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

• 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
• 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

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.

项目摘要 用于治疗严重动脉粥样硬化的血管干预措施通常由于动脉的发展而失败 再狭窄继发于新内膜增生。在美国，唯一批准用于使用的疗法 旨在减少再狭窄的人类是毒品洗脱支架和气球。但是，这些药物洗脱 事实证明，在重新内皮化，血栓形成和死亡方面已被证明是有问题的，并且已有 导致2019年发行了FDA警告。这非常需要新技术来促进 血运重建后健康脉管系统的恢复。该提议的总体目标是发展 一种新颖的，有针对性的药物释放纳米疗法，将被静脉注射但本地化 Kibbe博士和Stuppp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R01的资助， 开发了一种高度创新的针对性纳米治疗性完成的辣椒两亲物（PA）分子 自组装成三维纳米纤维，并经过共价修改以包括胶原蛋白结合 将纳米纤维靶向胶原蛋白的肽（CBP）。一氧化氮（NO）被纳入治疗 鉴于其许多促进血管健康并抑制新生素增生的血管保护特性。我们的 实验室表明，这种不释放的靶向纳米纤维具有生物相容性，特别是针对的。 尾静脉注射后血管损伤部位，并抑制2时新内膜增生的发展 几周 - 健康大鼠的效果仍然持久至7个月。随着这些研究的成功，这是 是时候将这项研究推向最终临床翻译所需的下一阶段了。在人类中，血管 干预措施是在动脉粥样硬化及其相关氧化应激的情况下进行的。那我们的目标 通过结合其他 靶向对动脉粥样硬化环境敏感的部分和治疗。我们假设我们的 在 动脉粥样硬化环境。为了研究这一假设，我们提出了以下特定目的：1） 开发和评估针对动脉粥样硬化大鼠动脉损伤部位特异性的靶向纳米纤维 模型； 2）研究针对纳米纤维的多模式疗法的安全性，效率和生物分布 在动脉粥样硬化大鼠模型中伪影损伤后抑制新内膜增生的平台； 3） 评估多模式靶向纳米纤维平台的安全性和效率 临床前动脉粥样硬化猪的动脉气囊损伤模型中的增生和再狭窄。完成 这些目标将导致开发多模式的针对性治疗纳米纤维平台，该平台将 在动脉粥样硬化环境中进行血管干预后，预防再狭窄。此外，完成 这些研究将使我们开始与FDA进行预先安排会议，以开始首次人类测试。