Synthetic Polymers for Cartilage Uptake and Stimuli-Responsive Hydrogels
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.