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

开发多模式靶向纳米治疗药物以预防动脉粥样硬化环境中的再狭窄

基本信息

批准号：
10364365
负责人：
Melina Rae Kibbe
金额：
$ 66.44万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-18 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364365
关键词：
3-Dimensional Antioxidants Apolipoprotein E Arterial Fatty Streak Arterial Injury Arteries Ascorbic Acid Atherosclerosis Balloon Angioplasty Binding Biodistribution Biomedical Engineering Blood Blood Vessels Cell Proliferation Cessation of life Clinical Collagen Development Devices Disease Dose Drug Kinetics Elements Endothelial Cells Endothelium Environment Exposure to Family suidae Funding Goals Health Human Hyperplasia Injections Injury Intervention Intravenous Investigational Therapies Laboratories Modeling Morbidity - disease rate Nitric Oxide Oxidative Stress Peptides Pharmaceutical Preparations Positioning Attribute Property Rattus Research Safety Secondary to Site Specificity Stents Tail Technology Testing Therapeutic Thinness Thrombosis Time United States United States National Institutes of Health Urine Veins Vision biomaterial compatibility clinical translation efficacy evaluation first-in-human improved injured innovation interest meetings mortality multimodality nanofiber nanotherapeutic new technology novel peptide amphiphiles porcine model pre-clinical prevent professor restenosis restoration success targeted treatment therapeutic target vascular injury

项目摘要

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.

项目概要用于治疗严重动脉粥样硬化的血管干预措施常常因动脉粥样硬化而失败。在美国，这是唯一批准用于治疗继发于新生内膜增生的再狭窄的疗法。人们旨在减少再狭窄的方法是药物洗脱支架和球囊，但是这些药物洗脱支架。已证明装置在再内皮化、血栓形成和死亡方面存在问题，并且导致 FDA 在 2019 年发布警告。因此，非常需要新技术来促进血运重建后恢复健康的脉管系统该提案的总体目标是发展。一种新颖的、靶向的、药物释放的纳米疗法，将通过静脉注射但局部给药 Kibbe 博士和 Stupp 教授的实验室专门针对损伤部位预防新生内膜增生。通过美国国立卫生研究院生物工程研究合作伙伴关系 R01 的资助，开发了一种高度创新的靶向纳米疗法，由肽两亲物 (PA) 分子组成，自组装成三维纳米纤维并进行共价修饰以包含胶原蛋白结合将纳米纤维靶向胶原蛋白的肽（CBP）被纳入作为治疗剂。鉴于其许多血管保护特性，可促进血管健康并抑制新内膜增生。实验室证明，这种释放 NO 的靶向纳米纤维具有生物相容性，特别针对尾静脉注射后血管损伤部位并抑制新内膜增生的发展在 2 数周——在健康大鼠中这种效应可持续持续 7 个月。随着这些研究的成功，这种效应是存在的。是时候将这项研究推进到人类血管最终临床转化所需的下一阶段了。干预措施是在动脉粥样硬化及其相关氧化应激的背景下进行的。因此，我们的目标是。通过整合额外的技术来推进技术平台超越我们已经开发的对动脉粥样硬化环境敏感的靶向部分和疗法。多模式纳米疗法将针对血管损伤并预防介入部位的再狭窄为了研究这一假设，我们提出以下具体目标：1) 开发并评估对动脉粥样硬化大鼠动脉损伤部位具有特异性的靶向纳米纤维模型；2) 研究多模式治疗靶向纳米纤维的安全性、有效性和生物分布抑制动脉粥样硬化大鼠模型动脉损伤后新生内膜增生的平台；3) 评估多模式靶向纳米纤维平台预防新生内膜的安全性和有效性动脉球囊损伤的临床前动脉粥样硬化猪模型中的增生和再狭窄。这些目标将导致多模式靶向治疗纳米纤维平台的开发，该平台将预防动脉粥样硬化环境中血管介入治疗后的再狭窄。这些研究将使我们能够与 FDA 开始 IND 前会议，开始首次人体测试。