Development and characterization of targeted poly(NIPAm) nanoparticles for delivery of anti-inflammatory peptides in peripheral artery disease and osteoarthritis

Inflammation is the underlying cause of several severe diseases including cardiovascular disease and osteoarthritis. Peripheral artery disease (PAD) is characterized by atherosclerotic occlusions within the peripheral vasculature. Current treatment for severe PAD involves mechanical widening of the artery via percutaneous transluminal angioplasty. Unfortunately, deployment of the balloon damages the endothelial layer, exposing the underlying collagenous matrix. Circulating platelets can bind to this collagen and become activated, releasing proinflammatory cytokines that promote proliferation of local smooth muscle cells. These proliferating cells eventually reocclude the vessel, resulting in restenosis and necessitating the need for a second procedure to reopen the vessel. Current treatments for moderate osteoarthritis include local injection of anti-inflammatory compounds such as glucocorticoids. Unfortunately, prolonged treatment carries with it significant side effects including osteoporosis, and cardiovascular complications. Our lab has developed an anti-inflammatory cell-penetrating peptide that inhibits mitogen-activated protein kinase activated protein kinase 2 (MK2). MK2 is implicated in the inflammatory cascade of atherosclerosis and osteoarthritis, making it a potentially effective strategy for reducing inflammation in both disease states. Unfortunately, these peptides are untargeted and quickly degraded in the presence of serum proteases, making the development of an effective delivery system of paramount importance. The overall goal of the research presented here is to detail the development of a poly(N-isopropylacrylamide) nanoparticle that is able to effectively load and release anti-inflammatory peptides for the treatment of these inflammatory diseases. In this dissertation, I will discuss the development of a collagen-binding nanoparticle that is able to inhibit platelet binding following angioplasty, thereby halting the initial inflammatory cascade. Additionally, these particles demonstrate the ability to reduce inflammation by through the loading and release of MK2-inhibiting cell-penetrating peptides. Additionally, I will cover the development of a hollow nanoparticle system that is designed to load increased quantities of these anti-inflammatory peptides for the treatment of osteoarthritis. This particle demonstrated increased macrophage uptake and prolonged drug release, resulting in a progressive inhibition of osteoarthritic inflammation over 8 days. The results presented here advance our understanding of these nanoparticle platforms, and suggest that they may serve at effective platforms for the treatment of restenosis following angioplasty, as well as osteoarthritis