An Injectable Hydrophobic Delivery Formulation Based on Poly(Trimethylene Carbonate) for Therapeutic Angiogenesis

Abstract

The aim of this thesis was to determine the feasibility of an injectable delivery formulation based on low molecular weight poly(trimethylene carbonate) (PTMC) for localized delivery of vascular endothelial growth factor (VEGF). Formulations based on modified conjugated PTMC, ester or anhydride-linked PTMC, and poly(trimethylene carbonate-co-5-hydroxy trimethylene carbonate) (P(TMC-co-HTMC)), were synthesized. Polymers/copolymers were amorphous and injectable viscous liquids at 37 ºC. In vitro degradation study of the conjugated PTMCs showed that the anhydride bond cleaved within 24 hours, generating acidic products that lowered the pH of the buffered degradation medium. In contrast, hydrolysis of the ester bond did not result in an acidic pH; however, it degraded too slowly for the intended application. Preparing P(TMC-co-HTMC) using different catalysts revealed that HCl·Et2O is able to provide a random comonomer distribution and low toxicity burden. In vitro degradation of the resulting random copolymers was tailored by adjusting the initial HTMC content, initial molecular weight and the choice of initiator. During in vitro degradation, the pH of the medium surrounding the copolymer always remained near neutral. In vivo degradation study of P(TMC-co-HTMC)s at the molecular weight range of 1000-2000 Da with 30 mol% initial HTMC content revealed rapid degradation of the HTMC units followed by gradual elimination of the short chains produced via HTMC degradation. The inflammatory response to the injected copolymers subsided by time but was still ongoing after 22 weeks. The observed tissue response was comparable with the tissue response of a commercial MONOCRYL suture indicating that the copolymer can be considered biocompatible. In vitro protein release from the same copolymers was characterized by using lysozyme, bovine serum albumin and VEGF. This study revealed that the rate of protein release was controlled by the solubility of the lyophilized protein in the aqueous environment within the copolymer, the concentration of the salt included in the lyophilized powder, and the flexibility of the copolymer chains to form superhydrated regions. The released VEGF showed greater than 80% bioactivity throughout the release period. This delivery formulation can be used to deliver acid sensitive proteins for short or long-term delivery approaches depending on the protein physical properties.