PEGylation and folate conjugation effects on the stability of chitosan-tripolyphosphate nanoparticles

Int J Biol Macromol. 2020 Apr 21:158:1055-1062. doi: 10.1016/j.ijbiomac.2020.04.118. Online ahead of print.


Chitosan-based nanoparticles (Ch-NPs) prepared via ionotropic gelation of Ch with sodium tripolyphosphate (TPP) have been widely examined as potential drug carriers. Yet, recent studies have shown these particles to be unstable in model (pH 7.2-7.4) physiological media. To this end, here we explored the possibility of improving TPP-crosslinked Ch-NP stability through chemical Ch modification. Specifically, Ch samples with either 76% or 92% degrees of deacetylation (DD) were grafted with either polyethylene glycol (PEG), a hydrophilic molecule, or folic acid (F), a hydrophobic molecule. Limited variation in dispersion light scattering intensity, particle size and apparent ζ-potential, and lack of macroscopic precipitation were chosen as analytical evidence of dispersion stability. TPP titrations were performed to determine the optimal TPP:glucosamine molar ratio for preparing particles with near 200-nm diameters, which are desirable for systemic administration of drugs, cellular uptake, and enhancing NP blood circulation. Both DD and Ch modification influenced the particle formation process and the evolution in NP size and ζ-potential upon 30-day storage in virtually salt-free water at 25 °C and 37 °C, where the NPs underwent partial aggregation (along with possible dissolution and swelling) but remained colloidally dispersed. Under model physiological (pH 7.2; 163 mM ionic strength) conditions, however (where the chitosan amine groups were largely deprotonated), the particles quickly became destabilized, evidently due to particle dissolution followed by Ch precipitation. Overall, within the degrees of substitution used for this work (~1% for PEG, and 3 and 6% for F), neither PEG nor F qualitatively improved Ch-NP stability at physiological pH 7.2 conditions. Thus, application of TPP-crosslinked Ch-NPs in drug delivery (even when Ch is derivatized with PEG or F) should likely be limited to administration routes with acidic pH (at which these NPs remain stable).

Keywords: Chitosan; Folic acid; Nanoparticles; PEG; Stability; Tripolyphosphate.