Dual-action drug coated balloon to mitigate neointimal hyperplasia and promote endothelialization. - Project Summary The management of atherosclerotic vascular stenosis has undergone major advances over the past decades, yet challenges remain. Bare metal stents (BMS) were plagued by unacceptably high rates of in-stent restenosis (ISR). Although drug-eluting stents (DES) were developed primarily to reduce neointimal hyperplasia (NIH), rates of ISR remain at least 5-15%. Furthermore, the use of stents remains controversial in certain situations, including within vessels with small diameters, long lesions, bifurcations, repeated ISR, and in segments of peripheral artery disease (PAD). It is estimated that 8.5 million people in the U.S. alone have PAD, which can lead to further morbidities including life-style limiting claudication, amputation, and stroke. In certain locations in the legs, stents carry a significant risk of stent fracture: stent fracture rates can approach 37%, often resulting in restenosis or total vessel occlusion. The use of drug-coated balloons (DCB) has emerged as an attractive alternative to treat both PAD and ISR lesions without leaving behind a permanent stent. DCB are angioplasty balloons coated with an anti-proliferative drug to prevent restenosis, usually paclitaxel. However, recent studies have called the safety of paclitaxel-coated balloons into question; thus, alternative anti- restenosis strategies are needed. Furthermore, the drugs utilized on DCBs impair re-endothelialization, which can lead to late thrombosis, inflammation, restenosis, and neoatherosclerosis. Ideally, the DCB would prevent neointimal proliferation and restenosis while encouraging endothelial cell growth and restoration of vascular function. Endomimetics, LLC has developed a novel dual-action coating for DCB that could reduce NIH and restenosis and enhance re-endothelialization and vascular healing. The coating consists of a nitric oxide (NO) releasing bionanomatrix composed of biocompatible peptide-based material along with liposome-encapsulated sirolimus. The liposome encapsulated sirolimus and bionanomatrix can be effectively transferred to the vessel wall and provide sustained delivery to reduce NIH and restenosis. Additionally, the bionanomatrix provides sustained release of NO from the multi-layered bionanomatrix to stimulate endothelialization and reduce inflammation. This dual- action strategy could overcome the limitations of current therapies for PAD and ISR by reducing NIH and restenosis and enhancing re-endothelialization and vascular healing. In this Phase I SBIR, we propose to evaluate and optimize the dual-action DCB coating. This will include evaluation of coating stability, release kinetics, and assessment of drug transfer and retention in an in vitro hydrogel vessel mimicking system as well as an ex vivo porcine artery bioreactor model under physiological conditions. We will then evaluate the novel dual-action DCB in vivo in a rabbit model. Development of a DCB coating that can reduce NIH and restenosis and enhance re-endothelialization and vascular function may have significant impact for treatment of patients with PAD and ISR. With successful completion of Phase I, we plan to move forward in Phase II to larger animal studies and then to GLP evaluation.
