Synthesis of Nanogels: Current Trends and Future Outlook

Abstract

Nanogels represent an innovative platform for tunable drug release and targeted therapy in several biomedical applications, ranging from cancer to neurological disorders. The design of these nanocarriers is a pivotal topic investigated by the researchers over the years, with the aim to optimize the procedures and provide advanced nanomaterials. Chemical reactions, physical interactions and the developments of engineered devices are the three main areas explored to overcome the shortcomings of the traditional nanofabrication approaches. This review proposes a focus on the current techniques used in nanogel design, highlighting the upgrades in physico-chemical methodologies, microfluidics and 3D printing. Polymers and biomolecules can be combined to produce ad hoc nanonetworks according to the final curative aims, preserving the criteria of biocompatibility and biodegradability. Controlled polymerization, interfacial reactions, sol-gel transition, manipulation of the fluids at the nanoscale, lab-on-a-chip technology and 3D printing are the leading strategies to lean on in the next future and offer new solutions to the critical healthcare scenarios.

Keywords: 3D printing; chemical crosslinking; colloids; lab-on-a-chip; microfluidics; nanogels; physical crosslinking.

Figure 1

Summary of the chemical and physical crosslinking methods in nanogels (NG) design. (A) The formation of covalent bonds (crosslinking points, in red) between the reactive moieties (yellow and green) of polymers X and Y can be addressed through different chemical reactions exploiting the nature of the reacting groups. (B) The physical interactions between polymers W and Z enables the formation of a self-assembled nanoscaffold.

Figure 2

NG synthesis by inverse emulsification in the presence of Brij-L4 surfactant. (A) Protocol used in NG formation; (B) polymerization between hydroxylethylacrylamide and cystine diacrylamide giving rise to the nanonetwork. Reprinted with permission from Raghupathi et al. [22]. Copyright (2017) American Chemical Society.

Figure 3

Sonochemically induced reversible addition–fragmentation chain transfer polymerization (RAFT) polymerization to design thermosensitive NGs. (A) Synthesis of (PPEGA-b-PNIPAM) NGs; (B,C) Dynamic Light Scattering analysis (DLS) of the obtained NGs: the size (hydrodynamic diameter, D_h) of the nanonetwork differs in heating (45 °C) and cooling (25 °C) experiments, demonstrating the thermosensitive behavior. Adapted with permission from Piogè et al. [61]. Copyright (2018) American Chemical Society.

Figure 4

Click chemistry reactions involved in NG synthesis.

Figure 5

Self-assembling of hyaluronic acid (HA) NGs functionalized with cholesteryl groups. (A) Scheme of nanoscaffold design, protein loading and administration. (B) Protein-hosting capacity in the proposed NGs, using different payloads: rhGH (a), EPO (b), lysozyme (c) and exendin-4 (d). Adapted with permission from Nakai et al. [105]. Copyright (2012) WILEY-VCH Verlag GmbH and Co. KGaA.

Figure 6

Microfluidics-assisted NG production. (A) Polydimethylsiloxane (PDMS) replica molding; (B,C) microfabricated microfluidic platforms: schematic of a Y-shaped microfluidic mixer (B, left), cross-shaped planar flow focusing mixer (B, right) and droplet microfluidic platform (C).