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

在美国，每年有超过350,000例开放式外科手术治疗心血管疾病， 更多的演出正在世界各地上演。其中许多最终会由于内膜增生而失败。 (Ih)，其主要原因是平滑肌细胞(SMC)从静止状态转变为病理性状态 (增殖性、迁移性和炎症性)表型。目前预防高血压的临床方法(例如，药物- 洗脱支架)不适用于传统的开放外科手术，例如搭桥、动脉内膜切除术或 透析通道。因此，值得注意的是，临床上缺乏给药的选择，以阻断随后的IH 开胸心血管手术。我们开发了一种新型的单分子纳米颗粒(NP)，它提供了一种 独一无二的机会，通过其多个有利的性能来满足这一医疗需求，其中包括卓越的 稳定性，提供持续药物释放的能力，以及与配体结合的化学多功能性 或以外膜周围胶原为靶点的分子(用于创建血管周围储存库)或致病分子 SMCS(用于更精确地控制IH)。我们的初步研究表明，NPs能够延长 在动物模型中，临床使用的药物雷帕霉素的释放导致对IH的更持久的抑制 来自IH的。本项目的目标是开发一种新型的NPI介导的多功能药物传递平台：(1) 在开放手术时很容易应用于血管外表面，(2)产生持续的 药物释放时间长达3个月及以上，以及(3)以致病的SMC为靶点 将毒性集中在这些细胞上，同时保留静止的细胞。为了实现药物的持续释放，我们将 通过将NPs隔离在血管周围，产生雷帕霉素的“血管周围NP储存库” 一种水凝胶或通过将纳米粒子“涂”到容器的外表面上。在后一种情况下，NP是共轭的 用小分子或多肽来促进它们与外膜的附着。测试……的效果 靶向给药，我们将使NPs与与受体结合的配体偶联，这些受体在 病理性SMC的表面。因此，在特定的目标1中，我们将检验血管周围的假设 将雷帕霉素/NP储存库保存在1个月的耐用水凝胶中，可产生持久的效果 抑制IH的作用。在特定的目标2中，我们将测试这样的假设，即雷帕霉素/NP储存库被“绘制”到 血管外表面产生对IH的持续抑制。在具体的目标3中，我们将测试 假设雷帕霉素/纳米粒能够靶向致病的SMC在缓解IH方面更有效 而不是无针对性的NPs。我们的长期目标是创造一种易于应用的血管周围纳米平台 在开放血管重建时，通过耐久有效地预防血管疾病的复发 和靶向药物输送。我们相信，这些研究的成功将通过合作促进 该团队包括一名血管外科科学家、一名生物医学工程师和一名生物化学家，将使数百人受益 数以千计的病人。

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.