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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，每年进行超过350，000例治疗心血管疾病的开放式外科手术，世界各地还有更多的演出。其中大量最终由于内膜增生而失败 (IH)主要由平滑肌细胞（SMC）从静止状态向致病状态转化引起，（增殖性、迁移性和炎性）表型。目前用于预防IH的临床方法（例如，表示“药物”之义洗脱支架）不适用于传统的开放外科手术，例如旁路手术、动脉内膜切除术或透析通路。因此，显著缺乏用于递送阻断以下IH的药物的临床选择：开放性心血管手术我们已经开发了一种新的单分子纳米颗粒（NP），独特的机会，以满足这一医疗需求，通过其多种有利的性质，其中包括优良的稳定性、提供持续药物释放的能力以及与配体缀合的化学多功能性或靶向外膜周围胶原蛋白（用于产生血管周围储库）的分子或致病性 SMC（用于更精确地控制IH）。我们的初步研究表明，纳米颗粒能够延长释放临床使用的药物雷帕霉素，导致在动物模型中对IH的更持久抑制的IH。本课题的目标是开发一种新型的NP介导的多功能药物载体平台，该平台具有以下特点：（1）在开放手术时易于应用于血管的外表面，（2）产生持续的药物释放长达3个月或更长的时间，和（3）特异性靶向致病性SMC，从而将毒性集中在这些细胞上，而不影响静止细胞。为了实现药物的持续释放，我们将产生雷帕霉素的“血管周围NP储库”，或者通过使用水凝胶或通过将NP“涂敷”到血管的外表面上。在后一种情况下，NP是缀合的。用小分子或肽促进它们附着到外膜上。为了测试靶向药物递送，我们将结合纳米粒子与配体结合的受体是高度表达的，致病SMC的表面。因此，在具体目标1中，我们将检验以下假设：应用维持在1个月耐久水凝胶中的雷帕霉素/NP储库产生持续的抑制IH。在具体目标2中，我们将测试雷帕霉素/NP储库“涂”在血管的外表面产生持续的IH抑制。在《特定目标3》中，我们将测试能够靶向致病性SMC的雷帕霉素/NP在减轻IH中更有效的假设非目标NP。我们的长期目标是创造一种血管周围纳米平台，在开放性血管重建时，通过持久的治疗，和靶向给药。我们相信，这些研究的成功将通过合作来促进。包括一名血管外科医生科学家，一名生物医学工程师和一名生物化学家在内的团队，将使数百人受益成千上万的病人。