Synthetic Degradable Polymer Systems for Drug Delivery
Abstract
Drug delivery technologies can play a crucial role in enhancing treatment outcomes by improving therapeutic efficacy, reducing toxicity, and increasing patient compliance. Osteoarthritis (OA) is a degenerative disease that affects all joint tissues, leading to pain and loss of mobility, with no current disease-modifying drugs available to slow or halt its progression. Intra-articular (IA) delivery has the potential to target joint tissues and minimize the side effects of new therapeutics; however, challenges remain due to the rapid clearance of drugs from the joint. Chapter 2 describes the study of a thermo-responsive injectable hydrogel for the controlled release of GSK3787, a potential disease-modifying therapeutic for OA. The hydrogel was prepared from methacrylate-capped poly(caprolactone-co-lactide)- poly(ethylene glycol)-poly(caprolactone-co-lactide) (M-PCLA-PEG-PCLA-M). The physical properties and drug release rates of the GSK3787-loaded hydrogel were studied. In addition, the in vivo treatment efficacy of the GSK3787-loaded hydrogel was evaluated in a surgical OA murine model. This chapter offers new perspectives on the injectable, thermo-responsive hydrogel as an IA drug delivery vehicle, as well as GSK3787 as a potential therapeutic. Cancer is a condition characterized by the unregulated proliferation of aberrant cells and is responsible for millions of fatalities annually. As for OA, delivery vehicles have been gaining attention to enhance the efficacy of anti-cancer therapeutics and reduce their side effects. Chapter 3 outlines the adaptation of the M-PCLA-PEG-PCLA-M hydrogel system with investigation of new covalent cross-linking approaches to enable the encapsulation and release of all-trans retinoic acid (ATRA), a promising anti-cancer therapeutic. The effect of the cross-linking approach and ATRA loading on the physical properties of the hydrogels were evaluated, and the ATRA release profile as well as hydrogel cytotoxicity were evaluated in vitro. Finally, to enable the delivery of biomacromolecular therapeutics for OA, cancer, or other diseases, while also introducing responsiveness to stimuli, Chapter 4 describes the preparation and study of dual-responsive, self-immolative polyion complexes (PICs) nanoparticles. Depolymerization of the PICs using two complementary stimuli was demonstrated and the cytotoxicity of the PICs was investigated, followed by preliminary investigations of protein loading. Overall, this thesis introduces new insights and methods that can facilitate the future advancement of drug delivery vehicles.