Free Radical Polymerization

Most nanogels are prepared by free radical polymerization, which have the advantages of fast reaction speed, high molecular weight of the products, and the increasing of conversion rate with the extension of reaction time (Noordergraaf et al., 2018; Gao et al., 2020). The structures and properties can be adjusted by changing monomer, crosslinking agent, initiator, reaction medium, reaction time, and reaction temperature to achieve optimal drug delivery effect (Ahmed, 2015). Precipitation polymerization, (micro) emulsion polymerization, and dispersion polymerization are common polymerization techniques. Utilizing N-isopropylacrylamide as the monomer, acrylic dendritic polyglycerol as the crosslinking agent, sodium lauryl sulfate as the stabilizer, temperature-sensitive nanogels loading coumarin six were prepared by precipitation polymerization. The results showed that the drug release was thermo-dependent with a remarkable increase above the volume phase transition temperature of 32–37°C (Sahle et al., 2017). Sengel prepared a drug carrier with N-(2-mercaptoethyl)acrylamide as a monomer and ethylene glycol dimethacrylate as a cross-linker through dispersion polymerization (Sengel and Sahiner, 2019). Emulsion polymerization means monomers are dispersed in water with the help of emulsifiers and mechanical stirring, and micelles are formed above the critical micelle concentration, where polymer chains keep sustained growth. On this basis, micro (mini) emulsion polymerization and reverse (micro) emulsion polymerization have been developed (Lovell and Schork, 2020; Pereira et al., 2020). The pH-sensitive H40-based nanogels with new structures were synthesized through mini-emulsion polymerization and click reaction (Abandansari et al., 2014). Firstly, the synthesized reactants were added dropwise to the aqueous phase with sonication to obtain the milky macroemulsion. Then the formed macroemulsion was constantly ultrasonicated under ice cooling to form a stable milky miniemulsion. Subsequently, the miniemulsion was heated and catalysts were added to induce the azide-alkyne click reaction and the pure nanogels were collected through dialysis (Figure 1).

Schematic illustration of the mini-emulsion technique (Abandansari et al., 2014). Copyright (2014) Elsevier.

With the development of free radical polymerization and controlled drug delivery systems, controllable/living free radical polymerization has attracted much attention (Matyjaszewski and Xia, 2001; Kim et al., 2016; Lou et al., 2017). These prepared polymers have the characteristics of narrow molecular weight distribution and uniform particle size distribution, which facilitate the construction of homogeneous polymer networks and drug loading. ATRP relies on external catalysts (usually transition metal complexs) to reversibly deactivate the free radicals to a dormant state (Matyjaszewski and Xia, 2001). Most of the biodegradable, well-defined and water-dispersed nanogels prepared by ATRP technology occur in reversed micro (mini) emulsions (Siegwart et al., 2009; Averick et al., 2011). The disulfide crosslinked biodegradable nanogels were designed and synthesized employing inverse miniemulsion ATRP (Oh et al., 2007). The releases of encapsulated molecules such as the fluorescent dye rhodamine and the anticancer drug Dox were triggered by the biodegradation of nanogels, demonstrating that these nanogels can be developed as targeted drug delivery carriers for biomedical applications. Compared with ATRP, RAFT with simpler procedures usually uses chain transfer agent (thiocarbonyl compound) rather than poisonous catalysts (Xin et al., 2020). The poly (methyl methacrylate) hair nanoparticles with core-shell structures were prepared through RAFT method. The carriers had high passive drug loading capacity for DOX, exhibiting fast and adjustable drug release behavior at intracellular pH (Qu et al., 2017). It is noticeable that although there are lots of merits of controlled living free radical polymerization, these preparations are rarely studied in vivo, and there is little information about biodistribution, clearance and long-term tolerance.

At present, photo-initiated polymerization has become an effective preparation method due to the short reaction time, mild reaction conditions, and controllable time and space (Fu et al., 2015). Messager reported a synthetic method for hyaluronic acid-based nanogels with controllable structures (Messager et al., 2013). Under UV light irradiation, the methacryloyl hyaluronic acid precursor started crosslinking in the droplets of water-in-oil emulsion, which obtained nanoparticles with homogeneous sizes. However, UV radiation may cause potential cell damage, and UV light tends to be scattered by large monomer droplets. Therefore, visible light-induced photopolymerization has been developed because they have longer wavelengths, less scattered by larger objects and better penetration (Matsui et al., 2017; Le Quemener et al., 2018). For example, Bakó prepared nanogels using methacrylic acid poly-γ-glutamic nanoparticles loading antibiotic drug ampicillin by visible (blue) light-initiated photopolymerization, and the release kinetics showed the controlled and efficient release behaviors (Bakó et al., 2016). Notably, our lab has also developed some strategies on the preparation of nanogels through laser photopolymerization, which is related with the investigation of the initiating system, polymerization mechanism and biomedical applications (Li J. et al., 2021; Liu et al., 2021; Peng et al., 2021; Wang et al., 2021). Specifically, Wang chose biocompatible polyethylene glycol diacrylate (PEGDA) as a monomer and ultrasmall nanogels with around 30 nm in size were prepared successfully through surfactant-free photopolymerization at 532 nm. Subsequently, Li in our lab introduced the third component DPI into the EY/TEOA initiating system, which significantly increased the polymerization rate and conversion ratio, and multifunctional PEGDA hydrogels through a beam expansion device were investigated. Liu’s work concentrated on rapid preparation of nanogels through laser beam expansion under low monomer concentration. And the role of triethanolamine in the effect on the cross-linking degree of PEGDA nanogels was investigated by Peng, indicating that triethanolamine could adjust the double-bond conversion.