Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Chemistry
Supervisor
Gillies, Elizabeth R.
Abstract
Osteoarthritis (OA) is a progressive disease, leading to the breakdown of joint cartilage as well as changes to the synovium and bone. So far, there are no disease-modifying treatments that have been approved for the clinical treatment of OA. An increasing understanding of the molecular mechanisms of OA provides potential opportunities for treatment. However, better intra-articular (IA) delivery vehicles are needed to more effectively deliver therapeutics to their targets in the joint. This thesis provides new knowledge towards the development of drug delivery vehicles for OA. One challenge is that potential therapeutics may have difficulties to penetrate cartilage, which is highly dense, negatively charged, and avascular cartilage. Previous studies have thus far mostly focused on proteins and nanoparticles. Polymers are beginning to be explored, but the effects of molar mass and architecture have not yet been investigated. The first part of this thesis (Chapter 2) details the synthesis of a small library of polycations composed of N-(2-hydroxypropyl)methacrylamide (HPMA) and N-(3-aminopropyl)methacrylamide (APMA) with linear, 4-arm or 8-arm structures and varying degrees of polymerization. Uptake, retention, and cytotoxicity of the resulting polycations in ex vivo bovine articular cartilage were evaluated, revealing that the molar mass and architecture can be tuned to maximize uptake while minimizing cytotoxicity. The second part of the thesis (Chapters 3 and 4) takes advantage of stimuli-responsive polymers to prepare hydrogels which can potentially release therapeutics in response to disease-related stimuli. Using light as a model stimulus, two different hydrogel systems were developed and assessed for stimuli-responsive drug release. The first hydrogel was composed of self-immolative poly(ethyl glyoxylate) (PEtG) and 4-arm poly(ethylene glycol) (PEG) with a light-responsive end-cap linker enabling depolymerization of the hydrophobic PEtG blocks upon exposure to light. Celecoxib was loaded into the gels and released in a controlled manner. Another hydrogel was developed based on polyglyoxylamides (PGAms) conjugated to an amino acid, as a model peptide therapeutic, via a self-immolative linker. Irradiation led to cleavage of the linker and release of the model therapeutic from the hydrogel. Overall, this thesis presents new knowledge and approaches that can be applied for the further development of IA delivery vehicles.
Summary for Lay Audience
Osteoarthritis (OA) is the most common type of arthritis and can cause inflammation of the joint. It is also known as “wear and tear” arthritis. The cartilage in joints starts to break down and the bone shape changes over time. Currently, there are no therapeutics that can cure or reverse the progression of OA. Anti-inflammatory drugs only relieve pain. The final stage OA treatment is typically joint replacement surgery. However, new potential therapeutics are being investigated and may benefit from a local delivery approach. In particular, the delivery of drugs into the joint space may allow OA treatments to be administered at the site of action where they can be more effective and have fewer side effects. However, several studies have shown that direct delivery of free drugs to the joint does not work very well because drugs cannot stay in the joint for a long time. This thesis presents research aimed at addressing this challenge. One aspect is that it is difficult for drugs to penetrate cartilage since cartilage is dense and has no blood vessels. Scientists have found that positively charged species can help bring drugs into cartilage due to their interactions with negatively charged cartilage. The thesis documents the preparation of a series of positively charged molecules with different sizes and shapes. Studies were then performed to assess their penetration into cow cartilage as well as their toxicity to better understand how to design more effective systems for transporting drugs into cartilage. Another challenge is to better control the release of drugs in the joint so that release can occur more rapidly when the disease is most active. Hydrogels are water-insoluble, three-dimensional materials that can absorb a large amount of water. Stimuli-responsive hydrogels are a subset of hydrogels that have structural or mechanical changes when exposed to an external stimulus, such as temperature, pH or light. The thesis documents the development of two new stimuli-responsive hydrogels using light as a model stimulus. One hydrogel system undergoes degradation in response to light, activating a more rapid release of the loaded drug. Another system investigates the attachment of a drug by a specially designed linker that can be degraded and release the drug in response to light. Overall, it is anticipated that the new knowledge and designs can be applied and further adapted for the more effective delivery of OA therapeutics.
Recommended Citation
Gong, Jue, "Synthetic Polymers for Cartilage Uptake and Stimuli-Responsive Hydrogels" (2023). Electronic Thesis and Dissertation Repository. 9741.
https://ir.lib.uwo.ca/etd/9741