related to the main structure of the copolymer. The formed zwitterion shell on networked polymers (nanogel) via the copolymer precursor of 2-(dimethylamino) ethyl meta acrylate-2-tetrahydro pyranine meta acrylate (DMAEMA-THPMA) through 1,2-bis-(2-iodo ethoxy) ethane (BIEE) and tetra hydropyranile (THP) of hydrolysis has been reported by Armes et al . Hawker et al, carried out the synthesis of gel nanostructures by creating cross-links based on click chemistry. In this method, the alkylated and azide groups there are in the principal structure so that they are fabricated using spontaneous assembly of copolymers and also the enhancing of networking agent . They in their study also referred to cross-link based on an optic agent of coumarone and the formation of a nanogel .
In this synthesis process, the polymerization reaction of the monomers occurs in a heterogeneous phase and the nanogels creates. Generally, this method involves normal and reversible emulsions [50-51]. Few types of research have reported a method on the preparation of nano-gels by the process of water-oil (W/O) emulsion. in the other words, polymerization accomplishes between solvent monomers in water and monomers containing several functional groups to synthesis the networked nano-gels . In a study, Peppas et.al produced a suspension of polyethylene glycol (PEG) nanoparticles of conjugated to the polymethacrylic acid (PMA) molecules by employing UV for preparation of nanogels based on the reverse phase emulsion . Recently, atom transfer radical polymerization (ATRP) reported by Matyjaszewski et.al. In this syudy, the nanogels produce through the network of polymerization. This procedure carried out by selecting sulfide bridges of dual-function monomers .
The basis of this manner is the use of nanoparticles as a template that the most well-known of them are liposomes . A liposome is microscopy of a vesicular structure consisting of two layers of phospholipid that has been enclosed a water space around it . This method has been generally applied to synthesize the nano-gels due to its advantages such as non-toxicity  and biodegradability . The aqueous core of these nanomaterials is a good location for the polymerization reaction, which eventually by removing the template, the nanogels are produced [57-58]. In a study by Sudhakar et.al by using the in situ polymerization process to synthesize the nano-gels, at the first, the designed liposome modified with poly (N-isopropylacrylamide-co-acrylamide) (P (NIPAM-co-AAM)) and resulting they were utilized in oeder to DNS applications . Zoratto was carried out the hybrid cholesterol derivatives of nano-gel utilizing liposome template . One of the unique advantages of this method is the synthesis of hollow nanogels. For example, by selecting nanoparticles of gold as the template, the polymer at their surface is turned to the hydrogel, and by removing the template by KCN, a product of the hollow nanogels has resulted that is illustrated in Fig. 4 . In other research by Teng et.al, in an general process were developed the synthesis method of nanogels using precursors of glycol chitosan (GC) and poly (ethylene oxide) (PEO) . Generally, this synthetic approach in the future will exhibit a clear vision for composing drug carrier nanogels.
NANOGELS IN DRUG DELIVERY
The novel biomedical nano-gels systems are considered as a DDS based on their important properties such as high capacity to encapsulate drugs , capability to encapsulate the different drugs , uniformity , adjustable size , easy preparation , minimum toxicity , stability in blood serum , and external response capabilities . Natural derived nano- gels for drug delivery purposes can be synthesized from natural polymers like collagen, albumin and etc. . On the other hand, polymers like polylactic acid, poly-lactic-poly glycolic glycoproteins, polyacrylates (PC), poly-methacrylates (PMA) and poly (ε-caprolactone) are certain examples for preparation of polymers to the synthesis of nano-gels . Although nano-gels are often spherical particles but recent advances related to synthesis of nanogels has been led to synthesize nanogels with different shapes such as the core-shell structures with at least one polymeric network layer with uniform structure . Due to the highly hydrophilic and highly biocompatible properties of nano gels, they are suitable for placement of inorganic nanostructures, medications and biological molecules but without having direct effectiveness on their gel-like performance. The ability to encapsulate more than one biologically active materials with different physical properties is a particular advantage of these nanoparticles compared to some nanocarriers like mesoporous, metal organic framework (MOF), noisome, and quantum dot .
The nano-gel network prevents the in-vivo destruction and removal of encapsulated biological molecules and distributes them well in the target position during the release process for fabrication a controlled response as a result their features of hydrogels such as swelling [71-72], compatibility into their stimulus , and their flexibility . However, the conducted studies confirm the multiplicity of the nanogel applications and the diversity of their release systems. Du et al. a special nanogel were synthesized with different charges to absorb tumor cells and release doxorubicin. These nano-gels were generated through poly (2-aminoethyl methacrylate hydrochloride) (PAMAH) (Fig. 5).
The zeta potential related to this system was ranges from -17 mV to 0 mV within 35 minutes confirming with pH<7 media. Also, the release rate related to the loaded-doxorubicin PAMA-DMMA system indicated an increase as pH decreased . In other words, the release of therapeutic molecules has been studied in order to the treatment of inflammatory disorders. In the treatment, this type of disorder based on the dynamic light, macrophage cells of the immune system are attacked. Schmit et al developed the hyaluronate (HL)-loaded nanogels based on chitosan to disport macrophages. Then, the nanogels were loaded with one of the different sensitizing light sources such as tetraphenyl porphyrin-tetrasulfonate (TPPS4), tetra-phenyl chloride-tetracarboxylate (TPCC4), and chlorin e6. They in their study found that nano-gels of TPPS4 and TPCC4 were safe when combinated to macrophages of RAW 264.7 for mice and the human THP-1 in the dark situation while nano-gels of Ce6 were toxic. As a result, further studies showed that they were uptaken by the target cells in less than 4 hours and accumulated in the cytoplasm and their organelles .
In recent years, study the anesthetic drugs release has developed by using nanogels. In a conducted study by Yin et al, they reported the encapsulated- lidocaine biodegradable nano-gels with polymer precursor of poly (ε-caprolactone) – poly (ethylene glycol) - poly (ε-caprolactone) (PCL-PEG-PCL) nanoparticles. The results indicated that these nanocarriers drastically influenced the blood for long-term effects of these materials and are convenient for surgical therapy .
The synthesis of nano-gels with an useful drug absorption potential and controlled distribution has been introduced via Soni et.al by controlling different networking densities of polymers . In addition, synthesis of anticancer nano-carrier as the nucleoside 5-triphosphate (NTP) were reported by Vinogradov et al.. The NTP forms the capsule made of polyethylene-imine (PEI) molecules and polyethylene glycol-polaronic within a polymer nanoparticle. This model can prevent DNA polymerase activity (RNA) in the proliferation of cancer cells . However, like other nanoscale delivery systems, nanogels have limitations in terms of biodegradation optimization, degradation mechanism and toxicity of components. On the first problem, by increasing the component ratio can be overcome. The rapid disappearance of nano-gels from the bloodstream can be prevented by the absorption of macrophages. In this case, factors there are in the mechanism related to destroying nano-gel compounds that they can affect the toxicity of the drug that it is necessary to consider these factors. Hence, the choice of the precursor of the nano -gel should be done properly. In contrast, smoothness specifications of nano-gels have an impact effect on bioavailability and duability. In other words, the smaller adjustable size of nano-gel provides conditions to increase the circulation time after applying nano-gels so that it can active or non-active the target [76-77]. Therefore, it is hoped that synthesis of nanogels with new structures and strong potential applications can help to design the DNS with high drug material absorption and high loading. Due to, the controlled encapsulation, distribution and release at a specified time period and resulting treatment of different diseases in the future.
In the current review, one try was made to introduce the nano-gels as the carrier nanoplatform for DNS. In the targeted DNS, the stability of the nanocarriers as well as the adjusted release of the drugs materials is a critical problem. Nano-gels are considered as a nanocarrier for targeted drug delivery due to their good stability. With proper design, they can be susceptible to pH, temperature, and release the drug instantaneously. Nanogels are synthesized in a variety of routes so that the synthesized method can affect the specifications of the nanogel product. The amount of the drug release is varied by changing the cross-links, which is not possible in nanoparticles such as micelle. This issue has led to develop the polymer nanoparticles with good capability in drug delivery system.