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Polymeric Nanogels as Versatile Nanoplatforms for Biomedical Applications.

1. Introduction

Appropriate drug delivery systems can be characterized by several factors including pharmacodynamic, pharmacokinetic, and physiochemical properties of the drug. Different carrier systems including hydrogels, nanogels (NGs), dendrimers, drug conjugates, and micelles have been used for several years for the effective delivery of drugs [1]. One of the most prominent and convenient systems among them is the hydrogel which could be attributed to its physiochemical and biological characteristics to achieve a site-specific delivery of incorporated drugs [2]. Previously, hydrogels with macro sizes were extensively used for various medical applications. However, with the advancement in nanotechnology, NGs were developed which are considered more suitable for optimum delivery at the target site due to their small size, ease of formulation, improved retention time, and swelling properties [3-6]. NGs are hydrogels with a submicron size range of 100-200 nm [7] or particles less than 200 nm composed of a cross-linked network of polymers via different functional groups such as carboxyl (COOH), hydroxyl (OH), amino (N[H.sub.2]), and sulphonic (HS[O.sub.3]) [8-10]. NGs are composed of physiochemical-bound natural and synthetic polymers [11], active ingredients, and solvents [12, 13]. NGs may consist of a charged or non-charged system of amphiphilic molecules. The drug loading of NGs requires a basic physiochemical interaction between functional groups of polymeric compounds and drug substance [14, 15].

A nanosize regimen is designed to overcome some of the limitations of micron size particles, including surface area, site specificity, retention at targeting site, swelling behavior, drug loading, and release behavior. Ideally, NGs are considered as biocompatible, biodegradable, versatile, and safe from any kind of leakage [4,16-18]. Size control is easy in NGs to induce active or passive delivery [19]. NGs are utilized in many medical situations including cancer and inflammatory conditions owing to their stimulus-responsive behavior. Under various diseased conditions (for example, cancer and inflammation), body functionality changes due to altering metabolic and/or physiological states. The conventional delivery systems are unable to respond to these minor physiological variations such as pH and temperature, thereby making it very challenging to display a proper drug release profile and therapeutic effects [17, 20, 21]. In such cases, NGs are very useful because their stimulus responsiveness increases several times leading to the required drug delivery at the targeted site for a desired therapeutic effect [22]. One of the many reasons for selecting NGs as a drug delivery system is their toxicity reduction through transdermal delivery of active pharmaceutical ingredients (API), an example of which includes aceclofenac-loaded NG [23]. This could also be attributed to the fact that NG mostly consists of polymers which are biodegradable and degraded into nontoxic metabolites. Furthermore, NG formulation for psoriatic skin is a new area where recently a number of trials are performed. For cancer treatment, a variety of polymeric NGs loaded with doxorubicin are reported earlier [24,25].

In this review, we discuss different aspects of NGs, their classification, their methods of preparation, and their advanced biomedical applications in various ailments including brain disorders, cardiac diseases, pain management, diabetes, tissue engineering, cancer treatment, gene therapy, and inflammatory disorders (Figure 1). This review also highlights the advancement of nanotechnology in the field of NGs supported by the latest references from the literature.

2. Types of NGs

NGs can be classified into different types on the basis of their structural properties including artificial chaperones, layer-by-layer NGs, functionalized NGs, core-shell NGs, and hollow NGs [26]. A comprehensive description of all the types is given below.

2.1. Artificial Chaperones. These are cross-linked, self-assembled particles with extensive applications in various fields of biomedicine [26]. They are used as a drug transporter and synthetic molecular chaperones. The representative diagram of artificial chaperones is given in Figure 2. Artificial chaperones are made up of cross-linked, bifunctional systems of polyion and anionic polymers for the transport of polynucleotides (cross-linked PEI-PEG or PEG-CL-PEI). One of the examples of artificial chaperones is the development of cholesterol-bearing pullulan (CHP) [27, 28]. They have multihydrophobic zones which can entrap hydrophobic drugs and proteins inside them. CHP has been majorly employed as a drug carrier, in particular for hydrophobic drugs [29-31]. Similarly, another class of artificial chaperones (polysaccharide-based hybrid NGs) was reported to offer extensive opportunities for diagnosis and therapy [32]. These NGs not only exhibited exceptional stability as a drug carrier for a model anticancer drug temozolomide but also offered a pH-triggered sustained release of drug molecules from the gel network [33]. Furthermore, in comparison to the liposome-loaded quantum dots (QDs), NG-bearing QDs have improved the capacity for imaging utilizing a lesser quantity [33, 34].

2.2. Layer-by-Layer NGs. These are cross-linked, stimulus-responsive NGs and are also known as multilayer NGs (Figure 2). These multilayers are formulated in different dimensions to expose their efficiency as a best carrier for stimulus responsiveness. Different templates are used such as rigid particles, microgels, and NGs. NG is the most successful approach, and unlike the others, it does not lead to deformability and deposition at the site of action or inside the body [35]. Initially, a single particle light scattering technique was used for formulating multilayer NGs. However, this technique is not suitable for thermosensitive microgels because of their soft, porous, and solvent-penetrable polymeric networks, characterized by the alleged volume phase transition from an engorged to a collapsed state during heating. Various scanning techniques are used for evaluating the thickness of layer-by-layer assembly such as confocal laser electron microscopy, dynamic light scattering (DLS), and fluorescence correlation spectroscopy [36-38].

2.3. Functionalized NGs. These types of NGs are a cross-linked water-soluble polymeric nanoparticle network that is formulated to overcome the stability issues associated with layer-by-layer NGs (Figure 2). These are extensively used NGs; however, their formulation methods are very complicated and require high purification at every step [35], including the microemulsion or inverse microemulsion technique. For instance, water-soluble polymeric nanoparticles are incorporated in NGs using the inverse microemulsion method. In this regard, surface modification of layer-by-layer NGs is performed through cross-linking, covalent coupling, and physical, thermal, or chemical posttreatments [39]. This method of formation of functionalized NGs has advantages over other methods including its single-step process without the use of external cross-linkers, fast cross-linking reactions, no undesirable side products, and covalent grafting of active molecules (functional groups) to the surface. To formulate a stimulus-sensitive functional group, disulfide bonds are selected as these bonds are more sensitive to bioreductive agents such as glutathione (GSH) and thioredoxin. Additionally, thiol-containing functional groups, if added on polymers, result in higher reactivity which could be attributed to the functionalized property of pyridyl disulfide (PDS) bond of the thiol group as compared to several other disulfide functionalities. Therefore, nanoparticle-based NGs can easily be functionalized leading to their therapeutic application in control release formulations [4, 40].

2.4. Core-Shell NGs. These are cross-linked stimulus-sensitive NGs made up of polymers with different sensitivities and consisting of core and shell compartments. Core-shell NGs consist of two regions which are chemically coupled with one another (Figure 2). This coupling or cross-linking also affects their stimulus-responsive property and makes them different from other branched polymers. Backfolding of cross-link chains is not possible in core-shell NGs. There are many stimuli to which core-shell NGs are sensitive including temperature, pressure, and pH [41, 42]. The formulation of core-shell NGs is a very critical process depending upon several parameters such as size, core-shell density, and inclusion of functional groups in core-shell compartments. Various methods are used for the preparation of core-shell NGs such as precipitation polymerization, batch polymerization, and seed polymerization. NGs coated with different nanoparticles such as gold nanoshells and gold nanorods are available in the market and are applied in different temperature-sensitive therapies [43, 44]. Amphoteric core-shell NGs provide important information relevant to specific properties of core-shell NG. An evaluation of the internal structure of NGs can be done through theoretical modeling [45].

2.5. Hairy NGs. Hairy NGs consists of a dual structure having a core and a shell. The shell is composed of linear polymeric chains with high dispersibility (Figure 2). The core of hairy NGs consists of inorganic or polymeric material [46]. These nanomaterials respond to various stimuli including temperature, pH, light, and enzymes. Among all the other types of NGs, thermosensitive hairy NGs are of great importance because of their very small size and stimulus responsiveness [47].

Different methods of preparation of hairy NGs are currently in use. One of them is grafting onto the process, but particles formed through this process have a high density. To address this issue, the controlled radical polymerization method is used, which provides various advantages on the formation of hairy NGs. Another method is the two-pot synthesis method which is generally and specifically used for hairy particles. The process runs over two parts: firstly synthesis, isolation, and purification of NG particles and secondly the synthesis of hairs or grafted straight chains over the particle surface [35]. The most recently developed method is the one-pot synthetic route in which NGs are synthesized by copolymerization of the monovinyl monomer and divinyl cross-linker. The advantage of one-pot synthesis is its convenience and the lack of the need of purification of the intermediates. The size of hairy NGs can be adjusted by changing the concentration of monomers. Thus, synthesis of hairy NG through the one-pot method is more advantageous among others [47, 48].

2.6. Hollow NGs. Hollow NGs are fabricated by temperature-sensitive polymers that are predominantly favorable constituents. The stimulus sensitivity, large size, composite covering, thickness and permeability, large storage capability, and release pattern describe their main features [39]. Therefore, the finding and regulation of all these features are of utmost significance for the preparation of hollow NGs. Hollow NGs with considerably cross-linked shells depict discrete temperature sensitivity but retain virtually no void (14% of the initial core volume) and therefore hardly become hollow. NGs with a rigid shell (smaller void as compared to the core size of the template) are certainly hollow but have low-temperature sensitivity [49].

One of the many advantages of hollow NGs is their improved drug loading, which could be attributed to their greater storage volume (Figure 2). Various methods used for their preparation include layer-by-layer assembly, self-assembly of lipids or block copolymers, template method, and ultrasonic fabrication [35]. However, loading capacities of these hollow nanoparticles may not significantly be enhanced as expected. To encounter this issue, hollow NGs can be synthesized with mesoporous channels penetrating from the shell to the hollow inner core. Hollow NGs prepared through this method have easy fabrication in the aqueous phase without any inclusion of the organic phase [50]. Hollow NGs can be formulated as a dual stimulus-responsive carrier from the continuous association of two graft copolymers into polymersomes [51].

3. Synthesis of NGs

Various synthesis techniques are used for the development of NGs, depending upon their intended pharmacologic effect, desired characteristics, and quantity of the final dosage form. A descriptive detail of all the techniques is given below.

3.1. Polymerization of Monomers in a Homogeneous Phase or in a Microscale or Nanoscale Heterogeneous Environment. Uniform nucleation of the water-soluble monomer results in the formation of colloidal suspension of the polymer. This in turn is used to prepare stable NGs. This method is of great importance in cases where particle size control is of prime importance because particle size has a prominent role in the stability of colloidal formulations. This particle size control is accomplished by the use of the ionic surfactant, and there is an inverse relationship between particle size and surfactant concentration [52]. This method was utilized by Donini and coworkers for lipophilic and temperature-resistant drugs [53]. Similarly, Luisi and Straub reported copolymerization of monomers in reverse micelles for the entrapment of hydrophilic drug molecules [54].

3.2. Physical Self-Assembly of Interactive Polymers. In this technique, hydrogen bonding and van der Waals forces result in an interaction between drug moiety and solvent [55]. During the self-assembling process of NGs, micro- and macromolecules are captured inside them. This method is used to prepare protein-loaded NGs by the self-association of water-soluble polymers. Akiyoshi et al. developed insulin-loaded NGs using this technique. The particle size of NGs prepared with this technique had a particle size below 30 nm; however, it was dependent upon polymer concentration and various environmental factors including pH, temperature, and ionic strength. In a study, NGs with a particle size (120-150 nm) and enhanced stability were reported, using various ratios of two different polymers [30]. Furthermore, the reversible addition-fragmentation chain transfer (RAFT) technique [56] was used to make amphiphilic block copolymers which in turn were used to make NGs. The RAFT technique is a one-step production of PEGylated poly(N,N'-dimethylaminomethyl methacrylate) NG utilizing an amphiphilic trithiocarbonate which is a macro-RAFT agent along with hydrophobic (dodecyl) chain-assisting polymerization. Owing to the production of small particles, this technique is most suitable for the delivery of genes [57, 58]. The micellar behavior of amphiphilic block copolymers can be improved by alternating the temperature conditions and adding solvents [59, 60]. Similarly, a superficial behavior of NGs for site-specific targeting and their loading capacity can be enhanced.

3.3. Cross-Linking of Preformed Polymers. In this technique, oil in water emulsion followed by removal of solvent is used to prepare large-sized NGs [61]. Branched PEG (thiol-functionalized) and dimethyl sulfoxide containing DNA are mixed to obtain cross-linked NGs having a DNA by utilizing the oxidation process [62]. NGs obtained via this method are rod-shaped, spherical, and toroid-shaped. This method is suitable to controlling certain parameters like size and shape of the particles, as well as composition and surface properties of the NGs.

3.4. Novel Photochemical Approach. In the photochemical method, NGs are manufactured in an interlayer quartz flask (150 mL) furnished with a stirrer and a nitrogen gas inlet. A precise quantity of nanoparticles (usually 10 mg) is mixed with 60 mL deionized water containing 186 mg monomer. This mixture is stirred for 10 min followed by addition of 0.8 mL of 1 wt% cross-linker. Further, it is exposed to ultraviolet (UV) irradiation for 25 min. [N.sub.2] is effervesced throughout the preparation procedure. The NGs are collected, washed many times with distilled water, and redispersed in distilled water for further use [63]. This method was used to prepare amino-functionalized magnetic NGs of coated ferric oxide nanoparticles using N-(2-aminoethyl)methylacrylamide and N,N'-methylene-bis-acrylamide for their application as an MRI contrast agent [64]. Likewise, DNA-loaded diacrylated Pluronic and glycidyl methyacrylated chito-oligosaccharide NGs were prepared by using UV light at a wavelength of 365 nm along with a photoinitiator [65]. These NGs were formulated to improve injectable deposition schemes for gene therapy which results in the enhanced indigenous transgene expression at injection sites.

Photochemical internalization along with siRNA NGs is also used for the prolonged gene silencing. Basically, various nonviral siRNA carriers get attached to the endosomal layers resulting in limited gene silencing. However, photosensitizer (meso-tetraphenylporphine disulfonate) is used during formulation which is responsible for the rupture of the endosomal membrane leading to the release of genes into the cytoplasm, thereby improving the intracellular bioavailability of siRNA [66].

3.5. Novel Pullulan Chemistry Modification. In this method, chemical modification of pullulan is done. Cholesterol-based pullulan (CHP) NGs are prepared by using a combination of cholesterol in DMSO and pyridine. Modification is done by replacing 1.4 moieties of cholesterol per 100 glucoside units. Freeze-drying is a prerequisite for the formulations prepared via this technique [67]. The CHP-based technique behaves as an efficient carrier for protein NG formulations. Modification of the CHP method is also done by Michael addition reaction in which PEG replaces the acrylate and thiol groups [68]. Changes at the 1.1 unit of cholesteryl per 100 glucose units make it favorable to interact with the AB monomer as well as monomers responsible for the treatmentof diseases like Alzheimer [65]. When modification is made by using 1.6 units of glucose, pullulan suitable for targeting folate receptors is developed. NGs are formed when pullulan and the photosensitizer are conjugated with carbodiimide followed by dialysis. Such types of NGs are effectively used in cancer treatment [69]. For example, acetylated chondroitin sulfate augments the discharge of doxorubicin in HeLa cells for three weeks, which is very helpful in cancer therapy [70]. Similarly, the release profile and absorption of methotrexate are changed by saturation of butyl acrylate (BA) and N-isopropylacrylamide with sodium carbonate, changing the absorption and release profile of methotrexate [71]. Additionally, pH-modified hydroxypropyl methylcellulose- (HPMC-) polyacrylic acid is made by eliminating cadmium ions and polyacrylic acid and is exercised for bioimaging by detecting the physicochemical surrounding [72].

4. Biomedical Applications of NGs

4.1. Brain Diseases. Various nanoplatforms are recently utilized for the treatment of brain diseases including Alzheimer's disease (AD), depression, migraine, and schizophrenia. NGs are one of those nanodecorated drug delivery systems. Their efficacy in brain diseases is because of their improved therapeutic effects, better mechanism of targeting, and biological efficiency. AD is the irretrievable neurodegenerative illness leading to progressive loss of memory and intellectual abilities [73]. Although various pathological conditions are believed as the possible reasons of AD, amyloid hypothesis is, however, widely accepted in this regard [74]. The anomalous buildup, accretion, and accumulation of amyloid [beta]-protein (A[beta]) lead to the cerebral extracellular amyloid blockade that causes neurotoxicity [75, 76]. Therefore, avoiding A[beta] accumulation is believed as a favorable approach in the management of AD. For this purpose, NGs with a double inhibitor-modified hyaluronic acid function were fabricated with inhibiting capabilities of A[beta] accumulation, resulting in the management of AD [77]. Likewise, Elnaggar et al. assimilated piperine, a phytopharmaceutical agent in NGs for its neuroprotective effect in AD [78].

Similarly, NGs are reported to deliver olanzapine for the treatment of schizophrenia which is a brain disorder described by delusions and disordered behavior [79]. These NGs exhibited excellent entrapment and enhanced bioavailability. Moreover, Hu et al. prepared lidocaine hydrochloride-loaded NGs, for the management of migraine [80]. Lidocaine hydrochloride is a commonly used drug in the treatment of migraine; however, after incorporation in the NG, the drug showed better bioavailability with no toxicity. Furthermore, Dange et al. reported the development of venlafaxine-loaded NG for the treatment of depression [81]. This NG showed a quick onset of action with extended period of time as compared with the drug solution.

4.2. Cardiovascular Diseases. Cardiovascular diseases like myocardial infarction (MI) and heart failure are the main reason of human deaths globally [82]. Various strategies are adopted to treat these diseases including tissue engineering and stem cell transplantation [83, 84]. Among the different drug delivery systems, injectable NGs have been used to treat MI. These NGs have confirmed the improvement in cardiac condition via LaPlace's Law, an act which is exhibited by increased wall thickness and reduced wall stress [85]. One such study reported the heart restoration using NG-encapsulated human cardiac stem cells in mice and pigs with MI [86]. This study concluded that synthetic porous NGs act as a promising cell carrier for allogeneic/xenogeneic cell rehabilitations. Most particularly, these NGs inhibit the entry of immune cells while promoting the regenerative capabilities of the heart.

Another study demonstrated the development of thermoresponsive NGs to produce cell mass fragments for the treatment of ischemic diseases. Owing to their temperature-dependent behavior, the cell bodies are produced without proteolytic enzymes. The animal studies further exhibited the adherence of cell mass fragments with engraftment sites which in turn enhance the vascular density, hence treating the diseased condition of an infarcted heart [87].

4.3. Treatment of Oxidative Stress. Oxidative stress is a diseased condition in which the increased production of oxidants including hydroxyl radicals, singlet oxygen, and hydrogen peroxide lead to cellular disability. This increased level of oxidants may be produced by endogenous and exogenous sources which may result in development of many diseases including cardiovascular diseases, Parkinson's disease, and acute renal failure [88, 89]. Various drug delivery systems are utilized to treat the oxidative stress; however, NGs are considered as reliable drug delivery vehicles in this regard [90-92]. For instance, quercetin-encapsulated poly(b-amino esters) NGs were developed for the treatment of cellular oxidative stress [93]. NGs with a size range at the nanoscale were developed with 25-38 drug wt% and constant drug release over a period of 45-48 h. These NGs demonstrated an antioxidant activity of the drug for a prolonged time period. Another study exhibited the development of ferulic acid-loaded NG with improved penetrability and augmented antioxidant activity in rats for the treatment of oxidative stress. This NG exhibited excellent stability and sustained release of the drug with outstanding antioxidant activity which could be attributed to the increase solubility of the drug and augmented permeability from the NG [94].

4.4. Diabetes Management. Diabetes, a very prevailing chronic disease around the globe, has grabbed the attention of scientists, and new ways of its management are reported. Recently, a new improved therapeutic regimen, noninvasive glucose checking techniques, and new methods of insulin administration have been reported [95, 96]. In this aspect, the preparation of glucose-sensitive NGs has addressed the major hurdles linked with diabetes management. Most particularly, these NGs exhibited sustained release of the insulin by glucose-dependent swelling and shrinking mechanisms [97, 98].

4.5. Cancer Therapy. Various anticancer drugs, e.g., doxorubicin, cisplatin, 5-fluorouracil, and temozolomide, can be incorporated in NGs for the treatment of cancer. Temperature- and pH-sensitive hydrogels of doxorubicin based on maleic acid poly-(N-isopropyl acrylamide) polymer were used in cancer therapy in which doxorubicin release was dependent on temperature and pH. Chitin-based NG of doxorubicin can be used for various types of cancers including lungs, breast, liver, and prostate cancer [99]. Similarly, photosensitizer agent chlorin e6 has been recently used for the photodynamic therapy of cancer using chitosan-based NGs [100]. A descriptive detail of the anticancer applications of NGs is given in Table 1.

4.6. Tissue Engineering and Gene Therapy. NG-based formulations are widely used for tissue engineering and gene therapy. They are also used to deliver enzymes, genes, and proteins at a targeted site to achieve their intended effects. Artificial chaperons are usually utilized to modify polymers to carry enzymes and proteins. Similarly, pullulan is chemically modified by conjugating cholesterol moieties, and the functionalized molecules are self-assembled in water to develop NGs of up to 30 nm size. These NGs have an extraordinary biocompatibility which is utilized for bone regeneration [101, 102]. The properties usually depend on their size and density of NGs which alternatively depend upon the degree of substitution of the cholesterol fragments in NGs. Some of the NG formulations used in transport of enzymes, genes, and proteins are as follows (Table 2).

4.7. Inflammatory Disorders. NGs are considered as important delivery systems for various anti-inflammatory agents. For instance, siRNA-loaded NGs were prepared by polymerization and chemical cross-linking. Structurally, it was polymethacrylic acid-co-N-vinyl-2-pyrrolidone (P[MAA-co-NVP]) cross-linked with a trypsin-degradable peptide linker. A maximum amount of drug was released in the intestinal environment due to its pH and enzyme sensitivity and hence proved to be a suitable candidate for the treatment of inflammatory bowel disease [103]. Similarly, two anti-inflammatory drugs spantide II and ketoprofen were loaded with (HPMC) and Carbopol-based NGs to achieve enhanced percutaneous delivery for the treatment of skin inflammation [104]. Additionally, anti-TNF[alpha] agent etanercept (ETR) was recently loaded with thermoresponsive NGs which not only resulted in effective delivery but showed enhanced anti-inflammatory responses [105].

The NGs enhanced their ability to get deposited in skin's epidermis and dermis for the therapy of topical inflammatory diseases. They are prepared by either solvent evaporation or emulsification method [106]. Photosensitizers tetraphenylporphyrin tetrasulfonate (TPP[S.sub.4]), tetra-phenyl-chlorintetra-carboxylate (TPC[C.sub.4]), and chlorin e6 (Ce6) have a hyaluronate ligand-gated chitosan with tripolyphosphate (TPP) as a cross-linker in their structure. Their potential for extending the retention time and reducing clearance from the inflamed joints enlists NGs as real contenders for the selective delivery of photosensitizers to macrophages. Ionic gelation is the method applied in their preparation [107]. Activated NGs of methotrexate have copolymerized N-isopropylacrylamide (NIPAM) and BA (poly(NIPAM-co-BA)) polymers in its composition. It is synthesized by the emulsion polymerization method. Their advantages include amplified release, elevated concentration gradient, building flux of methotrexate along with depressing PG[E.sub.2] production, and hence effective anti-inflammatory effects [71, 108].

4.8. Pain Management. NGs have been successfully used for the local distribution of anesthetic medications for the pain management. They result in prolonged and sustained release of the incorporated drug [109]. Moreover, they resulted in lower cytotoxicity and enhanced drug uptake [110]. A detailed description of NGs as a local anesthetic drug delivery system is given in Table 3.

4.9. Ophthalmic Diseases. NGs can be employed for ocular delivery with an advantage of enhanced residence time, controlled release of the loaded drug, increased corneal penetration, enhanced bioavailability, etc. These advantages offer improved patient compliance and also reduce dosing frequency. Some of the ophthalmic applications of NGs are given below (Table 4).

4.10. Autoimmune Diseases. Autoimmune diseases can be effectively treated by using NG systems loaded with agents to be delivered to antigen-presenting cells to produce autoimmune responses. NGs containing KN93 and mycophenolic acid as therapeutic moieties are prepared by cross-linking and polymerization of the diacrylate-terminated co-block polymer of poly(lactic acid-co-ethylene glycol), CD [111]. The former specifically targeted CD4+T cells and reduced experimental autoimmune encephalomyelitis while later becoming effective for treating lupus by reducing cytokine production and enhancing immunosuppression [112, 113].

5. Conclusion

The vehicle for drug delivery may have numerous components that need to be effectual, productive, and finely tuned. NGs are versatile and attractive delivery systems having combined attributes of both nanoparticles and hydrogel. Ease in synthesis and purification of this delivery system provides exceptional drug encapsulation efficiency, response to numerous environmental stimuli, higher level of stability, and biologic consistency as compared to other delivery systems, also allowing for convenient functionalization to target cells. The size control for several applications in the delivery of drugs can be tailor-made for lesser cytotoxic with unique and versatile fabrication of NGs by designing a nontoxic delivery vehicle which become metabolized into harmless components in the body. NGs are proficiently internalized by the target cells, avoid accumulation in non-target tissues, and thereby lower the therapeutic dosage and minimize harmful side effects. The effectiveness and compatibility are enhanced multifolds by the NG delivery system with safety mostly for hydrophilic, hydrophobic, and small drug molecules due to their chemical conformation and formulations that are unsuitable for other preparations. These minute transporters can also hold an amalgamation of purpose depending on two or more agents for diagnosis, imaging, controlled release, and site-specific targeting. These practicalities of NGs have unlocked the opportunities for more development in the field of biomedical applications and drug delivery.

5.1. Future Perspectives. Nanomaterials have gained increased clinical interest in recent times on account of a drastic need for improvements in conventional drug delivery and diagnostic tools. Drug delivery scientists over the past three decades have extensively investigated various nanomaterials for drug delivery applications. Owing to their extremely small size with large surface area, these nanomaterials have produced delivery systems with altered basic properties and bioactivity of drug cargos, improved pharmacokinetics, reduced toxicity, controlled drug release, and targeted delivery of therapeutics. In this context, NGs offer versatile platforms with combined properties of cross-linking gelling materials and nanotechnology. Hydrogel properties improve the physicochemical characteristics of NGs, while nanometric size facilitates their transport and biodistribution in different sites of the body. NG technology has earned a wide use in biomedicine ranging from drug delivery to tissue engineering, from imaging to diagnosis and biosensing. Surface functionalization and stimulus responsiveness have added a lot to the advantages and applications of NGs.

A widespread application and versatility of NGs hold them with a great potential for future innovative research to cover the yet unmet needs. A tremendous amount of research is currently in progress to design and fabricate NGs with novel polymers to have more control over the release of their payloads. Likewise, a multitude of preparation techniques have been explored in the past few years to synthesize NGs with the desired set of attributes for various applications. Targeted delivery of NGs by surface functionalization is an area that still has a lot of potential for research in the days to come. However, antibody-conjugated NGs have newly been developed for the targeted delivery of anticancer drugs. However, targeting only a single cancer antigen is improbable because of the heterogeneous expression of cancer antigens in tumor sites. Development of multitargeted NG systems will result in superior cancer diagnostics and therapeutics. Furthermore, a design of NGs in terms of high uptake in selected cancer cells needs to be improved through the collaboration of polymer chemists and biologists. They can elucidate the specific interactions of biomolecules and receptors, which are then prudently attached to NG systems for a more precise targeted delivery. Investigation is required to determine the mechanisms of uptake of NGs at the neuron and/or glial cell level within the central nervous system. It will confirm that NGs prefer a cytosolic destination over an endosomal target. This sort of studies is essential if NGs are ever to be projected as specific drug delivery systems for targeting at the subcellular level.

Whereas NGs have provided a substantial advancement in the current drug delivery and therapeutic and diagnostic tools, a number of shortcomings need urgent attention. Development of cost-effective methods and resolution of technological issues are required for a large-scale production of NGs. A number of questions pertaining to pharmacokinetics and pharmacodynamics need to be answered. Provided these shortcomings are satisfied, NGs can translate into efficient next-generation pharmaceuticals with enhanced clinical care in the near future.


NGs: Nanogels

API: Active pharmaceutical ingredient

PEI: Polyethyleneimine

PEG: Polyethylene glycol

PEG-CL-PEI: Cross-linked polyethylene glycol polyethyleneimine

QDs: Quantum dots

PDS: Pyridyl disulfide

UV: Ultraviolet

CHP: Cholesterol-based pullulan

HPMC: Hydroxypropyl methylcellulose

A[beta]: Amyloid [beta]-protein

MI: Myocardial infarction

NMR: Nuclear magnetic resonance

NIPA: N-Isopropylacrylamide

RAFT: Reversible addition fragmentation chain transfer

g-PEGs: Oligo polymer ethylene glycol

P[MAA-co-NVP]: Polymethacrylic acid-co-N-vinyl-2-pyrrolidone

PLGA: Poly lactic-co-glycolic acid

TPPS4: Tetra-phenyl-porphyrin-tetra-sulfonate

TPCC4: Tetra-phenyl-chlorin-tetra-carboxylate

TPP: Tripolyphosphate

BA: Butyl acrylate

CHA: Cholesterol-bearing pullulan

CHOPA: Acryloyl group-modified cholesterol-bearing pullulan

PEGSH: Pentaerythritol tetra (mercaptoethyl) polyoxyethylene

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

Fakhara Sabir and Imran Asad contributed equally to this work.


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Fakhara Sabir, (1) Muhammad Imran Asad, (1) Maimoona Qindeel, (1) Iqra Afzal, (1) Muhammad Junaid Dar, (1) Kifayat Ullah Shah [ID], (1) Alam Zeb [ID], (2) Gul Majid Khan, (1) Naveed Ahmed [ID], (1) and Fakhar-ud Din [ID] (1)

(1) Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan

(2) Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan

Correspondence should be addressed to Naveed Ahmed; and Fakhar-ud Din;

Fakhara Sabir and Muhammad Imran Asad contributed equally to this work.

Received 27 November 2018; Revised 15 March 2019; Accepted 27 March 2019; Published 16 May 2019

Academic Editor: Ruibing Wang

Caption: Figure 1: Advanced biomedical applications of NGs.

Caption: Figure 2: Types of NG formulations.
Table 1: Anticancer applications of NGs.

NG composition              Type of NG           Drug used

PVA (polyvinyl                Charge            Doxorubicin
alcohol)                 conversional and
                           sensitive NG

Dextrin with              pH-sensitive NG       Doxorubicin
as a

Poly(ethylene              Polypeptide-            17-AAG
glycol)-b-poly               based NG           Doxorubicin
(L-glutamic acid)

P(N-isopropyl-             Temperature-         Doxorubicin
acrylamideco-              sensitive NG
butyl                       dispersion

Poly (N-                 pH, thermal, and           Pc 4
isopropyl-                redox potential
methacrylamide)          triple-responsive
(PNiPMA),                  expansile NG
PDA-PEG, 4-                    (TRN)
acid (MBA)

Glycol chitosan              Acid pH-         Photosensitizer
(GC) conjugated            responsive NG            drug
with 2,3-
acid (dma) and
fullerene (C60)

Dextrin with              pH-sensitive NG       Doxorubicin
glyoxal as a

Chitin poly                pH-responsive        Doxorubicin
(L-lactic acid)            composite NG

Chitin                    pH-sensitive NG      5-Fluorouracil

Folic acid                 Ligand-gated          Cisplatin
conjugated poly           polyelectrolyte
(ethylene oxide)                NG
(methacrylic acid)

Acetylated                Self-organizing       Doxorubicin
chondroitin                     NG
sulfate (CS)

N-Isopropyla-            pH-thermal dual-        Cisplatin
crylamide (NIPAM),         responsive NG           (CDDP)
glycol) (PEG),
glycol) methyl
ether methacrylate

In situ                       pH and            Temozolomide
immobilization             temperature-
of CdSe quantum            responsive NG
dots in interior of
poly(acrylic acid)

                             Method of
NG composition              preparation

PVA (polyvinyl                Inverse
alcohol)                 nanoprecipitation

Dextrin with              Emulsion cross-
formaldehyde              linking method
as a

Poly(ethylene              Cross-linking
glycol)-b-poly                method
(L-glutamic acid)

P(N-isopropyl-               Emulsion
acrylamideco-             polymerization
butyl                         method

Poly (N-
acid (MBA)

Glycol chitosan              Two-step
(GC) conjugated              chemical
with 2,3-                    grafting
dimethylmaleic               reaction
acid (dma) and
fullerene (C60)

Dextrin with              Emulsion cross-
glyoxal as a              linking method

Chitin poly
(L-lactic acid)

Chitin                      Controlled

Folic acid                 Cross-linking
conjugated poly               method
(ethylene oxide)
(methacrylic acid)

Acetylated                Dialysis method
sulfate (CS)

N-Isopropyla-                Emulsion
crylamide (NIPAM),        polymerization
poly(ethylene                 method
glycol) (PEG),
glycol) methyl
ether methacrylate

In situ                   Polymerization
immobilization                method
of CdSe quantum
dots in interior of
poly(acrylic acid)

                               Results and
NG composition                 applications           References

PVA (polyvinyl             Better cell toxicity.         [114]
alcohol)                    Improved targeted
                               drug release.

Dextrin with              Efficacious antitumor          [104]
formaldehyde                     activity
as a                        It is an important
cross-linker                 candidate for the
                               treatment of
                            colorectal cancer.

Poly(ethylene              Improved anticancer         [33, 115]
glycol)-b-poly                   activity
(L-glutamic acid)         Effective cytotoxicity
(PEG-b-PGA)                 in a breast cancer
                                cell panel

P(N-isopropyl-              Improved efficacy            [116]
acrylamideco-                for transarterial
butyl                       chemoembolization
methacrylates)              (TACE) of iohexol
                            dispersion (IBi-D)
                             was observed on
                                rabbit VX2
                               liver tumors.

Poly (N-                    Targeted delivery            [117]
isopropyl-                  of pc 4 to sigma 2
methacrylamide)             receptors in head
(PNiPMA),                    and neck tumors.
acid (MBA)

Glycol chitosan            Beneficial to target          [118]
(GC) conjugated                endosomes and
with 2,3-                  in vivo photodynamic
dimethylmaleic             therapy in different
acid (dma) and              types of malignant
fullerene (C60)                   tumors.
                         Rapid release effective         [119]
Dextrin with                  internalization
glyoxal as a                  of doxorubicin.
cross-linker               Reduced side effects
                            to cardiomyocytes
                              and stem cells.

Chitin poly                Blood compatibility           [120]
(L-lactic acid)             of the system was
                           confirmed by in vitro
                          coagulation assay and
                             hemolytic assay.
                            Effective for the
                            treatment of liver

Chitin                       Loosening of the            [121]
                            epidermis after its
                             interaction with
                            negatively charged
                              chitin with no
                              Important drug
                             carriers for skin
                              cancer therapy.

Folic acid                  In vivo anticancer           [122]
conjugated poly             effect strengthens
(ethylene oxide)            their use for the
-b-poly                    treatment of ovarian
(methacrylic acid)                cancer.

Acetylated                Drug was internalized          [70]
chondroitin                 into the cytoplasm
sulfate (CS)               through endocytosis.
                          Effective drug carrier
                          for anticancer therapy.

N-Isopropyla-                    Extended                [123]
crylamide (NIPAM),           circulation time.
poly(ethylene              Reduced side effects
glycol) (PEG),               Better antitumor
poly(ethylene                activity for the
glycol) methyl                 treatment of
ether methacrylate            breast cancer.

In situ                     High drug loading,           [32]
immobilization               better stability,
of CdSe quantum              and pH-dependent
dots in interior of         sustained release.
hydroxypropyl              Used in cell imaging
cellulose                 and optical pH sensing.
poly(acrylic acid)

Table 2: Applications of NG tissue engineering and gene therapy.

NG composition                  Type of NG               used

CHOPA-PEGSH                      Hybrid NG            W9 peptide

Pullulan-                      PHD hybrid NG           1,2,7,8-
collagen;                                            Diepoxyoctane

Dendritic                     pH-sensitive NG            siRNA
(dPG) and

Chitosan-                     Cross-linked NG        Aryldialkyl-
myristic acid                                         phosphatase

Poly(N-                      Thermoresponsive      Biomacromolecules
isopropyla-                         NG

Poly(N-vinyl                 Functionalized NG     Oligonucleotides
pyrrolidone)                                             (ODN)

Polyethyleneimine            Microenvironment-           Gene
(PEI)                           responsive
                               functional NG

Poly(2-                       Thermosensitive           Protein
methacryloyloxyethyl                NG
glycol methacrylate)
and poly (2-aminoethyl

Enzymatically                   Artificial
synthesized                      chaperon
glycogen (ESG) with
cholesterol group

Cholesteryl                     Artificial
group-bearing                    chaperon
pullulan (CHP)
complexed with
cyclodextrin (M-b-CD)

                                  Method of
NG composition                   preparation

CHOPA-PEGSH                     Cross-linking

Pullulan-                       Cross-linking

Dendritic                       Thiol-Michael
polyglycerol                  nanoprecipitation
(dPG) and                          method

Chitosan-                      "Self-assembly
myristic acid                   via chemical
NG (CMA)                        modification"


Poly(N-vinyl                   Cross-linking
pyrrolidone)                         and
(PVP)                          polymerization

Polyethyleneimine              Cross-linking
(PEI)                                and

Poly(2-                      Reversible addition
methacryloyloxyethyl           -fragmentation
phosphorylcholine),          chain transfer [56]
poly                         and polymerization
(methoxydiethylene                technique
glycol methacrylate)
and poly (2-aminoethyl

Enzymatically                    Hydrophobic
synthesized                     modification
glycogen (ESG) with            self-assembly
cholesterol group                  method

pullulan (CHP)
complexed with
cyclodextrin (M-b-CD)

                                   Results and
NG composition                    applications          References

CHOPA-PEGSH                       Bone repair,             [124]
                                sustained release

Pullulan-                        Tissue filler             [125]
collagen;                           materials

Dendritic                         In vitro gene            [126]
polyglycerol                       silencing.
(dPG) and                         Gene therapy

Chitosan-                        Enhanced pH and           [127]
myristic acid                   thermal stability
NG (CMA)                            Used for
                                   of paraoxon

Poly(N-                        Enhanced stability          [128]
isopropyla-                  and release of protein
crylamide)-                     Effective for the
polyglycerol                   topical delivery of

Poly(N-vinyl                       Negligible              [129]
pyrrolidone)                      cytotoxicity
(PVP)                            Bypass cellular
                                for gene delivery
                              Reduced cytotoxicity

Polyethyleneimine                   Enhanced               [106]
(PEI)                             transfection
                                 Potential gene

Poly(2-                           Temperature-             [130]
methacryloyloxyethyl          sensitive controlled
phosphorylcholine),            release of proteins
poly                           from biodegradable
(methoxydiethylene                     NG
glycol methacrylate)
and poly (2-aminoethyl

Enzymatically                   Enhanced thermal           [131]
synthesized                    stability of enzyme
glycogen (ESG) with            Used for biomedical
cholesterol group                  and protein

Cholesteryl                    Protein synthesis           [132]
group-bearing                   was not affected.
pullulan (CHP)                 Help in folding of
complexed with                  active proteins.
cyclodextrin (M-b-CD)

Table 3: NGs for the management of pain.

NG composition              Type of NG           used

NIPAAM, MAA                Magnetic NG        Bupivacaine

Pluronic F127,              Thermogel         Bupivacaine
acid (HA)

Chitosan                    Thermogel         Rupivacaine

Poly(N-iso-                Temperature-       Bupivacaine
propylacrylamide)           sensitive
(PNIPAM)                        NG

Alginate,                       NG            Bupivacaine

Poly (e-                 Thermoresponsive      Lidocaine
caprolactone)-poly              NG
(ethylene glycol)-
Pluronic F-127

Methacrylic              pH-sensitive NG      Bupivacaine
with diallyl

                           Method of            Results and
NG composition            preparation           applications

NIPAAM, MAA               Free radical         Rapid release
                            emulsion               at low
                         polymerization          temperature
                             method                and pH

Pluronic F127,                                 Effective for
hyaluronic                                      the treatment
acid (HA)                                      of ankle block
                                               Easy to inject
                                              in situ gel for
                                              localized affect
                                               release profile
                                               Less cytotoxic

Chitosan                                     Controlled release
                                               delivery system
                                                 for local
                                              anesthetic affect

Poly(N-iso-              Polymerization        Less cytotoxic
propylacrylamide)                                 enhanced
(PNIPAM)                                         drug uptake

Alginate,                                        Acceptable
chitosan                                        cytotoxicity
                                                and stability
                                             Slower drug release

Poly (e-                   Emulsion              Prolonged
caprolactone)-poly          solvent           anesthetic affect
(ethylene glycol)-        evaporation       with lesser toxicity
poly                         method          Enhanced retention
(e-caprolactone)                             of local anesthetic
Pluronic F-127

Methacrylic                 Emulsion              Enhanced
acid-ethyl               polymerization         pH-dependent
acrylate                                      anesthetic affect
with diallyl

NG composition          References

NIPAAM, MAA                [133]

Pluronic F127,             [109]
acid (HA)

Chitosan                   [134]

Poly(N-iso-                [135]

Alginate,                  [136]

Poly (e-                   [137]
(ethylene glycol)-
Pluronic F-127

Methacrylic                [138]
with diallyl

Table 4: NGs for ophthalmic delivery.

NG composition               Type of NG    Drug/agent used

Nanodiamond, chitosan,       Diamond NG    Timolol maleate
poly(hydroxy ethyl
methacrylate) matrix

Polyvinylpyrrolidone             NG          Pilocarpine
and acrylic
acid (AAc)

PLGA, chitosan               In situ NG      Levofloxacin

Chitin                           NG          Fluconazole

Cyclodextrin                     NG         Dexamethasone

PLA, sodium                  In situ NG     5-Fluorouracil

N-Isopropyl                                   Tacrolimus

                                 Method of
NG composition                   preparation

Nanodiamond, chitosan,           Spontaneous
poly(hydroxy ethyl                cluster
methacrylate) matrix              formation

Polyvinylpyrrolidone              [gamma]
and acrylic                   radiation-induced
acid (AAc)                     Polymerization

PLGA, chitosan

Chitin                           Controlled
                              chemistry method

Cyclodextrin                  Emulsion-solvent

PLA, sodium                   Emulsion-solvent
alginate                         Evaporation


                                    Results and
NG composition                      applications           References

Nanodiamond, chitosan,           Lysozyme mediated            [139]
poly(hydroxy ethyl                sustained release
methacrylate) matrix             Enhanced retention
                                     in the eye
                                 Localized delivery
                                  to treat glaucoma

Polyvinylpyrrolidone               Sustained drug             [140]
and acrylic                     release and improved
acid (AAc)                        bioavailability
                                   Sustained drug

PLGA, chitosan                    Enhanced corneal            [141]
                                 Slow drug clearance

Chitin                            Good penetration            [142]
                                    to the cornea
                                 Effective for the
                                treatment of corneal
                                  fungal infection

Cyclodextrin                      Controlled drug             [143]
                                 release by adhering
                               to the ocular surface.
                                  Enhanced ocular
                                   Extended drug
                              retention at eye surface
                               Controlled drug release

PLA, sodium                      Enhanced retention           [144]
alginate                               of gel
                                Effective ophthalmic
                                 delivery system for
                                  the treatment of
                                   squamous cell
                                  carcinoma (CCSC)

N-Isopropyl                        Sustained drug             [98]
acrylamide,                        release profile
2-hydroxy-                     Increased penetration
methacrylate                        to the cornea
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Author:Sabir, Fakhara; Asad, Muhammad Imran; Qindeel, Maimoona; Afzal, Iqra; Dar, Muhammad Junaid; Shah, Ki
Publication:Journal of Nanomaterials
Date:Jun 1, 2019
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