| The aim of this dissertation is to understand peptide sorption to PLGA, with the goal of stabilizing octreotide against acylation within PLGA. These studies describe the first detailed investigations of peptide sorption to low Mw free-acid PLGA. A new class of inhibitors of the sorption and acylation of a model peptide, octreotide, has been described. Long-term sorption studies indicated that CaCl2 and MnCl2 disrupt peptide sorption to PLGA with the inorganic divalent cation inhibitors translates to inhibition of peptide acylation. The octreotide-PLGA interactions are mostly irreversible in aqueous solution and strongly increase solubility of octreotide in acetonitrile. Only the addition of solvent or 5% SDS resulted in a substantial desorption from PLGA, strongly suggesting the irreversibility is due to hydrophobic interactions or hydrogen-bonding between the peptide and PLGA.;The kinetics of peptide sorption to PLGA was studied, suggesting octreotide sorption is not diffusion-limited. A biexponential model described the sorption kinetics. Sorption is reduced at low octreotide concentrations, high ionic strength and low temperature, suggesting polymer mobility plays a critical role in the sorption interaction. Although irreversible, peptide sorption follows Langmuir behavior. Sorption of octreotide decreased as the pH of the solutions tested was decreased towards the pKa of PLGA carboxylates. Reducing the number of total acid end-groups by increasing the PLGA molecular weight also decreased octreotide sorption. These results indicate the critical role of ionized PLGA acid end-groups during the peptide sorption pathway. Quantification of the maximal amount of peptide sorbed at high solution concentration showed this value to be similar to the total number of PLGA acid end-groups for RG502H and RG503H. The low amount of sorption to the higher molecular-weight RG504H is also consistent with peptide partitioning into the polymer phase. Film sectioning after peptide sorption showed a proportional decrease in peptide remaining in the polymer with fraction of film removed. Hence, these results suggest both multilayer adsorption and absorption of peptide to free-acid PLGA. |
