Covalent Cross-Linking as a Strategy to Prepare Water-Dispersible Chitosan Nanogels

Due to the environmental problems generated by petroleum derivative polymers as mentioned in Agenda 2030, the use of natural polymers is increasing. Among them, cellulose and chitin are the most widespread biopolymers available in nature. Chitosan, obtained from chitin, is a really good candidate to develop nanocarriers due to its polyelectrolyte nature and ease of chemical modification. However, chitosan presents a solubility drawback in an aqueous medium at physiological pH (pH = 7.4), which restricts its applicability in biomedicine. In this work, nanogels were successfully synthesized from chitosan systems with different water solubilities (chitosan, oligosaccharide chitosan, and quaternized chitosan) using the reverse microemulsion method and polyethylene glycol diacid (PEGBCOOH) as a covalent cross-linking agent. Cross-linking with PEGBCOOH was analyzed by proton nuclear magnetic resonance (¹H-NMR), which allowed for nanogels to be prepared whose size and swelling were comparatively studied by transmission electron microscopy (TEM) and dynamic light scattering (DLS) and zeta potential, respectively. The particle size of the swollen nanogels showed a different pH-responsive behavior that decreased for chitosan, increased for oligosaccharide chitosan, and remained constant for quaternized chitosan. Nevertheless, a drastic reduction was observed in all cases in the culture medium. Along the same line, the dispersibility of the synthesized nanogels in different media was comparatively evaluated, showing similar values for the nanogels prepared from soluble chitosans than for water insoluble chitosan as a consequence of the cross-linking with PEGBCOOH. After 6 months of storage of the dried nanogels, the water dispersibility values remained constant in all cases, demonstrating the stabilizing effect of the employed cross-linking agent and the potential use of synthesized nanogels as substrates for drug delivery.