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.

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，全球范围内还有许多此类手术最终因内膜增生而失败。 (IH)，主要是由平滑肌细胞 (SMC) 从静止状态转变为致病状态引起的（增殖、迁移和炎症）表型。目前预防 IH 的临床方法（例如药物）。洗脱支架）不适用于传统的开放式外科手术，例如搭桥术、动脉内膜切除术或因此，明显缺乏阻断 IH 的药物的临床选择。我们开发了一种新型单分子纳米颗粒（NP），它提供了通过其多种有利的特性来满足这种医疗需求的独特机会，其中包括优异的稳定性、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的分子（用于形成血管周围储库）或致病性 SMC（用于更精确地控制 IH）。我们的初步研究表明，NP 能够延长时间。临床使用的药物雷帕霉素的释放，在动物模型中产生更持久的 IH 抑制该项目的目标是开发一种新型 NP 介导的多功能药物递送平台：(1) 在开放手术时很容易适用于血管外表面，（2）产生持续的药物释放时间长达 3 个月或更长时间，并且 (3) 专门针对致病性 SMC 集中对这些细胞的毒性，同时保护静止细胞。为了实现药物的持续释放，我们将通过使用以下方法将纳米颗粒隔离在血管周围，生成雷帕霉素的“血管周围纳米颗粒储存库” 水凝胶或将纳米粒子“涂”到容器的外表面上。在后一种情况下，纳米粒子被缀合。用小分子或肽促进它们附着在外膜上以测试其功效。靶向药物递送，我们将纳米颗粒与配体结合，这些配体与高表达的受体结合因此，在具体目标 1 中，我们将检验血管周围的假设。应用雷帕霉素/纳米粒子储存库维持在 1 个月的耐用水凝胶中，产生持续的在具体目标 2 中，我们将测试雷帕霉素/NP 储库“涂”在 IH 上的假设。血管外表面产生持续的 IH 抑制，在具体目标 3 中，我们将测试假设能够靶向致病性 SMC 的雷帕霉素/纳米颗粒在缓解 IH 方面更有效我们的长期目标是创建一个易于应用的血管周围纳米平台。在开放性血管重建时，通过持久的作用有效预防复发性血管疾病我们相信，合作将促进这些研究的成功。团队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，将使数百人受益数以千计的患者。