Development of a multi-modal targeted nanotherapeutic to prevent restenosis in an atherosclerotic environment

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PROJECT SUMMARY Vascular interventions used to treat severe atherosclerosis often fail due to the development of arterial restenosis secondary to neointimal hyperplasia. In the United States, the only therapies approved for use in humans aimed at reducing restenosis are drug-eluting stents and balloons. However, these drug-eluting devices have proven to be problematic with respect to re-endothelialization, thrombosis, and death, and have led to the release of FDA warnings in 2019. Thus, there is a great need for new technology that will promote restoration of a healthy vasculature following revascularization. The overall goal of this proposal is to develop a novel, targeted, drug-releasing nanotherapeutic that will be administered intravenously yet localize specifically to the site of injury to prevent neointimal hyperplasia. Dr. Kibbe and Professor Stupp’s laboratories, through funding from a National Institutes of Health Bioengineering Research Partnership R01, have developed a highly innovative targeted nanotherapeutic comprised of peptide amphiphile (PA) molecules that self-assemble into three-dimensional nanofibers and are covalently modified to include a collagen-binding peptide (CBP) that targets the nanofiber to collagen. Nitric oxide (NO) was incorporated as the therapeutic given its many vasoprotective properties that promote vascular health and inhibit neointimal hyperplasia. Our laboratories demonstrated that this NO-releasing targeted nanofiber is biocompatible, specifically targets the site of vascular injury following tail vein injection and inhibits the development of neointimal hyperplasia at 2 weeks—an effect that remains durable out to 7 months in healthy rats. With the success of these studies, it is time to advance this research to the next stage required for ultimate clinical translation. In humans, vascular interventions are performed in the setting of atherosclerosis with its associated oxidative stress. Thus, we aim to advance the technology platform beyond what we have already developed by incorporating additional targeting moieties and therapeutics that are sensitive to the atherosclerotic milieu. We hypothesize that our multi-modal nanotherapeutic will target vascular injury and prevent restenosis at the site of intervention in an atherosclerotic environment. To investigate this hypothesis, we propose the following specific aims: 1) Develop and evaluate a targeted nanofiber with specificity for the site of arterial injury in atherosclerotic rat models; 2) Investigate the safety, efficacy and biodistribution of a multi-modal therapeutic targeted nanofiber platform at inhibiting neointimal hyperplasia following arterial injury in atherosclerotic rat models; and 3) Evaluate the safety and efficacy of the multi-modal targeted nanofiber platform at preventing neointimal hyperplasia and restenosis in a preclinical atherosclerotic swine model of arterial balloon injury. Completion of these aims will result in the development of a multi-modal targeted therapeutic nanofiber platform that will prevent restenosis following vascular interventions in an atherosclerotic environment. Further, completion of these studies will position us to start pre-IND meetings with the FDA to begin first-in-human testing.