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 每项治疗心血管疾病的开放外科手术超过350,000例 年在美国演出，还有更多的演出在世界各地进行。一大堆这样的东西 最终失败的原因是内膜增生(IH)，这主要是由平滑肌细胞引起的 (SMC)从静止状态转变为致病状态(增殖性、迁移性和 炎症性)表型。目前预防高血压的临床方法(如药物洗脱支架) 不适用于传统的开放外科手术，如搭桥术、动脉内膜切除术或 透析通道。因此，对于阻断IH的药物，临床上缺乏明显的选择 在开放的心血管手术后。我们开发了一种新型的单分子纳米颗粒 (NP)，它提供了一个独特的机会，通过其多个 良好的性质，包括极好的稳定性，能够提供持续的药物 释放，以及与靶向配体或分子结合的化学多功能性 外膜周围胶原(用于形成血管周围储存库)或致病的SMC(用于 更精确地控制IH)。我们的初步研究表明，NPs有能力 延长临床用药雷帕霉素的释放时间，使其更持久 在IH动物模型中抑制IH。该项目的目标是开发一种新的NP- 一种介导型多功能给药平台，其特征在于：(1)易于外表面使用 开放手术时的血管，(2)产生持续的药物释放 长达3个月及以上，以及(3)专门针对致病的SMC，从而集中 对这些细胞的毒性，同时保留静止的细胞。为了实现药物的持续释放，我们将 通过隔离血管周围的NPs，产生雷帕霉素的“血管周围NP库” 使用水凝胶或将纳米粒子“涂抹”到血管的外表面。在 在后一种情况下，NPs与一个小分子或多肽结合，从而促进它们的 附着在外膜上。为了测试靶向给药的效果，我们将结合 具有与致病细胞表面高表达的受体结合的配体的NPS SMCS。因此，在特定的目标1中，我们将检验这样的假设，即血管周围应用 雷帕霉素/NP储存库在1个月的耐用水凝胶中保持可产生持续抑制 来自IH的。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“绘制”到 血管的外表面产生对IH的持续抑制。在具体目标3中，我们将 验证雷帕霉素/纳米粒能够靶向致病SMC的假设 在缓解IH方面比非靶向NPs有效。我们的长期目标是创造一个血管周围 在开放血管重建时可以方便地应用的纳米平台，并且是 通过持久和有针对性的药物输送，有效预防复发的血管疾病。我们 相信这些研究的成功将得到一个合作团队的推动，其中包括 血管外科科学家、生物医学工程师和生物化学家，将使数百名 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.