Drug Coated Balloon Peptide Delivery to Block Post-angioplasty Restenosis in PAD

About This Grant

PROJECT SUMMARY/ABSTRACT Peripheral arterial disease (PAD), characterized by blockage of lower limb arteries, causes patients to experience debilitating pain, and in the worst cases, leads to limb amputation. PAD is commonly treated by inflating an angioplasty balloon directed to the blocked arterial site using an intravascular catheter. Inflation of the balloon mechanically opens the site of the greatest blockage, improving blood flow, but injury to the vessel wall triggers a cellular stress response that ultimately causes restenosis, or re-narrowing of the vessel at the site of the intervention. Drug coated balloons (DCBs) can be used with angioplasty to transfer a drug coating from the balloon into the vessel wall at the site of inflation. The drug used in clinically-approved PAD DCBs is paclitaxel (PTX), a cytotoxic drug that causes cells attempting to proliferate to instead undergo cell death. Delivery of PTX in conjunction with angioplasty inhibits cell and tissue in-growth into the vessel lumen post-angioplasty, helping to reduce restenosis. However, PTX does not modulate the root cause of restenosis, and ultimately, even with usage of taxol DCBs, almost half of angioplasty sites lose patency within 1 year. PTX also, unfortunately, can hinder healing of the endothelial lining of the vessel lumen, increasing the potential for thrombosis and vascular dysfunction. The overall goal of the proposed work is to develop non-cytotoxic DCB therapies that can be delivered from an intravascular catheter to the vessel wall in conjunction with angioplasty to improve long-term vessel patency. The proposed therapies would be peptide-based and will block a “stress response” signaling pathway that initiates inflammatory signaling and activates smooth muscle cells in the vessel wall. The activated cells secrete extracellular matrix, migrate, and proliferate within the lumen of the artery, causing tissue in-growth that re-narrows the artery at the angioplasty site. Two different therapeutic peptides will be developed and tested in DCB formulations that have different mechanisms of action targeting the stress response pathway. The aims of the proposed project will be to: (1) Develop a DCB platform for intracellular peptide delivery to arterial sites in conjunction with angioplasty; (2) Benchmark peptide-based DCBs against PTX DCB in a clinically-relevant model. This high impact project will be tackled by an interdisciplinary team with expertise in vascular surgery and percutaneous vascular procedures (angioplasty, etc), polymeric drug delivery technologies, translationally- relevant animal models of cardiovascular pathologies. We are poised to establish a new therapeutic platform technology to be used in conjunction with angioplasty to reduce post-procedure restenosis in PAD, an unmet clinical need.