Novel Vehicles for Targeted Cardiovascular Repair

描述（由申请人提供）：动脉粥样硬化仍然是美国死亡和残疾的主要原因。目前治疗严重冠状动脉和外周动脉疾病的治疗方式包括球囊血管成形术和支架置入术、动脉内膜切除术或旁路移植术。不幸的是，由于动脉再狭窄继发于新生内膜增生，这些手术大量失败。该生物工程研究伙伴关系（BRP）的总体目标是开发高度创新的靶向治疗方法，通过生物启发的可定制结构来预防血管干预后的再狭窄。我们期望开发出生物相容性的纳米和微尺度疗法，在动脉介入时进行全身输送，靶向被操纵的动脉段，并将分子疗法和药物输送到该部位以抑制再狭窄。提出的三个平台中的每一个都是受生物启发的，并具有共同的物理化学特性，这样每个平台的独特方面都可以被其他平台利用，以达到最大的治疗效果。初步数据表明，一种新型可注射肽两亲体（PA）在动脉注射后成功合成并在体内靶向血管损伤部位。我们还设计了一种仿生高密度脂蛋白（HDL），使用金纳米颗粒（AuNP）作为模板来控制形成的高密度脂蛋白AuNP的大小、形状和表面化学性质。最后，微米尺度的细胞样结构被合成来模拟血液中的元素。总的来说，我们假设小说；靶向生物工程治疗剂将防止动脉介入后再狭窄的发展。为了验证这一假设，具体目标如下：1)合成并表征针对血管损伤部位并递送有效治疗药物的新型仿生递送载体；2)评价靶向工程化治疗递送载体对体外血管壁细胞的作用；3)确定靶向工程化治疗递送载体在体内抑制新生内膜增生的特异性、安全性、生物相容性和有效性。通过我们的多学科研究团队，我们已经积累了支持我们方法可行性的初步数据。在该BRP的支持下，我们将为接受任何血管介入治疗的患者提供靶向治疗，以防止再狭窄。这些疗法可能会彻底改变动脉粥样硬化的治疗方式，因此代表了一种范式转换技术。最后，本提案中开发的生物工程疗法将针对多种细胞类型。因此，项目成功将对介入心脏病学、介入放射学、心胸外科、血管外科等领域产生深远影响，但对预防心脏病学、癌症、炎症、风湿病等领域的影响更为广泛。

DESCRIPTION (provided by applicant): Atherosclerosis remains the leading cause of death and disability in the United States. Current therapeutic modalities for the treatment of severe coronary and peripheral artery disease include balloon angioplasty and stenting, endarterectomy, or bypass grafting. Unfortunately, a large number of these procedures fail due to the development of arterial restenosis secondary to neointimal hyperplasia. The overall goal of this Bioengineering Research Partnership (BRP) is to develop highly innovative targeted therapeutics delivered by bio-inspired tailorable constructs to prevent restenosis following vascular interventions. We expect to develop biocompatible nano- and microscale therapies that will be delivered systemically at the time of arterial intervention, target the manipulated arteria segment, and deliver molecular therapies and drugs to that site to inhibit restenosis. Each of the three platforms proposed are bio-inspired and share common physicochemical properties such that unique aspects of each one may be leveraged by the others to achieve maximal therapeutic efficacy. Preliminary data demonstrate the successful synthesis and in vivo targeting of a novel injectable peptide amphiphile (PA) to the site of vascular injury following intra-arterial injectio. We have also designed a biomimetic high density lipoprotein (HDL) using a gold nanoparticle (AuNP) as a template to control the size, shape, and surface chemical properties of the formed HDL AuNPs. Lastly, micron scale cell- like structures has been synthesized to mimic elements in the blood stream. Overall, we hypothesize that novel; targeted bioengineered therapeutic agents will prevent the development of restenosis following arterial interventions. To investigate this hypothesis, the specific aims are as follows: 1) synthesize and characterize novel bio-inspired delivery vehicles that are targeted to the site of vascular injury and deliver effective therapeutic agents; 2) evaluate the effect of the targeted engineered therapeutic delivery vehicles on cells from the vascular wall in vitro; 3) determine the specificity, safety, biocompatibility, and efficacy of the targeted engineered therapeutic delivery vehicles at inhibiting neointimal hyperplasia in vivo. Through our multidisciplinary team of investigators, we have already accrued preliminary data that supports the feasibility of our approach. With the support of this BRP, we will provide targeted therapies to prevent restenosis for patients undergoing any vascular intervention. These therapies could revolutionize how atherosclerotic arteries are treated and thus represent a paradigm-shifting technology. Finally, the bioengineered therapies developed in this proposal will be targeted to multiple cell types. Thus, project success will profoundly impact the fields of interventional cardiology, interventional radiology, cardiothoracic surgery, and vascular surgery, but will have more broad ranging impact in the fields of preventive cardiology, cancer, inflammation, and rheumatology.