
Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Chemistry
Supervisor
Gillies, Elizabeth R.
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.
Summary for Lay Audience
Drug delivery technologies can be very beneficial for improving treatment results. They make medications more effective, minimize side effects, and help patients stick to their iv treatment plans. Osteoarthritis (OA) is a condition that causes the joints to break down over time, affecting all the parts of the joint. This can lead to pain and difficulty moving. There are currently no medications available that can slow down or stop the progression of the disease. Direct injection of drugs into the joint is promising for targeting specific joint tissues and reducing side effects. However, challenges persist because drugs can be cleared from the joint quickly. Cancer is a condition marked by the uncontrolled growth of abnormal cells, leading to millions of deaths each year. Delivery vehicles are being studied designed to help deliver anti-cancer drugs directly to the tumor while sparing healthy tissues. By targeting the treatment more precisely, these vehicles can make the therapy more effective and reduce unwanted side effects. Hydrogels are three-dimensional materials that don't dissolve in water but can absorb a significant amount of it. Injectable hydrogels are special materials that stay in liquid form during storage and take on a gel-like form upon injection into human body, making them useful for delivering medicines directly to specific areas, like joints or tumors. Previous studies have shown that injectable hydrogels can be effective for delivering treatments directly into joints and for cancer therapy. This thesis documents the preparation of a new injectable, thermo-responsive hydrogel for the delivery of a the potential diseasemodifying drug GSK3787 into the joint. The effectiveness of the GSK3787-loaded hydrogel for treating osteoarthritis was tested in a rat model that simulates the condition. This hydrogel system was then adapted to explore the encapsulation and release of anti-cancer drugs. Finally, an endeavor was made to develop nanoparticles with responsiveness to various stimuli. These tiny particles can degrade upon light irradiation or in a mildly acidic environment, ideally facilitating the delivery of biomacromolecules such as proteins for the treatment of osteoarthritis, cancer, or other diseases. Overall, this thesis presents new ideas that can help improve drug delivery systems in the future.
Recommended Citation
Mei, Xueli, "Synthetic Degradable Polymer Systems for Drug Delivery" (2024). Electronic Thesis and Dissertation Repository. 10611.
https://ir.lib.uwo.ca/etd/10611
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