Nanomaterials have found extensive biomedical applications in the past few years because of their small size, low molecular weight, larger surface area, enhanced biological, and chemical reactivity. Among these nanomaterials, nanogels (NGs) are promising drug delivery systems and are composed of cross-linked polymeric nanoparticles ranging from 100 to 200 nm. NGs represent an innovative zone of research with speedy developments taking place on a daily basis. An incredible amount of focus is placed on the fabrication of NGs with novel polymers to achieve better control over the drug release. This review article covers a number of aspects of NGs including their types, associated pros and cons, and methods of preparation along with technical and economical superiority and therapeutic efficacy over each other. The last part of review summarizes the applications of NGs in the drug delivery and treatment of various diseases including brain disease, cardiovascular diseases, oxidative stress, diabetes, cancer therapy, tissue engineering, gene therapy, inflammatory disorders, pain management, ophthalmic and autoimmune diseases, and their future challenges. NGs appear to be an outstanding nominee for drug delivery systems, and further study is required to explore their interactions at the cellular and molecular levels.
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 [
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 [
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
Advanced biomedical applications 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 [
These are cross-linked, self-assembled particles with extensive applications in various fields of biomedicine [
Types of NG formulations.
These are cross-linked, stimulus-responsive NGs and are also known as multilayer NGs (Figure
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
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
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
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 [
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 [
One of the many advantages of hollow NGs is their improved drug loading, which could be attributed to their greater storage volume (Figure
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.
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 [
In this technique, hydrogen bonding and van der Waals forces result in an interaction between drug moiety and solvent [
In this technique, oil in water emulsion followed by removal of solvent is used to prepare large-sized NGs [
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. N2 is effervesced throughout the preparation procedure. The NGs are collected, washed many times with distilled water, and redispersed in distilled water for further use [
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 (
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 [
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 [
Similarly, NGs are reported to deliver olanzapine for the treatment of schizophrenia which is a brain disorder described by delusions and disordered behavior [
Cardiovascular diseases like myocardial infarction (MI) and heart failure are the main reason of human deaths globally [
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 [
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 [
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 [
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 [
Anticancer applications of NGs.
NG composition | Type of NG | Drug used | Method of preparation | Results and applications | References |
---|---|---|---|---|---|
PVA (polyvinyl alcohol) | Charge conversional and reduction-sensitive NG | Doxorubicin | Inverse nanoprecipitation | Better cell toxicity. |
[ |
Dextrin with formaldehyde as a cross-linker | pH-sensitive NG | Doxorubicin | Emulsion cross-linking method | Efficacious antitumor activity |
[ |
Poly(ethylene glycol)-b-poly(L-glutamic acid) (PEG-b-PGA) | Polypeptide-based NG | 17-AAG |
Cross-linking method | Improved anticancer activity |
[ |
P(N-isopropyl-acrylamide-co-butyl methacrylates) | Temperature-sensitive NG dispersion | Doxorubicin | Emulsion polymerization method | Improved efficacy for transarterial chemoembolization (TACE) of iohexol dispersion (IBi-D) was observed on rabbit VX2 liver tumors. | [ |
Poly (N-isopropylmethacrylamide) (PNiPMA), PDA-PEG, 4-methoxybenzoic acid (MBA) | pH, thermal, and redox potential triple-responsive expansile NG (TRN) | Pc 4 | Targeted delivery of pc 4 to sigma 2 receptors in head and neck tumors. | [ | |
Glycol chitosan (GC) conjugated with 2,3-dimethylmaleic acid (dma) and fullerene (C60) conjugate (GC-g-DMA-g-C60) | Acid pH-responsive NG | Photosensitizer drug | Two-step chemical grafting reaction | Beneficial to target endosomes and in vivo photodynamic therapy in different types of malignant tumors. | [ |
Dextrin with glyoxal as a cross-linker | pH-sensitive NG | Doxorubicin | Emulsion cross-linking method | Rapid release effective internalization of doxorubicin. |
[ |
Chitin poly (L-lactic acid) | pH-responsive composite NG | Doxorubicin | Blood compatibility of the system was confirmed by |
[ | |
Chitin | pH-sensitive NG | 5-Fluorouracil | Controlled regeneration chemistry method | Loosening of the epidermis after its interaction with negatively charged chitin with no inflammation. |
[ |
Folic acid conjugated poly(ethylene oxide)-b-poly(methacrylic acid) | Ligand-gated polyelectrolyte NG | Cisplatin | Cross-linking method | [ | |
Acetylated chondroitin sulfate (CS) | Self-organizing NG | Doxorubicin | Dialysis method | Drug was internalized into the cytoplasm through endocytosis. |
[ |
N-Isopropylacrylamide (NIPAM), poly(ethylene glycol) (PEG), poly(ethylene glycol) methyl ether methacrylate (mPEGMA) | pH-thermal dual-responsive NG | Cisplatin (CDDP) | Emulsion polymerization method | Extended circulation time. |
[ |
pH and temperature-responsive NG | Temozolomide | Polymerization method | High drug loading, better stability, and pH-dependent sustained release. |
[ |
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 [
Applications of NG tissue engineering and gene therapy.
NG composition | Type of NG | Drug/agent used | Method of preparation | Results and applications | References |
---|---|---|---|---|---|
CHOPA-PEGSH | Hybrid NG | W9 peptide | Cross-linking | Bone repair, sustained release | [ |
Pullulan-collagen; 1,2,7,8-diepoxyoctane | PHD hybrid NG | 1,2,7,8-Diepoxyoctane | Cross-linking | Tissue filler materials | [ |
Dendritic polyglycerol (dPG) and low-molecular-weight polyethylenimine | pH-sensitive NG | siRNA | Thiol-Michael nanoprecipitation method | In vitro gene silencing. |
[ |
Chitosan–myristic acid |
Cross-linked NG | Aryldialkylphosphatase | “Self-assembly via chemical modification” method | Enhanced pH and thermal stability |
[ |
Poly(N-isopropylacrylamide)-polyglycerol | Thermoresponsive NG | Biomacromolecules | Enhanced stability and release of protein |
[ | |
Poly(N-vinyl pyrrolidone) (PVP) | Functionalized NG | Oligonucleotides (ODN) | Cross-linking and polymerization | Negligible cytotoxicity |
[ |
Polyethyleneimine (PEI) | Microenvironment-responsive functional NG | Gene | Cross-linking and polymerization | Reduced cytotoxicity |
[ |
Poly(2-methacryloyloxyethyl phosphorylcholine), poly(methoxydiethylene glycol methacrylate) (poly(MeODEGM)) and poly(2-aminoethyl methacrylamide hydrochloride) (poly(AEMA)) | Thermosensitive NG | Protein | Reversible addition−fragmentation chain transfer [ |
Temperature-sensitive controlled release of proteins from biodegradable NG | [ |
Enzymatically synthesized glycogen (ESG) with cholesterol group | Artificial chaperon | Hydrophobic modification self-assembly method | Enhanced thermal stability of enzyme |
[ | |
Cholesteryl group-bearing pullulan (CHP) complexed with methyl-b-cyclodextrin (M-b-CD) | Artificial chaperon | Protein synthesis was not affected. |
[ |
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 [
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 [
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 [
NGs for the management of pain.
NG composition | Type of NG | Drug/agent used | Method of preparation | Results and applications | References |
---|---|---|---|---|---|
NIPAAM, MAA | Magnetic NG | Bupivacaine | Free radical emulsion polymerization method | Rapid release at low temperature and pH |
[ |
Pluronic F127, hyaluronic acid (HA) | Thermogel | Bupivacaine | Easy to inject |
[ | |
Chitosan | Thermogel | Rupivacaine | Controlled release |
[ | |
Poly(N-isopropylacrylamide) |
Temperature-sensitive NG | Bupivacaine | Polymerization | Less cytotoxic enhanced drug uptake | [ |
Alginate, chitosan | NG | Bupivacaine | Acceptable cytotoxicity and stability |
[ | |
Poly (e-caprolactone)–poly(ethylene glycol)–poly(e-caprolactone) (PCL–PEG–PCL) |
Thermoresponsive NG | Lidocaine | Emulsion solvent evaporation method | Prolonged anesthetic affect with lesser toxicity |
[ |
Methacrylic acid–ethyl acrylate cross-linked with diallyl phthalate | pH-sensitive NG | Bupivacaine | Emulsion polymerization | Enhanced pH-dependent anesthetic affect | [ |
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
NGs for ophthalmic delivery.
NG composition | Type of NG | Drug/agent used | Method of preparation | Results and applications | References |
---|---|---|---|---|---|
Nanodiamond, chitosan, poly(hydroxy ethyl methacrylate) matrix | Diamond NG | Timolol maleate | Lysozyme mediated sustained release |
[ | |
Polyvinylpyrrolidone and acrylic acid (AAc) | NG | Pilocarpine | Sustained drug release and improved bioavailability response | [ | |
PLGA, chitosan | Levofloxacin | Sustained drug release |
[ | ||
Chitin | NG | Fluconazole | Controlled regeneration chemistry method | Good penetration to the cornea |
[ |
Cyclodextrin | NG | Dexamethasone | Emulsion-solvent |
Controlled drug release by adhering to the ocular surface. |
[ |
PLA, sodium alginate | 5-Fluorouracil | Emulsion-solvent |
Controlled drug release |
[ | |
Tacrolimus | Sustained drug release profile |
[ |
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 [
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 nontarget 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.
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.
Nanogels
Active pharmaceutical ingredient
Polyethyleneimine
Polyethylene glycol
Cross-linked polyethylene glycol polyethyleneimine
Quantum dots
Pyridyl disulfide
Ultraviolet
Cholesterol-based pullulan
Hydroxypropyl methylcellulose
Amyloid
Myocardial infarction
Nuclear magnetic resonance
Reversible addition fragmentation chain transfer
Oligo polymer ethylene glycol
Polymethacrylic acid-co-N-vinyl-2-pyrrolidone
Poly lactic-co-glycolic acid
Tetra-phenyl-porphyrin-tetra-sulfonate
Tetra-phenyl-chlorin-tetra-carboxylate
Tripolyphosphate
Butyl acrylate
Cholesterol-bearing pullulan
Acryloyl group-modified cholesterol-bearing pullulan
Pentaerythritol tetra (mercaptoethyl) polyoxyethylene.
The authors declare that they have no conflicts of interest.
Fakhara Sabir and Imran Asad contributed equally to this work.