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

• 批准号: 9177485
• 负责人: SHAOQIN GONG
• 金额: $ 55.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177485
• 关键词: Affect; Aldehydes; Angioplasty; Animal Model; Arteries; Avidin; Behavior; Binding; Biomedical Engineering; Biotin; Blood Vessels; Bolus Infusion; Bypass; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Cells; Chemicals; Clinical; Collagen; Complex; Country; Development; Dialysis procedure; Drug Delivery Systems; Drug Kinetics; Drug usage; Effectiveness; Endarterectomy; Evaluation; FGF1 gene; Fibronectins; Gel; Goals; Heart; Hydrogels; Hyperplasia; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Kinetics; Lead; Ligand Binding; Ligands; Measures; Mediating; Medical; Methods; Micelles; Modeling; Morbidity - disease rate; Nanotechnology; Operative Surgical Procedures; Paint; Pathogenesis; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Pluronics; Property; Public Health; Rattus; Recurrence; Recurrent disease; Scientist; Sirolimus; Smooth Muscle Myocytes; Stents; Stromal Cell-Derived Factor 1; Surface; Surgeon; Techniques; Testing; Time; Toxic effect; Tunica Adventitia; Vascular Diseases; Vein graft; cell behavior; cell transformation; chemical release; copolymer; design; efficacy testing; in vivo; injured; innovation; meetings; migration; mortality; nanomedicine; nanoparticle; novel; novel strategies; prevent; receptor; reconstruction; restenosis; small molecule; success; uptake

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.

项目概要 每年进行超过 350,000 例治疗心血管疾病的开放式外科手术 今年在美国演出，还有更多的演出在世界各地演出。 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）从静止状态转变为致病状态（增殖性、迁移性和 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 药物的临床选择。 在开放式心血管手术之后，我们开发了一种新型单分子纳米颗粒。 （NP）通过其多种方式提供了满足这种医疗需求的独特机会 良好的特性，包括优异的稳定性、提供持续药物的能力 释放，以及与靶向配体或分子缀合的化学多功能性 外膜周围胶原蛋白（用于形成血管周围储库）或致病性 SMC（用于 我们的初步研究表明 NP 能够更精确地控制 IH。 延长临床使用的药物雷帕霉素的释放，从而产生更持久的效果 在 IH 动物模型中抑制 IH 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）易于应用于外表面 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，并且 (3) 专门针对致病性 SMC，从而集中 为了实现药物的持续释放，我们将对这些细胞产生毒性，同时不影响静止细胞。 通过将纳米颗粒隔离在血管周围，产生雷帕霉素的“血管周围纳米颗粒储存库” 使用水凝胶或通过将纳米颗粒“涂”到血管的外表面来形成血管。 在后一种情况下，纳米粒子与小分子或肽缀合，以促进其 为了测试靶向药物递送的功效，我们将缀合。 带有配体的纳米颗粒可以与病原体表面高表达的受体结合 因此，在具体目标 1 中，我们将检验血管周围应用的假设。 雷帕霉素/NP 储存库保存在 1 个月的耐用水凝胶中，产生持续的抑制作用 在 IH 的具体目标 2 中，我们将测试雷帕霉素/NP 储库“绘制”到的假设。 血管的外表面产生持续的 IH 抑制，在具体目标 3 中，我们将。 检验能够靶向致病性 SMC 的雷帕霉素/纳米粒子更有效的假设 与非靶向 NP 相比，它能更有效地缓解 IH。我们的长期目标是创造一种血管周围的药物。 纳米平台可以在开放血管重建时轻松应用，并且 通过持久和有针对性的药物输送，有效预防复发性血管疾病。 相信包括以下人员在内的合作团队将促进这些研究的成功 血管外科医生科学家、生物医学工程师和生物化学家，将使数百人受益 数千名患者。