What is Nanogels and Its Applications?

Nanogels (NGs), namely nanoscale hydrogel particles, are three-dimensional network systems formed by physical or chemical cross-linking of polymers. Nanogels have received widespread attention in recent years due to their unique properties and potential applications in various fields such as drug delivery, tissue engineering, and diagnostics.

Fig. 1. Smart nanogels for targeted delivery (Journal of Science: Advanced Materials and Devices. 2019, 4(2): 201-212).

Classification of Nanogels

According to the phase change triggering mechanism of nanogels, nanogels can be divided into ordinary nanogels and environment-responsive nanogels. Ordinary nanogels will swell when absorbing water, and their drug administration and subsequent release behavior will be single. Environmentally responsive nanogels will swell or dissolve when exposed to different environments, and their administration and subsequent release behavior will be more intelligent. Common environmental factors include temperature, pH and light.

Temperature-sensitive Nanogels

Temperature-sensitive nanogels contain hydrophobic and hydrophilic groups, and their gelling behavior is related to the interaction between different groups and water. For example, when the ambient temperature of negative temperature-sensitive nanogels is lower than the critical solution temperature, hydrogen bonds are formed between water and hydrophilic groups, and the nanogels are in a swollen state. When the temperature is higher than the critical solution temperature, the hydrophobic interaction between hydrophobic groups dominates, and the three-dimensional structure of the nanogel is destroyed and dissolution occurs. Researchers have prepared emperature-sensitive nanogels based on poly(N-isopropylacrylamide-co-acrylic acid), poly(vinyl caprolactam), and Pluronic. These nanogels can release drugs at specific temperatures to achieve precise treatment.

pH-sensitive Nanogels

pH-sensitive nanogels contain anionic or cationic groups in their three-dimensional grid that can be protonated or deprotonated. Anionic groups include carboxylic acid or sulfonic acid groups, and cationic groups generally have terminal amino groups. When the pH of the environment changes, the proportion of different ionic states of these groups will change, which in turn leads to changes in hydrophilicity and ultimately changes in the three-dimensional network structure of the gel. The pH of healthy tissue (pH 7.4), stomach (pH 1.0-3.0), and tumor tissue (pH 6.5-7.0) are all different, so the nanogel's response to different pH can allow the contained drugs to be released at specific sites.

Light-sensitive Nanogels

The three-dimensional structure of light-sensitive nanogels generally contains photosensitive groups. Common photosensitive groups include argon benzene, spiropyran, o-nitrobenzyl, phenyl methyl ester and coumaryl ester. When light-sensitive nanogels are stimulated by light, the internal photosensitive groups will be isomerized or photodegraded, and the gel structure and morphology will also change, thereby releasing the contained drugs and obtaining the desired therapeutic effect.

Fig. 2. Preparation and drug delivery of DOX-loaded pullulan nanogels (Int J Biol Macrom. 2019, 139: 277-289).

There are also light-sensitive nanogels that contain metal particles. Some metal nanoparticles (such as gold nanoparticles) have photothermal conversion capabilities, so nanogels prepared by coupling some temperature-sensitive polymers and gold nanoparticles are also photoresponsive, that is, the metal nanoparticles first convert light into to heat, which then triggers a phase change in the temperature-sensitive gel. This kind of light-sensitive nanogel containing metal is sensitive to visible light or infrared light, while most of the light-sensitive nanogel containing photosensitive groups is sensitive to ultraviolet light, and the former is safer.

Nanogel Support Services from BOC Sciences

BOC Sciences can custom synthesize nanogels with specific properties and functionality to meet the specific requirements of a project. We also offer a variety of analytical services, including characterization of nanogels using techniques such as NMR, mass spectrometry, and chromatography.

How to Make Nanogel?

The carrier materials used to prepare nanogels mainly include acrylics, acrylamides, polysaccharides and pluronics. In addition, cationic polyethyleneimine, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone and polylactic acid are also used to prepare nanogels. Nanogels are formed by physical or chemical cross-linking of carrier materials. Physical cross-linking occurs through non-covalent bonds, while chemical cross-linking occurs through covalent bonds. The cross-linking methods are different, and the preparation methods of nanogels are also different.

Fig. 3. Different preparation methods of nanogels (Journal of Science: Advanced Materials and Devices. 2019, 4(2): 201-212).

Physical Cross-linking for Nanogels

Nanogels based on physical cross-linking can be prepared by self-assembly of polymers in aqueous solutions. After the polymer is mixed in an aqueous solution, it will be cross-linked through hydrogen bonds, van der Waals forces, hydrophobic forces and electrostatic interactions to form nanogels. A variety of natural polymers can be physically cross-linked to form nanogels. For example, cholesterol-modified pullulan can be physically cross-linked through hydrophobic forces to form monodisperse nanogels. Nisin and chondroitin sulfate, two biological macromolecules with opposite charges, can also be cross-linked through electrostatic interaction to form nanogels. This preparation method is easy to operate, and because the non-covalent interaction is relatively weak, when external conditions change, the nanogel will be destroyed and the drug will be easily released from the nanogel.

Chemical Cross-linking for Nanogels

The most commonly used method for chemical cross-linking is free radical polymerization technology, including conventional dispersion polymerization, precipitation polymerization and emulsion polymerization. The main process of conventional free radical polymerization is to dissolve free radical initiators, monomers and stabilizers in homogeneous or heterogeneous systems, and the polymerization of monomers is initiated by free radical initiators to form a three-dimensional network structure of nanogels. For example, in the presence of N-isopropyl acrylamide (NIPAM) monomer, vinylpyrrolidone (VP), maleic anhydride-modified polyethylene glycol and surfactant sodium dodecyl sulfate, NIPAM-based nanogels were prepared by dispersion polymerization, and by changing the ratio of NIPAM, VP and PEG-maleic anhydride, the particle size can be changed between 9-230 nm.

In addition, controlled/living radical polymerization (CRP) technologies such as atom transfer radical polymerization (ATRP), reversible addition fragmentation chain transfer (RAFT) polymerization and stable free radical polymerization (SFRP) is used to synthesize nanogels with precise size, specific composition and functionalization.

Other chemical cross-linking methods for nanogels include: copper-catalyzed click chemistry reactions of azides and alkynes, Michael addition of thiols and α,β-unsaturated carboxyl groups (such as acrylates and maleimides), Schiff base reaction between aldehyde and amine or acyl ester, thiol-disulfide exchange reaction, amide group cross-linking between amine and carboxylic acid or activated ester, and enzyme-catalyzed cross-linking of thiol. For example, protein nanogels have been cross-linked through a one-step Schiff reaction between the amino group of urokinase and PEGylated benzaldehyde. This nanogel is sensitive to pH and is expected to be used for intracellular delivery of proteins. In addition, X-rays, ultraviolet rays, y-rays, accelerated ions or electron beams can be used to irradiate the polymer to achieve cross-linking of the polymer. In short, nanogels prepared through chemical cross-linking methods are stronger and more stable, but monomers and surfactants may be introduced during the preparation process, which may cause safety issues. Therefore, it is necessary to explore safer green synthesis technologies to prepare nanogels.

PEG and Lipid Derivatives for Nanogels

What is the Difference Between Gel and Nanogel?

Nanogels have the advantages of both hydrogels and nanoparticles. These characteristics make nanogels have broad application prospects as drug delivery carriers:

• It can swell in water and has certain adhesion.
• The drug can be encapsulated in its internal three-dimensional network structure to prevent the drug from being damaged by the external environment.
• High drug loading and sustained release.
• The smaller the particle size, the higher the permeability.
• There is a huge specific surface area for modification.
• It has high biocompatibility and biodegradability.

What is Nanogel Used For?

Ocular Drug Administration

Topical administration is the most commonly used method for the treatment of eye diseases, but the physiological characteristics of the eye make the bioavailability of ophthalmic drugs relatively low. The physiological barrier of the eye, the rapid drainage of the nasolacrimal duct and the dilution effect of tear flow all limit the efficiency of conventional ophthalmic preparations. Moreover, the increase in the number of administrations of conventional preparations also reduces patient compliance. Nanogels have strong adhesion, which can reduce drug leakage and extend the corneal retention time of drugs. At the same time, the smaller particle size also makes nanogels have relatively high permeability. In order to overcome the shortcomings of conventional ophthalmic preparations, more and more researchers have used nanogels as carriers for ocular drug delivery.

Transdermal Administration

Transdermal drug delivery can be used for the treatment of local diseases as well as other systemic diseases. It has the advantages of convenient drug administration, avoiding the first-pass effect of the drug and reducing fluctuations in blood drug concentration. However, due to the structure and characteristics of the skin, the transdermal permeability of drugs is generally low, which limits the further application of transdermal drug delivery. Therefore, there is an urgent need to develop transdermal drug delivery preparations with high permeability. In recent years, more and more researchers have focused on nanogels. Studies have cross-linked temperature- and pH-sensitive poly(N-isopropylacrylamide) with 5% (W/v) acrylic acid (AAc) to obtain poly(NIPAM-CO-AAC) nanogels. And using caffeine as a model penetrant, the permeability of nanogels into porcine epidermis at 32°C was studied. The results showed that compared with caffeine-saturated solutions, caffeine-loaded nanogels penetrated the epidermis better and increased caffeine release.

Nasal Mucosal Administration

Nasal mucosal drug delivery takes advantage of the unique anatomical and physiological connection between the nasal cavity and the cranial cavity to allow drugs to bypass the blood-brain barrier and enter the brain, becoming a potential new method for the treatment of brain diseases. In addition, nasal mucosal administration also plays an important role in vaccine delivery. Nanogels can protect unstable drugs and vaccines from degradation, improve the solubility of insoluble drugs, and prolong the retention time of drugs and vaccines in the nasal mucosa. It can release drugs slowly and has become a commonly used drug carrier in nasal mucosa drug delivery. For example, insulin is covalently attached to poly(N-vinylpyrrolidone) nanogels and administered through the nasal mucosa to treat Alzheimer's disease. The results show that compared with free insulin, nanogel-loaded insulin has higher activity in the brain and can better activate protein kinase B (Akt) and thus have a therapeutic effect on Alzheimer's disease.

In Conclusion

The high water absorption, structural modification, high drug loading and good biocompatibility of nanogels make them excellent delivery carriers for various drugs including biomacromolecular drugs. The introduction of environmentally sensitive nanogels also makes the drug release behavior of nanogels more controllable, making drug delivery more precise. However, since the solvent needs to be removed during the preparation of nanogels, the preparation cost is high, and scale-up production is difficult. Therefore, more economical nanogel preparation methods still need to be explored. It is believed that with the development of pharmacy and related disciplines, nanogel related technologies will become more mature and related research will be further deepened, thereby developing more nanogel drugs. If you are interested in our nanogel support services, please contact us for more information.

References

1. Qureshi, M.A. et al. Different Types of Smart Nanogel for Targeted Delivery. Journal of Science: Advanced Materials and Devices. 2019, 4(2): 201-212.
2. Zheng, Y. et al. pH-sensitive and pluronic-modified pullulan nanogels for greatly improved antitumor in vivo. Int J Biol Macrom. 2019, 139: 277-289.