Factors affecting the stability of chitosan/tripolyphosphate micro- and nanogels: resolving the opposing findings

Micro- and nanogels prepared by ionically crosslinking chitosan with tripolyphosphate (TPP) attract keen interest as potential drug carriers. To achieve their optimal performance, it is essential to control their stability to aggregation and dissolution. Yet, literature on this subject (especially at physiological ionic strength and pH) remains filled with opposing reports. Recently, one of us hypothesized that these conflicting findings might stem from: (1) variations in the chitosan molecular structure; (2) the dissimilar particle concentrations used by the various groups; and (3) occasional overreliance on dynamic light scattering (DLS) as the sole analytical tool. To explore this hypothesis, here we use isothermal titration calorimetry, light scattering and UV-vis spectroscopy to analyze the effects of chitosan degree of deacetylation (DD) and particle concentration on chitosan/TPP particle stability. Their dissolution stability increases with the chitosan DD (due to the stronger chitosan/TPP binding) and when the particles are used at higher concentrations, and evidently depends on the chitosan molecular weight. Conversely, their aggregation stability decreases with the DD, because the chitosan is more prone to TPP bridging and becomes more lyophobic at near-neutral (physiological) pH. We also show how using DLS-derived size distributions as the sole tool for characterizing particle stability can lead to erroneous conclusions. Comparison of these findings to literature experimental conditions reconciles many of the opposing reports and provides essential guidelines for tuning chitosan/TPP particle stability.