| dc.description.abstract | Oxidative stress, the pathological elevation of reactive oxygen species (ROS), participates in the propagation of many diseases, including osteoarthritis and optic neuropathies. Polymers incorporating ROS-scavenging groups can recapitulate the body’s innate antioxidant defenses to restore oxidative homeostasis and prevent biomolecule oxidation, inflammation, and cell death. Alone or in combination with targeted therapeutics, antioxidant polymers or biomaterials represent a promising avenue for disease treatment. In this work, we first demonstrate the advantages of optimizing a hydrophilic copolymer incorporating the potent ROS-scavenging drug TEMPO for anti-inflammatory activity. The ratio of TEMPO and an inert hydrophilic spacer was varied, and an optimal formulation was determined in vitro. The lead candidate demonstrated ROS scavenging and suppression of cytokine TNFa in a mouse air pouch model of inflammation. In a related project, we formulated antioxidant microparticles for protein and nucleic acid delivery. Candidate polymers were screened for crystallinity and formulation stability, and the optimized structure was first tested for delivery of the protein erythropoietin (EPO) in mouse models of traumatic optic neuropathy and glaucoma. The combined chemical and biological antioxidant activity of the EPO microparticles outperformed the clinical standard poly(lactic-co-glycolic acid) (PLGA) and reduced tissue damage, leading to improved visual function. MP formulations were then adjusted to load small interfering RNA (siRNA) for gene knockdown of pathological targets in a mouse model of osteoarthritis. Sustained release of siRNA in the joint from microparticles resulted in target gene knockdown superior to free siRNA, and knockdown of catabolic protease MMP13 resulted in improved morphology of joint tissues. Overall, this work demonstrates that ROS-scavenging polymers can be used for a variety of applications to improve drug pharmacokinetics and activity, resulting in overall disease mitigation. | |
