Search

Ionically crosslinked chitosan nanocarriers have attracted significant attention as potential drug delivery vehicles due to their biocompatibility, mucoadhesiveness, payload protection ability, and mild formation/payload encapsulation procedures. Despite these advantages, however, most studies on these materials have tuned their drug uptake and release properties by trial and error, and not infrequently reported conflicting results. This dissertation aimed to address some of these issues.To better understand drug uptake properties, we have shown that, besides increasing with the drug/particle binding affinity, protein drug association efficiency (i.e., the fraction of the added protein that was taken up) increased almost linearly with the particle yield (the fraction of the added chitosan that self-assembled into particles). This scaling was explained via a predictive equilibrium binding model and suggested that many of the (often conflicting) variations in protein uptake reported in the literature might stem from the largely ignored variability in particle yield. Because sustained drug release could be affected by particle dissolution stability, ionically crosslinked chitosan particle dissolution was also examined. This revealed hysteresis in the ionic crosslink formation/dissociation cycle (where particle dissolution occurred at lower ionic crosslinker concentrations than those required for particle formation). Also explored was whether drug/particle binding (where the drug molecules served as additional physical crosslinks between the chitosan chains) enhanced the dissolution stability of chitosan/tripolyphosphate (TPP) particles. This indicated that, while protein/chitosan binding was insufficiently strong to generate a stabilizing effect, chitosan/TPP particles could be stabilized against dissolution through the uptake of DNA. Further, it has long been ignored that the in vitro drug release profiles obtained for chitosan particles via the common “solvent replacement” method may have been subject to strong experimental artifacts and not have reflected their true release behavior. To this end, we have explored the relevant experimental artifacts and showed that conflicting findings on drug release from chitosan/TPP particles can result from: (1) incomplete particle separation from the solvent; (2) irreversible particle coagulation; and (3) failure to maintain sink conditions. By analyzing these artifacts, this study provides guidelines for obtaining more-reliable release profiles for both chitosan/TPP particles and other colloidal drug carriers.