Hemostasis-Independent targeted treatment of thrombosis

血栓形成的非止血靶向治疗

• 批准号: 8984074
• 负责人: Amy Wen
• 金额: $ 1.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-19 至 2016-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984074
• 关键词: Acute; Address; Adhesions; Affinity; Alteplase; Antibodies; Anticoagulants; Antiplatelet Drugs; Binding; Biodistribution; Biological Assay; Bleeding time procedure; Blood Platelets; CD36 gene; Calcium; Carotid Artery Thrombosis; Cataloging; Catalogs; Cause of Death; Cerebral hemisphere hemorrhage; Clinical; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Encapsulated; Engineering; FDA approved; Family member; Fibrin; Fibrinolytic Agents; Flow Cytometry; Generations; Genes; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Homing; Hour; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Infusion procedures; Knockout Mice; Lead; Modeling; Mus; Myocardial; Nature; Patients; Penetration; Peptide Library; Peptides; Phage Display; Pharmaceutical Preparations; Plant Viruses; Protein Family; Pulmonary Embolism; Research; Risk; S100A8 gene; S100A9 gene; Safety; Shapes; Signal Transduction; Site; Stroke; Symptoms; System; Tail; Testing; Therapeutic; Thrombin; Thrombosis; Thrombus; Time; Tobacco Mosaic Virus; Translations; Treatment Efficacy; acute stroke; base; combinatorial; fluorescence imaging; immunogenic; improved; in vivo; innovation; mortality; mouse model; nanoparticle; nanotherapeutic; platelet typing; public health relevance; receptor; retinal rods; targeted delivery; targeted treatment; thrombolysis

 DESCRIPTION (provided by applicant): Thrombotic disorders, including myocardial infraction (MI), stroke, and pulmonary embolism (PE), are the leading causes of death worldwide. Current antiplatelet, anticoagulant, and fibrinolytic agents are effective at reducing ischemic complications but are associated with significant bleeding that adversely impacts mortality. The rationale for our proposal is that targeted anti-thrombotic drug delivery will enhance efficacy and reduce bleeding. Recently, MRP-14 was identified as a direct regulator of thrombosis through its association with the platelet receptor CD36. Therefore, MRP-14 targeting has potential as a dual-therapeutic approach - namely, it can be used to directly block thrombosis by interrupting MRP-14 binding to CD36 as well as for nanoparticle-directed delivery of a thrombolytic agent. Importantly, unlike alternate targets such as fibrin, MRP-14 deficiency has no effect on multiple hemostatic parameters, such as tail bleeding time, thrombin generation, or platelet adhesion/spreading. This proposal uses a combinatorial approach to determine peptides that simultaneously bind to MRP-14 while blocking binding to CD36. We will use nature-inspired tobacco mosaic virus (TMV), a 300 by 18 nm rod-shaped plant virus-based nanoparticle we have shown to have enhanced thrombus homing due to shape-based effects. The central hypothesis is that MRP-14 targeting will allow for inhibition of thrombosis and precise delivery of drug-bearing nanoparticles, thereby reducing the effective dose necessary for thrombolysis and limiting bleeding. This hypothesis will be tested with a photochemical mouse thrombosis model with the following two aims: peptides specific for MRP- 14 that blocks its downstream effects will be identified (Aim 1), and the the most promising peptides will be utilized to target thrombosis and the therapeutic efficacy will be evaluated in vitro and in vivo (Aim 2). This approach is innovative, as it will be the first to develop an MRP-14 targeting peptide that is capable of simultaneously disrupting MRP-14:CD36 signaling in platelets and targeting a thrombolytic agent to thrombus. This project paves the way for clinical translation, utilizing already FDA-approved alteplase and improving its safety and efficacy through active delivery. Completion of these aims will result in a targeted carrier system that will address current clinical challenges b providing a more efficacious therapeutic approach for thrombosis with limited bleeding.

 描述（由申请人提供）：血栓性疾病，包括心肌梗塞（MI）、中风和肺栓塞（PE），是全世界死亡的主要原因。目前的抗血小板、抗凝剂和纤溶药物可有效减少缺血性并发症，但效果不佳。与严重出血有关，对死亡率产生不利影响。我们建议的理由是，有针对性的抗血栓药物输送将提高疗效并提高疗效。 最近，MRP-14 通过与血小板受体 CD36 的结合被确定为血栓形成的直接调节剂，因此，MRP-14 靶向具有作为双重治疗方法的潜力 - 即，它可用于直接阻断血栓形成。重要的是，与纤维蛋白等替代靶点不同，MRP-14 缺乏对多种疾病没有影响。止血参数，例如尾部出血时间、凝血酶生成或血小板粘附/扩散该提案使用组合方法来确定同时结合 MRP-14 并阻断与 CD36 结合的肽。 TMV），一种 300 x 18 nm 的棒状植物病毒纳米颗粒，我们已证明由于形状效应而增强了血栓归巢。中心假设是： MRP-14 靶向将能够抑制血栓形成并精确递送 载药纳米颗粒，从而减少溶栓所需的有效剂量并限制出血。该假设将通过光化学小鼠血栓形成模型进行测试，其目的有以下两个：将鉴定出阻断其下游效应的 MRP-14 特异性肽（目的）。 1），最有前途的肽将用于靶向血栓形成，并在体外和体内评估治疗效果（目标2）。这种方法是创新的，因为它将是第一个开发的方法。 MRP-14 靶向肽能够同时破坏血小板中的 MRP-14:CD36 信号传导并将溶栓剂靶向血栓，该项目利用 FDA 批准的阿替普酶并通过活性提高其安全性和有效性，为临床转化铺平了道路。完成这些目标将产生一个有针对性的载体系统，该系统将解决当前的临床挑战，为出血有限的血栓形成提供更有效的治疗方法。

项目成果

Enhancing the Angular Sensitivity of Plasmonic Sensors Using Hyperbolic Metamaterials.

• DOI: 10.1002/adom.201600448
• 发表时间: 2016-11
• 期刊: Advanced optical materials
• 影响因子: 9
• 作者: Sreekanth KV;Alapan Y;ElKabbash M;Wen AM;Ilker E;Hinczewski M;Gurkan UA;Steinmetz NF;Strangi G
• 通讯作者: Strangi G

Designing S100A9-Targeted Plant Virus Nanoparticles to Target Deep Vein Thrombosis.

• DOI: 10.1021/acs.biomac.1c00303
• 发表时间: 2021-06-14
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Park, Jooneon;Wen, Amy M.;Gao, Huiyun;Shin, Matthew D.;Simon, Daniel, I;Wang, Yunmei;Steinmetz, Nicole F.
• 通讯作者: Steinmetz, Nicole F.