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

项目摘要 每年进行超过350，000例治疗心血管疾病的开放手术 今年在美国，与更多的是在世界各地进行。其中很多 最终由于内膜增生（IH）而失败，这主要是由平滑肌细胞引起的 (SMC)从静止到致病的转化（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，药物洗脱支架） 不适用于传统的开放性外科手术，如旁路、动脉内膜切除术，或 透析通路。因此，临床上明显缺乏阻断IH的药物 开放性心血管手术后我们开发了一种新的单分子纳米颗粒 (NP)它提供了一个独特的机会，以满足这种医疗需求，通过其多个 有利的性质，包括优异的稳定性，提供持续药物的能力， 释放，以及用于与靶向的配体或分子缀合的化学多功能性。 外膜周胶原蛋白（用于创建血管周储库）或致病性SMC（用于 更精确地控制IH）。我们的初步研究表明，纳米粒子能够 延长临床使用的药物雷帕霉素的释放，导致更持久的 在IH动物模型中抑制IH。该项目的目标是开发一种新型的NP- 介导的多功能药物递送平台，其：（1）易于应用于外表面 （2）在开放手术时产生持续的药物释放， 长达3个月及以上，和（3）特异性靶向致病性SMC，从而集中 对这些细胞的毒性，同时保留静止细胞。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"， 通过使用水凝胶或通过将NP "涂敷"到血管的外表面上，可以将NPs涂敷到血管上。在 在后一种情况下，NP与小分子或肽缀合，所述小分子或肽促进它们的结合。 附着于外膜。为了测试靶向药物递送的功效，我们将结合 具有与在病原体表面上高度表达的受体结合的配体的NP SMC。因此，在具体目标1中，我们将检验以下假设： 雷帕霉素/NP储库保持在1个月的持久水凝胶中产生持续的抑制 的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。在第三个目标中，我们将 检验雷帕霉素/纳米粒能够靶向致病性SMC的假设， 与非靶向NP相比，在缓解IH方面更有效。我们的长期目标是在血管周围 纳米平台可以在开放血管重建时容易地应用， 通过持久和靶向的药物递送有效预防复发性血管疾病。我们 我相信，这些研究的成功将由一个合作小组，包括一个 血管外科医生科学家，生物医学工程师和生物化学家，并将受益于数百人 成千上万的病人。

Project Summary 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 NP- mediated 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.