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

项目摘要 用于治疗严重动脉粥样硬化的血管介入术通常由于动脉粥样硬化的发展而失败。 继发于新生内膜增生的再狭窄。在美国，唯一被批准用于 旨在减少人再狭窄的是药物洗脱支架和球囊。然而，这些药物洗脱 已经证明这些装置在再内皮化、血栓形成和死亡方面存在问题， 导致FDA在2019年发布警告。因此，非常需要新技术， 在血管重建后恢复健康的脉管系统。该提案的总体目标是发展 一种新型的、靶向的、释放药物的纳米颗粒， 特别是损伤部位，以防止新生内膜增生。基布博士和斯图普教授的实验室 通过美国国立卫生研究院生物工程研究伙伴关系R 01的资助， 开发了一种高度创新的靶向纳米粒子，由肽两亲物（PA）分子组成， 自组装成三维纳米纤维，并被共价修饰以包括胶原结合蛋白， 肽（CBP），靶向胶原蛋白。一氧化氮（NO）作为治疗剂 因为它具有促进血管健康和抑制新生内膜增生的许多血管保护特性。我们 实验室证明，这种释放NO的靶向药物是生物相容的，特别是靶向 尾静脉注射后血管损伤的部位，并在2时抑制新生内膜增生的发展 在健康大鼠中，这种效果可持续7个月。随着这些研究的成功， 我们需要时间将这项研究推进到最终临床转化所需的下一阶段。在人类中， 在动脉粥样硬化及其相关氧化应激的情况下进行干预。因此，我们旨在 通过整合额外的技术， 对动脉粥样硬化环境敏感的靶向部分和治疗剂。我们假设我们的 多模式纳米血管将靶向血管损伤，并预防介入部位的再狭窄， 动脉粥样硬化环境。为了研究这一假设，我们提出了以下具体目标：1） 动脉粥样硬化大鼠动脉损伤部位特异性靶向药物的研制与评价 2）研究多模式治疗靶向药物的安全性、有效性和生物分布 在动脉粥样硬化大鼠模型中抑制动脉损伤后新生内膜增生的平台;和3） 评价多模式靶向血管内支架平台预防新生内膜的安全性和有效性 动脉球囊损伤临床前动脉粥样硬化猪模型中的增生和再狭窄。完成 这些目标将导致开发多模式靶向治疗药物平台， 预防动脉粥样硬化环境中血管介入后的再狭窄。此外，完成 这些研究将使我们能够与FDA开始IND前会议，开始首次人体试验。

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.