Development of unimolecular nanoparticle-mediated periadventitial drug delivery system for sustained and targeted inhibition of intimal hyperplasia following open vascular reconstruction

开发单分子纳米粒子介导的外膜周围药物递送系统，用于持续和靶向抑制开放血管重建后的内膜增生

基本信息

批准号：
10305283
负责人：
Lianwang Guo
金额：
$ 16.83万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305283
关键词：
Development unimolecular nanoparticle mediated periadventitial

项目摘要

Over 350,000 open surgical procedures to treat cardiovascular disease are performed each year in the USA, with many more being performed worldwide. A great number of these eventually fail due to intimal hyperplasia (IH), which is primarily caused by smooth muscle cell (SMC) transformation from a quiescent to a pathogenic (proliferative, migratory, and inflammatory) phenotype. Current clinical methods for preventing IH (e.g., drug- eluting stents) are not applicable for traditional open surgical procedures such as bypass, endarterectomy, or dialysis access. Thus, there is a notable lack of clinical options for delivery of drugs that block IH following open cardiovascular surgery. We have developed a novel unimolecular nanoparticle (NP) which provides a unique opportunity to meet this medical need through its multiple favorable properties, which include excellent stability, the ability to provide sustained drug release, and the chemical versatility for conjugation with ligands or molecules that target periadventitial collagen (for the creation of a perivascular reservoir) or pathogenic SMCs (for more precise control of IH). Our preliminary studies demonstrate that NPs are capable of prolonging the release of the clinically used drug rapamycin, resulting in a more durable inhibition of IH in an animal model of IH. The goal of this project is to develop a novel NPmediated multifunctional drug delivery platform that: (1) is readily applicable to the outer surface of blood vessels at the time of open surgery, (2) produces sustained drug release for periods of up to 3 months and beyond, and (3) specifically targets pathogenic SMCs thereby focusing toxicity to these cells while sparing quiescent cells. To achieve sustained drug release, we will generate a “perivascular NP reservoir” of rapamycin either by sequestering NPs around the blood vessel using a hydrogel or by “painting” NPs onto the outer surface of the vessel. In the latter case, the NPs are conjugated with a small molecule or peptide that facilitates their attachment to the adventitia. To test the efficacy of targeted drug delivery, we will conjugate NPs with ligands that bind to receptors that are highly expressed on the surface of pathogenic SMCs. Thus, in Specific Aim 1, we will test the hypothesis that the perivascular application of a rapamycin/NP reservoir maintained in a 1-month durable hydrogel produces sustained inhibition of IH. In Specific Aim 2, we will test the hypothesis that a rapamycin/NP reservoir “painted” onto the outer surface of the vessel produces sustained inhibition of IH. And in Specific Aim 3, we will test the hypothesis that rapamycin/NPs capable of targeting pathogenic SMCs are more efficacious in mitigating IH than non-targeted NPs. Our long-term goal is to create a perivascular nanoplatform that can be readily applied at the time of open vascular reconstruction and is effective in preventing recurrent vascular disease via durable and targeted drug delivery. We believe that the success of these studies will be facilitated by a collaborative team including a vascular surgeon scientist, a biomedical engineer and a biochemist, and will benefit hundreds of thousands of patients.

在美国，每年进行350,000次治疗心血管疾病的开放手术程序，全球范围内还有更多的演出。这些有时由于内膜增生而失败（IH），主要是由平滑肌细胞（SMC）从静止变为致病性引起的（增殖，迁移和炎症）表型。当前预防IH的临床方法（例如，药物 - 洗脱支架）不适用于传统的开放手术程序，例如旁路，内部切除术或透析访问。那是明显缺乏临床选择来交付阻碍IH的药物开放心血管手术。我们已经开发了一种新型的单分子纳米颗粒（NP），该纳米颗粒提供了一个通过其多个有利的特性来满足这种医疗需求的独特机会，其中包括出色稳定性，提供持续药物释放的能力以及与配体共轭的化学多功能性或靶向周围胶原蛋白的分子（用于产生血管周围的储层）或致病性 SMC（以更精确地控制IH）。我们的初步研究表明，NP能够延长临床使用的药物雷帕霉素的释放，导致动物模型中IH的耐用抑制作用。 ih。该项目的目的是开发一个新型的NPSIDIAD多功能药物输送平台，该平台：（1）在开放手术时很容易适用于血管的外表面，（2）产生持续的药物释放长达3个月及以后的期限，（3）特异性针对致病性SMC 在保留静态细胞的同时，将毒性聚焦于这些细胞。为了获得持续的药物释放，我们将通过使用血管周围的NP隔离，生成雷帕霉素的“血管周NP储层” 水凝胶或通过“绘画” NP到容器的外表面。在后一种情况下，NP被缀合用小分子或胡椒来促进他们对冒险的依恋。测试效率有针对性的药物输送，我们将与NP与高度表达在受体上的配体结合NP 致病SMC的表面。在特定目标1中，我们将检验以下假设在1个月耐用水凝胶中维持的雷帕霉素/NP储层的应用可产生持续在特定的目标2中，我们将测试雷帕霉素/NP储层“涂在”上的假设血管的外表面会产生持续的IH抑制作用。在特定的目标3中，我们将测试假设雷帕霉素/NP能够靶向致病性SMC的假设在缓解IH方面更有效比非目标的NP。我们的长期目标是创建一个可以容易应用的血管周纳米板。在开放性血管重建时，有效地防止耐用的复发血管疾病和针对性的药物输送。我们认为，这些研究的成功将由协作准备团队在内，包括一位血管外科医生，生物医学工程师和生物化学家，并将受益数百人成千上万的患者。