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: 9481524
• 负责人: SHAOQIN GONG
• 金额: $ 49.66万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9481524
• 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 Targeting; Drug usage; Effectiveness; Endarterectomy; Evaluation; FGF1 gene; Fibronectins; Gel; Goals; Heart; Hydrogels; Hyperplasia; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Kinetics; Ligand Binding; Ligands; Measures; Mediating; Medical; Methods; Micelles; Modeling; Morbidity - disease rate; Nanotechnology; Operative Surgical Procedures; Paint; Pathogenesis; Pathogenicity; 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; copolymer; design; efficacy testing; in vivo; injured; innovation; 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.

项目摘要 每次都进行了超过350,000个治疗心血管疾病的开放手术程序 在美国一年，全球范围内还进行了更多演出。其中很多 由于内膜增生（IH）而失败，这主要是由平滑肌细胞引起的 （SMC）从静止转变为致病性（增殖者，迁移和 炎症）表型。当前预防IH的临床方法（例如，洗脱支架） 不适用于传统的开放手术程序，例如旁路，内部切除术或 透析访问。那是明显缺乏临床选择来阻止IH的药物 开放性心血管手术后。我们已经开发了一种新型的单分子纳米颗粒 （NP）提供了一个独特的机会，可以通过其多重 有利的特性，包括出色的稳定性，提供持续药物的能力 释放，以及与靶向的配体或分子结合的化学多功能性 周期胶原蛋白（用于创建血管周围的储层）或致病性SMC（用于 对IH的更精确控制）。我们的初步研究表明，NP能够 延长临床使用的药物雷帕霉素的释放，使得更耐用 在IH动物模型中抑制IH。该项目的目的是开发一种新颖的NP- 介导的多功能药物输送平台：（1）容易适用于外表面 开放手术时的血管，（2）产生持续的药物释放时间 最多3个月及以后，（3）专门针对致病SMC，从而聚焦 在保留静态细胞的同时，对这些细胞的毒性。为了获得持续的药物释放，我们将 通过隔离NP，生成雷帕霉素的“周围NP储层” 血管使用水凝胶或将NP“绘画”到容器的外表面上。在 后一种情况，NP与小分子或胡椒粉结合，以促进其 附着Addeditia。为了测试目标药物输送的效率，我们将共轭 NP具有与受体结合的配体在致病表面上高表达的受体 SMC。在特定目标1中，我们将检验以下假设。 雷帕霉素/NP储层维持在1个月耐用的水凝胶中会持续抑制 ih。在特定目标2中，我们将测试雷帕霉素/NP储层“涂在”上的假设 血管的外表面产生持续的IH抑制作用。在特定的目标3中，我们将 检验雷帕霉素/NP能够靶向致病性SMC的假设更多 比非靶向的NP容易缓解IH。我们的长期目标是创建一个血管周围 可以在开放血管重建时很容易应用的纳米文化形式，并且 通过耐用和靶向药物递送有效防止复发性血管疾病。我们 认为这些研究的成功将由一个合作团队准备，包括 血管外科医生科学家，生物医学工程师和生物化学家，将受益数百名 成千上万的患者。