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Abstract

A nanogel is a cross-linked nano-sized, a three-dimensional network of hydrophilic polymers with an ability to swell by holding large amount of water while maintaining the structure due to chemical or physical cross-linking of individual polymer chains. Nanogels can be made up of synthetic and/or natural polymers resulting in a cationic, anionic, or neutral system depending on the bound groups’ charges. Currently, these materials are receiving tremendous attention in research due to their properties. They are extensively investigated as carriers in the biomedical field. At present, there is an expansion of research into dermatologic treatment due to a critical need for new treatment options to treat skin diseases. The skin itself provides a natural barrier against particle penetration for topical delivery. However, it also offers a potential approach for the delivery of therapeutics, especially in diseased skin via the openings of hair follicles. Recent innovation might be achieved in the field of dermatological treatment with improvement in the dermal localization of bio-actives into the affected skin region. This report looks at what has been done in the investigation of nanogels as drug carriers for topical therapy.

Keywords

Nanogels topical therapy skin hydrogels polymers

Introduction

Tremendous work has been published on hydrogels since the 1960s.¹ These materials have proven to be bioactive with remarkable biocompatibility, excellent biocompatibility, hydrophilicity, flexibility, versatility, and high-water absorptivity. For these reasons, many functional hydrogels have been prepared and studied in medical applications for drug delivery.^2,3 For a very long time, the delivery of drugs has been the major short coming for various drugs. Hence, pharmaceutical nanotechnology devoted studies to formulating therapeutical and biocompatible drug carriers in nanoforms.⁴ In the past years, nanotechnology has played an immense role in drug delivery since nanoparticles easily adhere to cells and are biocompatible and therapeutically active unlike macromolecules.⁵ However, there are still hurdles associated with the release mechanisms of the loaded agents to specific sites due to less effective polymeric network used, and most of these drugs suddenly dissolve before reaching their destination, causing side effects.⁶ The incorporation of nanoparticles and hydrogels into nanogels further improves the nanomaterials’ properties and abilities.^7–10 The polymeric system of nanogels has a variety of properties of interest which includes high capacity to load drugs and the ability to deliver the loaded drug into a targeted location and increasing the permeability of a drug without harming the normal cells.^11–17 Based on their properties, nanogels emerged as a new drug delivery system and received tremendous attention in the group of nanoparticulate systems as one of the most promising versatile drug carriers.¹⁸ Their ability to carry and deliver drugs is well known.^19,20 Dermal therapy has proven to be preferable route for drug delivery and localized drug action.²¹ This route is preferable for treating skin disorders as the skin can be a convenient entrance for chemicals. This is mainly due to the advantages such as sustained release kinetics, controlled delivery of bioactive, ease of self-administration, bypass first-pass metabolism, elimination of GIT degradations, bowel distress, which leads to the easy selective targeting of the damaged area, limited spreading of the drug and lower dosage which will result in the decreased chances of toxic side effects. However, penetration due to the barrier caused by the stratum corneum (SC) composition has been a limiting factor for the topical application therapy.²² When nanoparticles cannot penetrate through the skin SC therefore, they use the hair follicles as a way in. However, nanoparticles accumulate in skin furrows and hair follicles creating high local concentrations of loaded drugs that can further diffuse to the viable layers of the skin.²³ In the study where a drug loaded nanogel, it was observed that the permeability of the drug through the skin is influenced by the particle size. The release improves as the size of the particles decreases.²⁴ Rusu et al, conducted a research on biocompatible nanogels as carriers of Amox they noticed the embedding of these nanogels in Hyaluronic acid hydrogels to be an advantage as it improved the stability in physiological conditions and controlled the over rapid release of the loaded drug.²⁵ In the study conducted on “Self-assembled nanogel of Pluronic-conjugated heparin as a versatile drug nanocarrier” the ability of nanogels to solubilize hydrophobic drugs was further demonstrated, however, the amount of drug loaded is important. This study, likewise, showed that the swelling ratio of the nanogels is related to the kind of hydrophilic functional group and that the delivery of hydrophobic/hydrophilic drug highly depend on the structural properties of the polymer.²⁶ It is important to mention that nanogels are administered through different routes including injection, oral, pulmonary, nasal, parenteral, intra-ocular,²⁷ however this review focuses on the dermal therapy via topical routes of administration.

Classification of nanogels

Nanogels are generally classified into three major groups namely the linkage type, the responsive type as well as structural type (Figure 1)

Figure 1.

Nanogels classified into linkage, responsive and structural nanogels.^28–30

Linkage type nanogels are further categorized into chemically and physically linked nanogels. Essentially, this classification is based on the method of the synthesis. Chemically cross-linked nanogels have covalent bonds linking the polymer networks. The bonding mainly involves amide-based crosslinking, disulphide-based crosslinking, photo-induced crosslinking as well as Schiff-base reactions.^31,32 These nanogels are highly stable owing to the presence of covalent bonds in their structure. Physically cross-linked nanogels are formed through linkages such as hydrogen bonding, hydrophobic interactions as well as electrostatic interactions.³³ As the interactions are weak, physically crosslinked nanogels are less stable compared to chemically cross-linked. Responsive type nanogels category is divided into stimuli-responsive and non-responsive nanogels. While the nonresponsive nanogels only swell and de-swell due to water absorbance, the stimuli-responsive type swell depending on the environmental, physical, and chemical changes such as pH, temperature, ionic strength, and magnetic field.^33–35 The properties of the stimuli-sensitive nanogels highly depend significantly on the polymers. Nanogels can be pH sensitive when composed of cross-linked polyelectrolytes with weakly acidic e.g., carboxylic groups or weakly basic e.g. amino groups which can be used either as proton donors or receptors or through their combination. However, other polymers are thermo-responsive and are considered adequate for delivery systems in biomedical devices where there are specific temperatures. Copolymerization leads to obtaining multi-sensitive nanogels by incorporating polymers that can respond to different stimuli.^36–41 The pH-responsive gels control the drug release in an environment with certain pH through the ionization of the appropriate attached groups developing fixed charges on the polymer network, producing electrostatic repulsive forces responsible for pH-dependent swelling or de-swelling of the hydrogel.⁴² Structural type Nanogels can also be classified according to their structures. These vary from simple,⁴³ core-shell,⁴⁴ hairy,⁴⁵ hollow,⁴⁶ multi-layered⁴⁷ and functionalized nanogels. The core-shell nanogels have been reported to exhibit dual thermo-responsive behaviour as their core would have a lower critical solution temperature, while the shell would have an upper critical solution temperature behaviour.⁴⁸ A hairy nanogel has a core-shell type of structure with the nanosized core displaying the nano-effect while the shell has linear polymeric chains that have a greater affinity with the dispersion medium.^49,50 Multi-layered nanogels, prepared from linear polymers via hydrogen bonding or ionic pairing, can change their volume dramatically and can therefore accommodate different types of molecules.^51,52 The functionalization on the surface of the functionalized nanogels is advantageous as it helps to control the nanogel pathway toward a specific target as well as the cargo release kinetics thus limiting the toxicity on normal cells.^53,54

Synthesis of nanogels

Nanogels can be synthesized from either natural, synthetic, or both polymers. However, every design of nanogels is suitable for a specific application with carefully selected polymers. The advantage of using natural (carbohydrates) polymers is that they are biodegradable, biocompatible, and less toxic owing to their nature. However, when exposed to the external environment they give microbial contamination. Again, their dependents on the environment and different physical factors lead to uncontrollable hydration and heavy metal contaminants. On the other hand, Synthetic manufacturing is controllable which allows the attachments of all the desired branches when they are designed.^35,55 Figure 2 shows the general formation of nanogels and the examples of the PH, magnetic and thermo-responsive nanogels loaded with Doxorubicin. No. Two shows the reaction between N,Nbis (acryloyl)crystamine and N-isopropylacrylamide in the presence of acrylic acid to form temperature responsive nanogels which showed speed release in the tumor cell environment.⁵⁶ No.3 shows a reaction of nanogels loaded with magnetic nanoparticle as carriers for the drug. These nanogels showed accelerated delivery when exposed to the magnetic field since the application of high-frequency magnetic field is to magnetic nanoparticles generate heat.⁵⁷

Figure 2.

schematic reactions of the synthesis of nanogels with examples.^56,57

Various approaches have been utilized to formulate nanogels. These approaches can be classified into four: Physical assembly of polymers, chemical cross-linking of polymers, polymerization of monomers, and template-assisted fabrication.⁵⁸ Physical assembled polymers can form nanogels in the presence of amphiphilic copolymer and a therapeutic agent in an organic solvent through weak noncovalent interactions, such as Van der Waals, hydrogen bonding, stereo complexation, charge transfer, and polyelectrolyte complexation.⁵⁹ This self-assembly method when used shows versatility and simplicity. It has been utilized to fabricate chitosan-based nanogels that can be further functionalized in enhancement for biomedical applications.⁶⁰ Chemical synthesis of nanogels (Chemical cross-linking of polymers) in heterogeneous colloidal environments can give a wide spectrum of capabilities for various structures and properties of nanogel. This covalent cross-linking method has been extensively employed in the preparation of a wide range of functional nanogels for drug delivery as it is an approach that is likely to obtain nanogels with large pore sizes.⁶¹ For polymerization in a homogeneous phase approach, a colloidal suspension of the polymer is made via the homogeneous nucleation of water-soluble monomers used in the synthesis of stabilized nanogels.⁶² The approach is used to manipulate particle size with the particle size inversely related to surfactant concentration. For Polymerization in a heterogeneous phase, in general two methods are used to synthesize nanogels, the normal (oil/water) and reverse (water/oil) emulsions.^63,64 In the oil-in-water approach, aqueous nanodroplets of water-soluble monomers and bi-functional monomers are dispersed with the aid of oil-soluble surfactant in the organic solvent.⁶⁵ On the addition of a water-soluble initiator, polymerization then takes place in aqueous droplets affording cross-linked hydrophilic nanogels. The water-in-oil emulsion methods involve emulsification of aqueous droplets of water-soluble biopolymers in a continuous oil phase with the aid of oil-soluble surfactants followed by the crosslinking of biopolymers using water-soluble crosslinkers. Multiple approaches fall under this category, and they include general approaches including inverse (mini)emulsion, membrane emulsification, and reverse micellar methods.^66,67

Polymers in nanogel formulation for topical treatment

Nanogels have found application in various fields.^63,68–73 However, these materials have gained more attention in drug delivery research owing to their capability to carry drugs with significant sustainability.^74–76 Polymers are playing a vital role in the currently used drug delivery system’s development. Their controllable drug release while maintaining the doses over long periods, cyclic dosage, and their ability to release both hydrophilic and hydrophobic drugs is attracting a lot of attention.⁷⁷ Both Natural, synthetic and hybrid polymers have been extensively investigated, Table 1 shows some of the mostly studied polymers. Some synthetic polymers are biodegradable and form copolymers with natural macromolecules. While the high biocompatibility and less immunogenicity of natural polymers is an advantage.^78,79 PVA is one of the mostly studied synthetic polymers for wound dressing, however, it has insufficient elasticity, a thick membrane, and imperfect hydrophilic elements limiting its ability unless incorporated with another polymer.⁸⁰ In improving the effectiveness of these polymers their hybrids are formulated, a natural polymer is combined with a synthetic polymer to get the properties of both the synthetic and natural polymer systems in one system. The hybrid NGs are promising in advanced therapies, where high specificity, high efficacy, and low adverse effects are desirable.⁸¹ Some polymers are investigated and used because of their biocompatibility even though they have no biodegradability, their lipophilic nature helps in the incorporation of hydrophobic drugs with better skin penetration.⁸² The most widely used natural polymers in biomedical applications are polysaccharides and proteins. These polymers are used in various biomedical applications, such as wound dressings, wound healing, and drug delivery.⁸⁰ Also, some natural polymers studied with intriguing properties have proven to have disadvantages too. For example, Chitosan which is derived from natural polysaccharide chitin is known for its bioactivity and biodegradability however it is Immunogenic.⁸³ Hence, the studies of hybrid nanogels. Nanogels can be designed to be compatible with small molecules like drugs and fluorophores, proteins, peptides, nucleic acids, and even inorganic nanoparticles composed of gold, silver, or iron oxide.¹¹ For both transdermal and dermal applications of nanogels, Properties such as spread ability, pH, skin permeation, Skin tolerance, Viscosity, stability, and particle size of the loaded drug are essential.⁸⁴ Based on the previous reports, particles below 300 nm are more ideal for skin uptake.^85,86 In a recent review on transdermal application of nanogels, Liu and colleagues highlighted that, among all the characteristics, nanometer effects are obviously important, specifically referring to the phenomenon that the penetration capacities across the epidermal barriers of nanocarriers are size dependent. Also, hydrating effect as the skin hydration can promote the transdermal transport of both hydrophilic and hydrophobic drugs. Furthermore, pH together with temperature is one of the important stimulus response mechanisms that has been widely applied to trigger drug release from nano-systems. They also showed how the surface charge can affect functional nano-system permeation and penetration on the skin.⁸⁷ In a study done by testing Artemether (ART) loaded nanogels on pig ear skin, the nanogels showed reasonable drug concentration in the living epidermis even though higher in the stratum corneum. ART-nanogels had good pH storage stability, viscosity, spread ability, drug content, in vitro drug release, skin tolerance, and occlusivity leaving a thin film after application on the skin due to good hydration and ability to prevent skin trans-epidermal water loss.^66,84 With advancements in research of nanogels for dermal and transdermal application, nanotoxicology has become crucial to understand the physicochemical interactions of nanomaterials with different cells and tissues to undergo bench to market translation.⁸⁸ There are known undesired effects of these materials on the human body.⁸⁹ For instance, when foreign components penetrate in to eukaryotic cell, an automatic reaction is activated where in lysosomes release free radicals inducing oxidative stress. These free radicals can oxidize lipids, proteins, and DNA, causing damage to different cell organelles.⁹⁰ Therefore, when nanotoxicology is well understood the formulation of nanogels will be for the improvement and elimination of the side effects of the nanomaterials. For an example, since it is difficult to accumulate enough antigen in the epidermis for effective exposure to Langerhans cells due to of diffusion into the skin and muscle, transdermal vaccination for anticancer therapy is a challenge. Mao Toyoda and colleagues worked on antigen peptide loaded nanogels via iontophoresis, the peptide loaded nanogels were accumulated in the epidermis by iontophoresis. Iontophoresis of peptide loaded nanogels activated Langerhans cells and suppressed tumor growth.⁹¹ This is a highly promising finding.

Table 1.

The mostly studied polymers on different topical applications.

	Polymers used for hydrogels	Substance loaded on the hydrogel	Application studied	Ref
Natural polymers	Chitosan	Silver sulfadazine cubosomes	Topical treatment of burns	⁹²
	Chitosan	Nanoencapsulated phenytoin	Skin permeation/penetration and efficacy in wound healing	⁹³
	Hydroxyethyl cellulose	Rosmarinic acid-loaded nanoemulsions	Skin retention/permeation and safety profile study on HaCaT cells (immortalized human keratinocytes	⁹⁴
	Chitosan, collagen, genipin, keratin, pectin	-	Skin tissue regeneration	⁹⁵
	Chitosan-sodium alginate	Curcumin	Wound healing	⁹⁶
Synthetic polymers	Xanthan gum	Vitamin C	To enhance vitamin C retention in the skin and permeation through the skin	⁹⁷
	PEG (polyethylene glycol), carbopol	-	Skin tissue engineering and wound healing applications	⁹⁵
	Polyacrylamide
	Carboxymethyl cellulose
	Hyaluronic acid and polyethylene glycol	-	Wound healing	⁹⁸
	2,2-bis(hydroxymethyl)propionic acid (bis-MPA) dendrons and linear polyethylene glycol (PEG)	Antibiotics	Wound dressing	⁹⁹
Hybrid polymers	Chitosan-polyvinyl	Hibiscus Sabdariffa L	Escherichia coli and Pseudomonas aeruginosa antibacterial	¹⁰⁰
	Alcohol	Extract		¹⁰⁰
	Polyvinyl alcohol-chitosan-glutaraldehyde	Copper oxide nanoparticles	Wound healing Application	¹⁰¹

Nanogel drug release mechanisms

The release of drugs from nanogels has been reported to be dependent on the affinity of the drug to the polymer as well as the network mesh size of the nanogels. However, in the former case, polymer/drug interactions may significantly contribute to controlling and regulating the release of the drug.¹⁰³ In the latter case, nanogel swelling/de-swelling influences the likelihood of the drug going in or out of the network. Several mechanisms identified include diffusion, pH-responsive mechanism, thermosensitive transition mechanism, and nanogel degradation Figure 3.

Figure 3.

Nanogel drug release.¹⁰²

Diffusion

This is a very simple drug release mechanism expected when a drug is physically encapsulated in the nanogel. The sizes of the open spaces (meshes) between nanogel polymer networks control the steric interactions between the encased drugs and the polymer network and hence determine how drugs diffuse through the material.¹⁰⁴ The diffusional drug release mechanism was demonstrated by Missirlis et al. when they reported the release of doxorubicin from a nanogel based on pluronic block copolymer whose hydrophobic core provided considerable protection against hydrolytic degradation.¹⁰⁵ Coll Ferrer et al. also demonstrated the release of dexamethasone from dextran-lysozyme nanogels via the diffusion mechanism.¹⁰⁶

PH-responsive mechanism

In this mechanism, the swelling or de-swelling of nanogels containing weakly basic or acidic groups in their structure is caused by changes in pH. Thus, the mechanism exploits the changes in pH within the body for selective response in specific cellular compartments.¹⁰⁷ Moreover, the versatility of the pH-responsive nanogels is displayed when taking into consideration the fact that pH gradients exist between diseased and normal cells with, for example, cancerous cells. Zhou et al. have demonstrated that the Coulombic repulsions that exist between the deprotonated carboxylic groups of nanogels based on poly (methacrylic acid) (PMAA) at high pH induce the swelling of the nanogels, while under acidic conditions, the carboxylic acid groups are not ionized and the nanogels are in a collapsed state.¹⁰⁸

Thermosensitive mechanism

Nanogels have been developed incorporating polymeric networks that are sensitive to temperature variations. The thermo-responsive polymers making up these nanogels are categorized into polymers possessing a lower critical solution temperature (LCST) and those with an upper critical solution temperature (UCST).¹⁰⁹ The thermo-responsiveness of the polymers is a result of the delicate balance between the hydrophilic and hydrophobic segments of the polymer chains.¹¹⁰ The changes in temperature influence the interaction between segments in the polymer chains with water thus inducing a change in the solubility of the polymer network. According to Bajpai et al., when the temperature is be-low LCST, there is increased hydrogen bonding between the polymer and water molecules resulting in polymer swelling, whereas, for the temperature above the LCST, the increased temperature disrupts hydrogen bonding leading to polymer contraction.^111,112 The justification for the use of temperature as a signal is that the body temperature often deviates from the physiological value of 37°C in the presence of pathogens.¹¹³ Table 2 gives some examples of polymers with LCST in water.

Table 2.

Polymers exhibiting a lower critical solution temperature (LCST) in water.^114,115

Polymer	LCST (°C)	Ref
poly (2-oxazoline)s	∼25	¹¹⁶
Pluronic F127	∼25	¹¹⁵
poly (N-vinyl caprolactam)	37	¹¹⁷
Poly (N-isopropylacrylamide)pNIPAAM	∼40	¹¹⁸
Poly (propyleneglycol)PPG	∼50	¹¹⁴
Poly (N,N-diethylacrylamide) PDEA	∼55	¹¹⁹
Poly (vinyl methyl oxazolidone), PVMO	∼65	¹¹⁴
Poly (methylacrylic acid), PMAA	∼75	¹¹⁴
Methylcellulose, MC	∼80	¹¹⁴
Poly (ethyleneglycol), PEG	∼120	¹¹⁴
Poly (vinyl alcohol), PVA	∼125	¹¹⁴
Poly (vinyl pyrrolidine), PVP	∼160	¹¹⁴

Nanogel degradation mechanism

Nanogel degradation is another mechanism that is available for the release of drugs entrapped in the polymer network. The degradation causes an increase in nanogel mesh size resulting in drugs diffusing out of the material. Nanogel degradation, which is characteristically mediated by enzyme activity or hydrolysis, can occur in the polymer backbone of the cross-links.¹²⁰

Nanogels as drug carriers in the treatment of skin diseases

Many different skin diseases affect more than 50% of the population in the world. Nanogels are currently being investigated for the treatment of different skin diseases via topical drug delivery. The available medications can help reduce and cure some skin diseases. The most common approaches include skin maintenance care techniques, topical anti-inflammatory agents, systemic antihistamine, topical or systemic antibiotics, and selectively, systemic corticosteroids, however, most skin disorders are chronic diseases that cannot be permanently removed by any drug but needs a lifetime treatment and Psoriasis is one of them.^121–123 The challenge at hand is, most currently used medications are found toxic such that they result in a variety of drug-induced diseases.¹²⁴

Topical drug delivery promotes a localized effect thereby reducing the total drug to be used to reach the targeted site. The first direct evidence that nanogels can penetrate the skin and migrate across the epidermis was reported by Samah et al. using transmission electron microscopic images.^125–128 Hair follicles seem to be an easy way in through the skin of the nanogels, however, the particle size range is important as the medium-sized polymeric particles in the range 300 nm to 500 nm were found to penetrate effectively unlike the smaller particles.^129,130 Giulbudagian et al designed nanogels based on three thermo-responsive polymers poly (N-isopropylacrylamide), p (di(ethylene glycol) methyl ether methacrylate-co-oligo ethylene glycol methacrylate, and poly (glycidyl methyl ether-co-ethyl glycidyl ether) and studied their drug delivery properties.¹³¹ They proposed hydration mechanism as a particular mode of skin penetration enhancement mechanism that correlated well with the chemical composition of the nanogels. Shah et al. have demonstrated that the nanogel comprising surface-modified nanoparticles enhanced skin permeation of two anti-inflammatory drugs spantide II and ketoprofen across the deeper skin layers via the improvement of skin contact time and hydration of the surface of the skin (occlusive effect).¹³²

Nanogels as carriers for known active drugs

The ability of nanogels as carriers has been studied by investigating their effectiveness when loaded with the currently used drugs. Drugs such as Methotrexate, Acitretin, Etretinate, etc, are known for their efficacy in the treatment of different psoriasis types. Acitretin is known to be more unique compared to other systemic therapies for psoriasis as it is not immunosuppressive. It is therefore regarded as a safe option for patients with a history of chronic infection such as HIV, hepatitis B.¹³³

Gels are the best carriers to transport active pharmaceutical ingredients like methotrexate (MTX) into contact with the skin.¹³⁴ When the nanogels were investigated as carriers loaded with methotrexate against the imiquimod-induced psoriasis model developed, it was concluded that MTX-NLC gel showed the gradual release with more effective eradication of psoriatic manifestations when topically applied.¹³⁵ In another study, the niosomal methotrexate gel based on chitosan was tested in clinical studies. The niosomal encapsulation was made through the lipid layer hydration method with pH 5-phosphate buffer. The gel showed better results without any side effects when compared to the gels that are already in the market.¹³⁶ Tretinoin is well known for its activity against acne as a single agent therapy, however, it is often associated with serious side effects such as erythema, dryness, peeling, and burning which are likely to discourage patients from taking and finishing the treatment. Therefore, the incorporation of nanogels is studied to minimize these side effects. A clinical trial conducted in 2015 where Tretinoin Nanogel 0.025% as compared to its Conventional Gel 0.025% proved Tretinoin nanogel to be more effective and better tolerated.¹³⁷ Tretinoin incorporated in solid lipid nanoparticles showed better-sustained release, stability, and protection from degradation. The studies showed that chitosan solid lipid nanoparticles combined with Tretinoin resulted in an efficient topical treatment for psoriasis.¹³⁸ Diclofenac sodium was also successfully tested for dermal route administration through different glycol nanogels. The gels were optimized for homogeneity, particle size, pH, drug content, in vitro drug release, skin irritation test, spread ability, extrudability, and viscosity. In the beginning, the release rate was uncontrollable. However, when the gel phase had been reached the drug release rate slowed down. This proved that the formed gels can retain diclofenac sodium for the required duration.¹³⁹ On the other hand, the combination of existing drugs with the polymers was shown to be improving the activity of the drug with more additional advantages. An example is a study where Ibuprofen and Chitosan formed an interaction through the carboxylate ion of ibuprofen and the protonated amino group of chitosan. This led to a decrease in particle size of ibuprofen from 4580 (aspect ratio) to 14.15 nm (324-folds), Ex vivo releases studies on pig skin exhibited that the chitosan–ibuprofen–gellan conjugate nanogels are more permeable than the control ibuprofen gellan hydrogel by a factor of four.¹⁴⁰

Even though there have been successful cis-platin based chemotherapy there are still shortfalls of the chemotherapy which are: poor bioavailability, variety of side effects, drug resistance, and high dosage, to name a few. As a result, many target improved nanocarriers are being developed.¹⁴¹ Cisplatin-directed coordination crosslinking nanogels (Pt-PNA) were developed via the coordination bonds of Pt-carboxyl, the excellent antitumor efficacies of Pt-PNA nanogels were attributed to the improvement in the capacities of sustained release and long-term retention in tumor for water-soluble cisplatin. For water-soluble cisplatin, Pt-PNA nanogels showed a sustained release over 5 days at 37°C, and a pH-dependent release, in addition, Pt-PNA nanogels showed much stronger cisplatin retention abilities than free cis-platin.¹⁴² Nanogels loaded with well-known cancer therapeutic, cis-platin, are being studied. The targeted PEG-b-PMAA nanogels for cisplatin delivery to glioma synthesized by Baklaushev et al., showed limited penetration via the endothelial barrier towards the intracranial tumours when compared to free cisplatin. To improve the penetration and efficiency of drug delivery to the glioma, the nanogels were conjugated with mAbs (antibodies) against the targeted proteins. MRI confirmed a decreased tumor growth in comparison to other investigated formulations.¹⁴³ Moreover, the use of cisplatin incorporation with other effective drugs has shown an enhanced efficacy and improved safety, and nanogels can transport many different drugs.¹⁴⁴

Nanogels as carriers for herbal drugs

Nanogels have been found to be suitable carriers that can transport and improve herbal drug properties as well. Owing to their flexibility and versatility these materials have many chances in herbal drug developments as drug carriers. The effectiveness of herbal medicine depends highly on the cooperation of all its active compounds. Sadly, herbal drugs have solubility challenges that lead to less bioavailability and high systemic clearance. Nanogel derivatives of herbal drugs help to overcome such limitations.^145,146 When Aloe-emodin-loaded chitin-based nanogels were tested against psoriasis they were found to be effective, however, were less effective when compared to the acitretin-loaded chi-tin-based nanogels. Nevertheless, the irritation study revealed that the aloe emodin-loaded gels did not produce any histopathological changes on skin such as erythema or wrinkles and showed better effectiveness against psoriasis when combined with the acitretin loaded gels.¹⁴⁷ Sabitha et al., formulated curcumin-loaded chitin nanogels and studied their activity against skin cancer through topical application. The nanogels showed selective toxicity towards the skin cancer cells and with no destruction of red blood cells and toxicity on normal cells which proved that curcumin uptake through the transdermal route might be the option for the future.¹⁴⁸ They also showed sustained release of the drug with enhanced permeation and less toxic effects when tested for Squamous Cell Carcinoma.¹⁴⁹ Mangalathillam et al. have investigated the use of curcumin-loaded chitin nanogels (CCNGs) in the treatment of skin cancer.¹⁴⁸ They showed that the cationic nature of the chitin polymer facilitated the interaction of the drug-loaded nanogels with skin lipids thus enhancing drug delivery via both the transcellular and intercellular pathways. They further demonstrated that the CCNGs were selectively toxic to melanoma cells and not toxic to normal cells.

Potential of nanogels in different diseases

For most skin related diseases, some of challenges faced by the drugs currently in use is water insolubility, low transdermal capacity, low drug bioavailability, skin permeability that can contribute to poor therapeutic efficacy.¹⁵⁰ In accelerating the pharmaceutical and medical development through technology, nanogels have shown an interesting potential in a vast spectrum of disease. For dermal therapy nanogels are studied against Bacterial, Fungal, Viral, and Parasitic Skin Infections. Topical application of nanogels in bacterial infection studies are underway. In a study where the in vivo experiments done by testing efficacy of the nanogels formulated from Hyaluronan tetrabutylammonium, it was proven that these gels might be used to deliver antimicrobials against intracellular pathogens. However, they still need to be improved for better skin penetration.¹⁵¹ On the other study the nanogel at a concentration of 80 µg/mL reduced the viability of the tested parasitic infections to 0%.¹⁵² This is very promising. Nanogels are evaluated also on the treatment of non-healing chronic wounds such as chronic diabetic ulcers. A lot has been done in the attempt of improving the healing process of these wounds, the literature offers a broad spectrum of different models of treatments studied to better the experience of patients with these chronic wounds.^153,154 There has been tremendous growth in the interest of developing three-dimensional bioengineered substitute’s microfibers, and nanofibers with desired functions loaded onto gels.¹⁵⁵ When the activity of peptide-based nanogels was studied in the treatment of wounds the nanogels showed an ability to promote the proliferation of fibroblast cells without any wound inflammation.¹⁵⁶ In 2009, Choi and Yoo prepared wound-adhesive and thermo-responsive hydrogels loaded with recombinant human epidermal growth factor (rhEGF) and these showed release rates that were dependent on degradation rates of the hydrogels.¹⁵⁷ Covalent crosslinked alginate gels are currently playing a role in wound dressing as they have an ability to absorb the wound excaudate in both gel and freeze-dried form and provide a physiologically moist environment while prohibiting the bacterial infection growth.¹⁵⁸ Polymers such as Chitosan¹⁵⁹ and alginate¹⁶⁰ have proven to be vital when it comes to wound dressing as individuals and as a combination.¹⁶¹ Alginate and Chitosan composite after clinical tests is now commercially available for the treatment of chronic ulcers.¹⁶² Alginate-based wound dressings exist in the form of hydrogels, films, foams, nanofibers, membrane, and sponges; However, these materials have their disadvantages low adherence of alginate is one of the challenges.¹⁶³ Currently to develop alginate-based materials, the nanoparticle related mostly silver-loaded nanoparticles studies show the composite are potentially advantageous in wound healing process.¹⁶⁴ On transdermal studies done nanogels were studied for ocular diseases, see for an example the eye drops and ointments used for topical therapy for ocular diseases have bioactivity of 5%.¹⁶⁵ Nanogels from different polymers have been and continues to be studied for application in different ocular diseases.¹⁶⁶ Nanogels are also investigated for central nervous system, these gels containing therapeutic T lymphocytes for localized delivery to glioblastoma cells for brain tumor immunotherapy were developed using poly (ethylene glycol)-g-chitosan They showed greater efficacy in killing glioblastoma cells compared with the Matrigel control.¹⁶⁷ However, one of the challenges faced by the nanogels in central nervous system application is passing through the blood–brain barrier which means that the shape, size and structure of a nanogel will have a huge impact in the development of their central nervous system application.¹⁶⁸

Permeability of nanogels

Many penetration enhancers have been investigated e.g., Hydration, Sulphoxides, Azone and derivatives, pyrrolydones, urea and derivatives, disubstituted amino acetates, propylene glycol, surfactants, terpenes and terpenoids, fatty acids, esters, and cyclodextrins as represented in Figure 4. Moreover, the aim is to find potential substances that will have both drug penetration-promoting effects and a low or no skin irritating potential.¹⁶⁹ Fatty acids have shown to possess both the ability to enhance skin penetration and the ability to delay or minimize penetration. Even so this capability highly depends on the structure and the formulation.¹⁷⁰ The combination of 95% of propylene glycol with oleic acid was tested for the ability to hold the penetration instead the results showed a significant increase in skin penetration.¹⁷¹

Figure 4.

Investigated penetration enhancers.¹⁷⁶

Recently it has been discovered that the use of oil-rich transportation formulas for drugs hinder the penetration of the drug through the skin as they make it difficult for the drugs to diffuse well, resulting in low drug distribution in the skin. Mostly the active drugs are not soluble in water. Therefore, to increase their water solubility polymers have a role to play, this leads the research direction to the encapsulation of hydrophobic drugs into water soluble polymers. When the hydrophobic drug was encapsulated in poly (ethylene glycol)–poly (gamma-benzyl-l-glutamate) micelles the penetra-tion through the stratum corneum was significantly improved.¹⁷² Terconazole (Tr) is the first approved triazole for the treatment of vaginal candidiasis, even though it was the most active against candidiasis it's poor skin permeation and challenging physicochemical properties could not allow it to be utilized for the treatment of cutaneous candidiasis. However, in a study when the terconazole was incorporated in lecithin organogels the permeation barrier weakened therefore allowing the Tr through the skin.¹⁷³ Nanogels seem to be making it easy for drugs to penetrate through the SC as they enhance their ability to get deposited in the skin's epidermis and dermis layer.¹⁷⁴ However, not all polymers used in the formulation of nanogels have this ability. The release rate and penetration ability of the compound highly depend on the polymer composition that tailored the nanogel. There are many factors to be considered when choosing materials for the design of these compounds. For controllable permeation, a polymer should be an inert drug carrier with desirable stability. The molecular weight, physical and chemical functionality characteristics of the polymer must allow free distribution of the drug at a required rate. It should be biocompatible with skin and toxic less. It must be able to carry and deliver multi drugs.¹⁷⁵ The transdermal nanogel drug delivery systems are being formulated for the treatment of a variety of ailments like eczema, cardiovascular disorders, Parkinsonism, Alzheimer’s disease, depression, and skin cancer with the hope that they will be able to penetrate the skin barriers.²⁸

Conclusions

The known shortcomings of the most marketed topical administered drugs are that they are linked with different toxicities that lead to their side effects and the disadvantage of the abnormal or affected organ. Their lack of curative treatment and poor effectiveness in topical therapy is the main force behind the design of new, safe, and more effective drug carriers. The main aim of the research in the pharmaceutical drug carriers is the discovery of a safe method to get the drug where it is needed and with less damage on other parts of the body. The researchers have focused more on improving the efficacy of the existing drugs by designing safer carriers and changing the method of administration. Nanogels have been proven to be an outstanding option for dermal therapy. This is based on their size, safety, biodegradability, and biocompatibility. However, particle size, polymers used, the charge, the density all play a role in designing the nanogels that will be suitable for this application. The degradability, surface chemistry, and size of the particles play a major role in the penetration of the drug through the skin. A clear and well understanding on these factors will surely help the design of these polymer nano-carriers. Moreover, it has been noticed that the corporation of the existing drugs with these nanogels enhances the therapeutic profile, safety, and efficacy of the drugs. Therefore, for the future, polymer nano-carriers are promising and may also help in the drug discovery search that has been continuing forever. However, to fully assess the toxic effects of nanoparticles, further complementary tests are needed to be carried out in addition to MTT method.

Footnotes

Acknowledgments

The authors would like to extend their gratitude to the South African National Research Funding, University of the Western Cape, UNESCO-University of South Africa and iThemba labs (NRF).

Author contributions

Nandipha L. Botha wrote the review Paul Moshonga and Martin Onani read and corrected the paper.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the University of the Western Cape and National Research Foundation (NRF).

ORCID iD

Nandipha L Botha

References

Wichterle

Lím

. Hydrophilic gels for biological use. Nature 1960; 185: 117–118.

Guan

Chen

, et al. Fabrication of biopolymer hydrogel containing ag nanoparticles for antibacterial property. Ind Eng Chem Res 2015; 54: 7393–7400.

Biondi

Borzacchiello

Mayol

, et al. Nanoparticle-integrated hydrogels as multifunctional composite materials for biomedical applications. Gels 2015; 1: 162–178.

Jung

Ray

Siegwart

. The development of nanogels for drug delivery applications. Prog Polym Sci 2008; 33(4): 447–448.

Davis

Azadi

. New progress and prospects: the application of nanogels in drug delivery. Mater Sci Eng C 2016; 60: 560–568.

Hamidi

Rafiei

. Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev 2008; 60: 1638–1649.

Urakami

Hentschel

Seetho

, et al. Surfactant-free synthesis of biodegradable, biocompatible, and stimuli-responsive cationic nanogel particles. Biomacromolecules 2013; 14: 3682–3688.

Rahman

FAL

Magbool

Elnim

, et al. Nanogel as a pharmaceutical carrier–review article. Scholars J Appl Med Sci 2017; 5(11F): 4730–4736.

Neamtu

Rusu

Diaconu

, et al. Basic concepts and recent advances in nanogels as carriers for medical applications. Drug Deliv 2017; 24(1): 539–557.

10.

Basso

Miranda

Nunes

, et al. Hydrogel-based drug delivery nanosystems for the treatment of brain tumors. Gels 2018; 4(62): 1–28.

11.

Soni

Desale

Bronich

TKB

. Nanogels: an overview of properties, biomedical applications and obstacles to clinical translation. J Contr Release 2016; 240(240): 109–126.

12.

Saloni

Kumar

Saumya

, et al. An overview of nanogel–novel drug delivery system. Asian J Pharmaceut Res Dev 2019; 7(2): 47–55.

13.

Cuenot

Radji

Alem

, et al. Control of swelling of responsive nanogels by nanoconfinement. Small 2012; 8(19): 2978–2985.

14.

Farag

Mohamed

. Synthesis and characterization of carboxymethyl chitosan nanogels for swelling studies and antimicrobial activity. Molecules 2013; 18: 190–203.

15.

Eckmann

Composto

Tsourkas

, et al. Nanogel carrier design for targeted drug delivery. J Mater Chem B 2014; 2(46): 8085–8097.

16.

Quan

Zhang

Cheng

, et al. Biodegradable polymeric architectures via reversible deactivation radical polymerizations. Polymers 2018; 10(7): 758.

17.

Yuan

Song

, et al. Biocompatible and functionalizable polyphosphate nanogel with a branched structure. J Mater Chem 2012; 22(18): 9322–9329.

18.

Azadi

. Chitosan-based hydrogel nanoparticle amazing behaviors during transmission electron microscopy. Int J Biol Macromol 2016; 84: 31–34.

19.

Cho

Jammalamadaka

UJK

Tappa

Nanogels for pharmaceutical and biomedical applications and their fabrication using 3D printing technologies. Materials 2018; 11: 1-15.

20.

Zarekar

Lingayat

Pande

. Nanogel as a novel platform for smart drug delivery system. J Nanosci Nanotechnol 2017; 4(1): 25–31.

21.

Singh

Upadhyay

Kumar

. Nanocrystal for dermatological application: a comprehensive review. Curr Nanosci 2022; 18(1): 48–60.

22.

Priya

Mohan Raj

Vasanthakumar

, et al. Curcumin-loaded layer-by-layer folic acid and casein coated carboxyme-thyl cellulose/casein nanogels for treatment of skin cancer. Arab J Chem 2017; 13(1). DOI: 10.1016/j.arabjc.2017.07.010

. Nanocarrier-based topical drug delivery for the treatment of skin diseases. Expet Opin Drug Deliv 2012; 9(7): 783–804.

24.

Shen

Zhong

, et al. Nanoparticle-loaded gels for topical delivery of nitrofurazone: effect of particle size on skin permeation and retention. J Drug Deliv Sci Technol 2018; 45: 367–372.

, et al. Nanostructured hyaluronic acid-based hydrogels encapsulating synthetic/natural hybrid nanogels as promising wound dressings. Biochem Eng J 2022; 179: 108341.

, et al. Self-assembled nanogel of pluronic-conjugated heparin as a versatile drug nanocarrier. Macromol Res 2011; 19(2): 180–188.

. Nanogels as novel drug delivery systems-a review. A review. J Pharm Pharm Res 2017; 1: 5.

, et al. Nanogels: a new dawn in antimicrobial chemotherapy. Antimicrobial Nanoarchitectonics 2017: pp. 101–137, Elsevier.

, et al. “Nanogels as drug carriers-introduction, chemical aspects, release mechanisms and potential applications”. Int J Pharm 2020; 581: 119268.

, et al. Nanogel–a future drug delivery tool. Int J Pharmaceut Sci Rev Res, 2020 60(2),: 27-32.

31.

Qiao

Zhang

, et al. Multi-responsive nanogels containing motifs of ortho ester, oligo (ethylene glycol) and disulfide linkage as carriers of hydrophobic anti-cancer drugs. J Contr Release 2011; 152(1): 57–66.

, et al. Micro- and nanogels with labile crosslinks-from synthesis to biomedical applications. Chem Soc Rev 2015; 44: 1948–1973.

. Nanogels as novel drug delivery systems-a review. Journal of Pharmacy and Pharmaceutical Research 2017; 1(1): 1–8.

. Stimulus responsive nanogels for drug delivery. Soft Matter 2011; 7(13): 5908–5916.

, et al. Stimulus-responsive polymeric nanogels as smart drug delivery systems. Acta Biomater 2019; 92: 1–18.

36.

Vicario-de-la-Torre

Forcada

. The potential of stimuli-responsive nanogels in drug and active molecule delivery for targeted therapy. Gels 2017; 3(16): 1–37.

. Preparation of stimuli-responsive nanogels based on poly (N,N-diethylaminoethyl methacrylate) by a simple “surfactant-free” methodology. Soft Mater 2018; 16(1): 37–50.

, et al. Facile approach to prepare pH and redox-responsive nanogels via Diels-Alder click reaction. Express Polym Lett 2018; 12(8): 688–698.

39.

Han

Chester

, et al. Micro 3D printing of a temperature-responsive hydrogel using projection micro-stereolithography. Sci Rep, 2018, 8: 1-10.

, et al. The characteristics of the smart polymeras temperature or ph-responsive hydrogel. Procedia Chem 2016; 19: 406–409.

41.

Klouda

Mikos

. Thermoresponsive hydrogels in biomedical applications. Eur J Pharm Biopharm 2008; 68(1): 34–45.

. Hydrogels: from controlled release to pH-responsive drug delivery. DDT. 2002, 7,: 569-579.

. Synthesis, characterization, and intracellular delivery of reducible heparin nanogels for apoptotic cell death. Biomaterials 2008; 29(23): 3376–3383.

44.

Yao

, et al. Lysozyme−dextran core−shell nanogels prepared via a green process. Langmuir 2008; 24(7): 3486–3492.

45.

Luo

Morin

, et al. UCST-type thermosensitive hairy nanogels synthesized by raft polymerization-induced self-assembly. ACS Macro Lett 2017; 6(2): 127–133.

, et al. Effect of the cross-linking density on the thermoresponsive behavior of hollow PNIPAM microgels. Langmuir 2015; 31(3): 1142–1149.

47.

Liu

. Layer-by-layer polyelectrolyte complex coated poly (methacrylic acid) nanogels as a drug delivery system for controlled release: structural effects. RSC Adv 2014; 4(99): 56323–56331.

48.

Rajan

Matsumura

, Tunable dual-thermoresponsive core-shell nanogels exhibiting UCST and LCST behavior. Macromol Rapid Commun 2017, 38(1): 1700478.

49.

Yang

Zhang

, et al. Facile synthesis of hairy microparticle-/nanoparticle-supported MacMillan and its application to Diels-Alder reaction in water. Colloid Polym Sci 2017; 295(4): 573–582.

, et al. Surface-initiated ring-opening polymerization: a versatile method for nanoparticle ordering. Macromolecules 2002; 35: 8400–8404.

, et al. Temperature-responsive nanogel multilayers of poly (N-vinylcaprolactam) for topical drug delivery. J Colloid Interface Sci 2017; 506: 589–602.

. Amphoteric surface hydrogels derived from hydrogen-bonded multilayers: reversible loading of dyes and macromolecules. Langmuir 2007; 23: 175–181.

. Nanogel functionalization: a versatile approach to meet the challenges of drug and gene delivery. ACS Appl Nano Mater 2018; 1: 6525–6541.

, et al. Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of CD44-positive and drug-resistant tumors. Bioconjugate Chem 2013; 24: 658–668.

. Natural biodegradable polymers as matrices in transdermal drug delivery. Int J Drug Dev Res 2011; 3(2): 85–103.

56.

Yin

Yuan

, et al. Nanogel: a versatile nano-delivery system for biomedical applications. Pharmaceutics 2020; 12: 290.

, et al. Thermoresponsive nanogels based on different polymeric moieties for biomedical applications. Gels 2020; 6: 20.

. Polymeric nanogels as vaccine delivery systems. Nanomed Nanotechnol Biol Med 2013; 9: 159–173.

. Application of nanogel systems in the administration of local anesthetics. Local Reg Anesth 2010; 3: 93–100.

, et al. Chitosan as a natural copolymer with unique properties for the development of hydrogels. Appl Sci 2019 9: 1-11.

61.

Kabanov

Vinogradov

. Nanogels as pharmaceutical carriers: finite networks of infinite capabilities. Angew Chem Int Ed 2009; 48(30): 5418–5429.

, et al. Polymer nanogels: a versatile nanoscopic drug delivery platform. Adv Drug Deliv Rev 2012; 64(9): 836–851.

. Core-shell nanogels by RAFT crosslinking polymerization: Synthesis and characterization. J Polym Sci Polym Chem 2012; 50: 4277–4287.

, et al. Microfabricated particulate drug-delivery systems. Biotechnol J 2011; 6: 1477–1487.

65.

Yoon

, et al. Chapter 7: ATRP: a versatile tool toward uniformly cross-linked hydrogels with controlled architecture and multifunctionality. In: Andrew Lyon

(ed).Michael Joseph Ser-pe, Hydrogel Micro and Nanoparticles. 2012; 22: 169–86.

, et al. Nanogel-an advanced drug delivery tool: current and future. Artif Cell Nanomed Biotechnol 2016; 44(1): 165–177.

67.

Jia

Shan

. Synthesis and characterization of Schiff base contained dextran microgels in water-in-oil inverse microemulsion. Carbohydr Polym 2016; 152: 156–162.

. Nanogels for pharmaceutical and biomedical applications and their fabrication using 3D printing technologies. Materials 2018; 11(302): 1–15.

, et al. Stimuli-responsive nanogel composites and their application in nanomedicine. Chem Soc Rev 2015; 44(17): 6161–6186.

, et al. Nanogel-quantum dot hybrid nanoparticles for live cell imaging. Biochem Biophys Res Commun 2005; 331(4): 917–921.

, et al. Multifunctional hybrid nanogel for integration of optical glucose sensing and self-regulated insulin release at physiological pH. ACS Nano 2010; 4(8): 4831–4839.

, et al. One-pot synthesis of responsive catalytic Au@PVP hybrid nanogels. Chem Commun 2012; 48(96): 11751–11753.

, et al. Novel bioactive scaffolds incorporating nanogels as potential drug eluting devices. J Nanosci Nanotechnol 2010; 10(4): 2826–2832.

, et al. Hollow core−porous shell structure poly(acrylic acid) nanogels with a superhigh capacity of drug loading. ACS Appl Mater Interfaces 2010; 2(12): 3532–3538.

75.

Rahdar

Sayyadi

, et al. Nano-gels: a versatile nanocarrier platform for drug delivery systems: A re-view. Nano Res J 2019; 4(1): 1–9.

76.

Kashaw

Iyer

. Biodegradable topical nanogels in the treatment of skin and superficial tumors. Global Journal of Na-nomedicine 2017; 1(2): 0038–0040.

, et al. Polymers for drug delivery systems. Annu Rev Chem Biomol Eng 2010; 1: 149–173.

, et al. Polymers in drug delivery technology, types of polymers and applications. Scholars Acad J Pharm 2016; 5(7): 305–308.

. Polymers in pharmaceutical drug delivery system: a review. Int J Pharmaceut Sci Rev Res 2012; 14(2): 57–66.

, et al. Biopolymer and synthetic polymer-based nanocomposites in wound dressing applications: a review, Polymers 2021; 13: 1962.

, et al. Recent advances in degradable hybrids of biomolecules and NGs for targeted delivery. Molecules 2019; 24: 1–32.

. Utilization of biodegradable polymeric materials as delivery agents in dermatology. Clin Cosmet Invest Dermatol 2014; 7, 23-34.

, et al. A Comparative review of natural and synthetic biopolymer composite scaffolds. Polymers 2021; 13: 1105.

, et al. Formulation and evaluation of transdermal nanogel for delivery of artemether. Drug Delivery and Transl Research 2021; 11: 1655–1674.

85.

Allen

. Transdermals: the skin as part of a drug delivery system. Int J Pharm Compound 2011; 15(4): 15–308.

, et al. In-silico model of skin penetration based on experimentally determined input parameters. Part I: experimental determination of partition and diffusion coefficients. Eur J Pharm Biopharm 2008; 68: 352–367.

87.

Liu

Zhao

, et al. Functional nano-systems for transdermal drug delivery and skin therapy. Nanoscale Adv 2023; 5: 1527–1558.

Nanocarriers for skin applications: where do we stand?

Angew Chem Int Ed 2022; 61: e202107960.

89.

Zhao

Castranova

. Toxicology of nanomaterials used in nanomedicine. J Toxicol Environ Health B Crit Rev 2011; 14: 593–632.

90.

Clichici

Filip

. In vivo assessment of nanomaterials toxicity. Nanomaterials-Toxicity and Risk Assessment. Intech 2015; 15: 93–121.

, et al. Anti-cancer vaccination by transdermal delivery of antigen peptide-loaded nanogels via iontophoresis. Int J Pharm 2015; 483: 110–114.

. Silver sulfadiazine based cubosome hydrogels for topical treatment of burns: Development and in vitro/in vivo characterization. Eur J Pharm Biopharm 2014; 86: 178–189.

, et al. Chitosan hydrogels containing nanoencapsulated phenytoin for cutaneous use: Skin permeation/penetration and efficacy in wound healing. Mater Sci Eng C 2019; 96: 205–217.

, et al. Development, physico-chemical characterization and in-vitro studies of hydrogels containing rosmarinic acid-loaded nanoemulsion for topical application. J Pharm Pharmacol 2019; 71: 1199–1208.

. Hydrogel based scaffolding polymeric biomaterials: Approaches towards skin tissue regeneration. J Drug Deliv Sci Technol 2020; 55: 101456.

, et al. Microwave-assisted physically cross-linked chitosan-sodium alginate hydrogel membrane doped with curcumin as a novel wound healing platform. AAPS PharmSciTech 2022; 23: 72.

, et al. Self-double-emulsifying drug delivery system incorporated in natural hydrogels: a new way for topical application of vitamin C. J Microencapsul 2018; 35(1): 90–101.

98.

Zhu

Wang

, et al. Hyaluronic acid and polyethylene glycol hybrid hydrogel encapsulating nanogel with hemostasis and sustainable antibacterial property for wound healing. ACS Appl Mater Interfaces 2018; 10(16): 13304–13316.

, et al. Nanogel encapsulated hydrogels as advanced wound dressings for the controlled delivery of antibiotics. Adv Funct Mater 2021; 31(7): 2006453.

. Synthesis, characterization and antimicrobial activity of chitosan/polyvinyl alcohol blend doped with hibiscus Sabdariffa L. extract. J Mol Struct 2019; 1197: 603–609.

, et al. Fabrication of Chitosan/PVA/GO/CuO patch for potential wound healing application. Int J Biol Macromol 2020; 143: 744–762.

102.

Sultana

Manirujjaman Imran-Ul-Haque

, et al. An overview of nanogel drug delivery system. J Appl Pharmaceut Sci 2013; 3(8 Suppl 1): S95–S105.

. Nanogels for regenerative medicine. J Contr Release 2019; 313: 148–160.

104.

Mooney

. Designing hydrogels for controlled drug delivery. Nat Rev Mater 2016; 1: 16071, DOI: 10.1038/natrevmats.2016.71

, et al. Doxorubicin encapsulation and diffusional release from stable, polymeric, hydrogel nanoparticles. Eur J Pharmaceut Sci 2006; 29: 120–129.

, et al. ICAM-1 targeted nanogels loaded with dexamethasone alleviate pulmonary inflammation. PLoS One 2014; 9(7): e102329. DOI: 10.1371/journal.pone.0102329

107.

Qiu

Park

. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev 2001; 53(3): 321–339.

108.

Zhou

Chu

. Synthesis and volume phase transition of poly(methacrylic acid-co-N-isopropylacrylamide) microgel particles in water. J Phys Chem B 1998; 102(8): 1364–1371.

109.

Huang

Chen

, et al. Thermo-sensitive hydrogels for delivering biotherapeutic molecules: a review. Saudi Pharmaceut J 2019; 27: 990–999.

110.

Connal

Forbes

, et al. A review of temperature-responsive polymers as novel reagents for solid-liquid separation and froth flotation of minerals. Miner Eng 2018; 123: 144–159.

, et al. Responsive polymers in controlled drug delivery. Prog Polym Sci 2008; 33: 1088–1118.

, et al. Stimulus-sensitive hydrogels and their applications in chemical (micro) analysis. Analyst 2003; 128: 325–331.

113.

Kotas

Medzhitov

. Homeostasis, inflammation, and disease susceptibility. Cell 2015; 160: 816–827.

. Thermosensitive sol-gel reversible hydrogels. Adv Drug Deliv Rev 2002; 54: 37–51.

, et al. Multifunctional injectable pluronic-cystamine-alginate-based hydrogel as a novel cellular delivery system towards tissue regeneration. Int J Biol Macromol 2021; 185: 592–603. DOI: 10.1016/j.ijbiomac.2021.06.1.

116.

Wang

Yan

, et al. Thermosensitive hydrogel based on poly(2-ethyl-2-oxazoline)-poly(D,L-Lactide)-Poly(2-Ethyl-2-Oxazoline) for sustained salmon calcitonin deliery. AAPS PharmSciTech 2020; 21: 71, DOI: 10.1208/s12249-020-1619-1

, et al. Drug release characteristics of physically cross‐linked thermosensitive poly (N‐vinylcaprolactam) hydrogel particles. J Pharmaceut Sci 2008; 97(11): 4783–4793.

118.

Wei

, et al. A novel thermo-responsive hydrogel based on salecan and poly (N-isopropylacrylamide): synthesis and characterization. Colloids Surf B Biointerfaces 2015; 125: 1–11.

119.

Wang

Liu

, et al. Effect of urea on phase transition of poly(N-isopropylacrylamide) and Poly(N,N-diethylacrylamide) hydrogels: a clue for urea-induced denaturation. Macromolecules 2016; 49(1): 234–243.

, et al. Synthesis, characteriza-tion and drug loading of multiresponsive p[NIPAm-co-PEGMA] (core)/p[NIPAm-co-AAc] (Shell) Nanogels with Monodis-perse Size Distributions. Polymers 2018; 10: 1–14.

. Skin disease among preschool children. J Bacteriol Res 2009; 1(2): 25–29.

, et al. Models in the research process of psoriasis. Int J Mol Sci 2017; 18: 2514.

. Pattern of skin diseases and prescribing practice in dermatology in public and faith based hospitals in three regions of Tanzania. J Pharmaceut Sci Res 2017; 9(1): 55–62.

. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 2009; 16: 3041–3053.

. Nanogel particulates located within diffusion cell receptor phases following topical application demonstrates uptake into and migration across skin. Int J Pharm 2010; 401: 72–78.

, et al. Crossing biological barriers with nanogels to improve drug delivery performance. J Contr Release 2019; 307: 221–246.

, et al. Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes. Nanotoxicology 2017; 11(2): 267–277.

, et al. Polymeric nanoparticles-based topical delivery systems for the treatment of dermatological diseases. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 2013; 5: 205–218.

, et al. Temperature-enhanced follicular penetration of thermoresponsive nanogels. Zeitschrift für Physikalische Chemie 2018; 232(5–6): 805–817.

130.

Yapar

İnal

. Nanomaterials and cosmetics. J Fac Pharm Istanbul 2012; 42(1): 43–70.

, et al. Correlation between the chemical composition of thermoresponsive nanogels and their interaction with the skin barrier. J Contr Release 2016; 243: 323–332. DOI: 10.1016/j.jconrel.2016.10.022

, et al. Skin permeating nanogel for the cutaneous co-delivery of two anti-inflammatory drugs. Biomaterials 2012; 33(5): 1607–1617.

133.

Lee

. A review of acitretin for the treatment of psoriasis. Expet Opin Drug Saf 2009; 8(6): 769–779.

. Topical nano drug delivery for treatment of psoriasis: progressive and novel delivery. Asian J Pharm 2018; 12(3): S835–S848.

, et al. A novel nanogel formulation of methotrexate for topical treatment of psoriasis: Optimization, in vitro and in vivo evaluation. Pharmaceut Dev Technol 2015; 29: 1–9.

, et al. Niosomal methotrexate gel in the treatment of localized psoriasis: Phase I and phase II studies. Indian J Dermatol, Venereol Leprol 2007, 73: 157-161.

, et al. Conventional Gel 0.025% in patients with acne vulgaris: a randomized, active controlled, multicentre, parallel group, phase IV clinical trial. J Clin Diagn Res 2015; 9(1): WC04–WC09.

Progress in psoriasis therapy via novel drug delivery systems. Dermatol Rep 2014; 6: 16–18.

, et al. A Research article on nanogel as topical promising drug delivery for Diclofenac sodium. Indian Journal of Pharmaceutical Education and Research 2017; 51(4S): S580–S587.

. Ex vivo skin permeation and retention studies on chitosan-ibuprofen-gellan ternary nanogel prepared by in situ ionic gelation technique-a tool for controlled transdermal delivery of ibuprofen. Int J Pharm 2015; 490: 112–130.

, et al. Controlled drug delivery vehicles for cancer treatment and their perfor-mance. Signal Transduct Targeted Ther 2018; 3(7): 1–19.

142.

Zhao

Wan

, et al. Cisplatin-directed coordination-crosslinking nanogels with thermo/ph-sensitive triblock polymers: improvement on chemotherapic efficacy via sustained release and drug retention. Nanoscale 2017; 00: 1–3.

, et al. Treatment of glioma by cisplatin-loaded nanogels conjugated with monoclonal antibodies against Cx43 and BSAT1. Drug Deliv 2015; 22(3): 276–285.

, et al. Recent progress in nanotechnology-based novel drug delivery systems in designing of cisplatin for cancer therapy: an overview. Artif Cell Nanomed Biotechnol 2019; 47(1): 1674–1692.

145.

Baskar

, et al. Historic review on modern herbal nanogel formulation and delivery methods. Int J Pharm Pharmaceut Sci 2018; 10(10): 1–10.

146.

Sonawane

Katti

. Natural polymers: carriers for transdermal drug delivery system. IJRPC 2016; 6(3): 534–542.

, et al. Acitretin and aloe-emodin loaded chitin nanogel for the treatment of psoriasis. Eur J Pharm Biopharm 2016; 107: 97–109.

, et al. Curcumin loaded chitin nanogels for skin cancer treatment via the transdermal route. Nanoscale 2012; 4: 239–250.

, et al. Design and development of curcumin nanogel for squamous cell carcinoma. J Pharmaceut Sci Res 2019; 11(4): 1638–1645.

150.

Teng

Tang

, et al. Medical applications of hydrogels in skin infections: a review. Infect Drug Resist 2023; 16: 391–401.

, et al. Biodistribution and intracellular localization of hyaluronan and its nanogels. A strategy to target intracellular S. aureus in persistent skin infections. J Contr Release 2020; 326: 1–12.

, et al. A nanoemulsion-based nanogel of Citrus limon essential oil with leishmanicidal activity against Leishmania tropica and Leishmania major. J Parasit Dis 2021; 45: 441–448.

, et al. Development and use of biomaterials as wound healing therapies. Trauma 2019; 7(2): 1–9.

, et al. The discovery and development of topical medicines for wound healing. Expet Opin Drug Discov 2019; 14(5): 485–497.

, et al. An injectable self-healing coordinative hydrogel with antibacterial and angiogenic properties for diabetic skin wound re-pair. NPG Asia Mater 2019; 11(3): 1–12.

, et al. Evaluation of peptide nanogels for accelerated wound healing in normal micropigs. Front Nanosci Nanotech 2018; 4(4): 1–9.

, et al. Skin and skin disease throughout life. Atlas of dermatology In: Atlas of Dermatology, Dermatopathology and Venereology: Cutaneous Anatomy, Biology and Inherited Disorders and General Dermatologic Concepts 2021 (pp. 405–428). Cham: Springer International Publishing.

, et al. Alginate-based hydrogels as drug delivery vehicles in cancer treatment and their applications in wound dressing and 3D bioprinting. J Biol Eng 2020; 14: 8.

, et al. Design and evaluation of mesenchymal stem cells seeded chitosan/glycosaminoglycans quaternary hydrogel scaffolds for wound healing applications. Int J Pharm 2019; 570: 118632.

, et al. A rapid-curing alginate gel system: utility in periosteum-derived cartilage tissue engineering. Biomaterials 2004; 25: 887–894.

, et al. Improvement of dermal burn healing by combining sodium alginate/chitosan-based films and low level laser therapy. J Photochem Photobiol B Biol 2011; 105: 51–59.

162.

Willi

Chandra

. Chitosan and alginate wound dressings: a short review. Trends Biomater Artif Organs 2004; 18(1): 18–23.

163.

Blessing Atim Aderibigbe Aderibigbe

Buyana

. Alginate in wound dressings. Pharmaceutics 2018; 10(2): 42.

, et al. Alginate-based materials loaded with nanoparticles in wound healing. Pharmaceutics 2023; 15(4): 1142.

165.

Zhu

Wang

. A novel thermo-sensitive hydrogel-based on poly (N-Isopropylacrylamide)/hyaluronic acid of ketoconazole for ophthalmic delivery. Artif Cell Nanomed Biotechnol 2018; 46: 1282–1287.

166.

Tao

Xie

, et al. Advances in nanogels for topical drug delivery in ocular diseases. Gels 2023; 9: 292, DOI: 10.3390/gels9040292

, et al. Thermoreversible poly (ethylene glycol)-g-Chitosan Hydrogel as a Therapeutic T Lymphocyte Depot for Localized Glioblastoma Immunotherapy. Biomacromolecules 2014; 15: 2656–2662.

, et al. Nanogels as potential drug nanocarriers for CNS drug delivery. Drug Discov Today 2018; 23(7): 1436–1443.

, et al. Design principles of chemical penetration enhancers for transdermal drug delivery. Proc Natl Acad Sci USA 2005; 102(13): 4688–4693.

. Fettsäuren und Epidermis. Hautarzt 1997; 48: 303–310.

, et al. Evaluation of drug penetration into human skin ex vivo using branched fatty acids and propylene glycol. Int J Pharm 1996; 145: 187–196.

, et al. Improvement of the skin penetration of hydrophobic drugs by polymeric micelles. Int J Pharm 2018; 553: 132–140.

, et al. Novel lecithin-integrated liquid crystalline nanogels for enhanced cutaneous targeting of terconazole: development, in vitro and in vivo studies. Int J Nanomed 2016; 11: 5531–5547.

, et al. Polymeric nanogels as versatile nanoplatforms for biomedical applications. J Nanomater 2019; 2019: 1–16.

175.

Gaikwad

. Transdermal drug delivery system: formulation aspects and evaluation Comprehensive. J Pharmaceut Sci 2013; 1: 1–10.

. Overcoming the stratum corneum: the modulation of skin penetration. Skin Pharmacol Physiol 2006; 19: 106–121.

Review on nanogels and their applications on dermal therapy

Abstract

Keywords

Introduction

Classification of nanogels

Synthesis of nanogels

Polymers in nanogel formulation for topical treatment

Nanogel drug release mechanisms

Diffusion

PH-responsive mechanism

Thermosensitive mechanism

Nanogel degradation mechanism

Nanogels as drug carriers in the treatment of skin diseases

Nanogels as carriers for known active drugs

Nanogels as carriers for herbal drugs

Potential of nanogels in different diseases

Permeability of nanogels

Conclusions

Footnotes

Acknowledgments

Author contributions

Declaration of conflicting interests

Funding

ORCID iD

References