Anti-Inflammatory Therapeutics for Cardiovascular Disease

描述(由申请人提供)：动脉粥样硬化斑块中的炎症是急性血管综合征(即血栓形成)的关键促进者。细胞因子、生长因子和免疫细胞浸润物的全套融合，通过创造一个高凝的、富含组织因子的环境，使斑块破裂或侵蚀暴露，从而显著增强不稳定斑块的局部血栓形成潜力，从而导致血管闭塞和缺氧组织死亡。我们持续的多学科翻译工作的首要主题是 基于纳米颗粒的诊断和治疗血栓性心血管疾病的方法的开发和临床测试，以检测、治疗和监测不稳定的动脉粥样硬化。该计划的初始阶段致力于新的分子成像策略，最终获得FDA批准的整合素靶向纳米颗粒用于斑块血管生成检测的临床试验。在下一阶段的工作中，我们寻求开发和量化新的纳米治疗剂的有效性，以减轻斑块炎症，临床目标是降低急性血管综合征的血栓形成倾向。我们将评估以下最重要的假设：抗炎治疗纳米粒可以调节急性血管综合征的血栓形成状态，并恢复动脉粥样硬化病变的稳定性，其益处超过传统疗法。具体目的是：1.设计、配制和评价体外定向抗炎纳米疗法；2.在标准化的载脂蛋白E-/-小鼠血栓形成模型中测试体内治疗制剂；3.在体内测试纳米粒组合和复合纳米粒的协同疗效

DESCRIPTION (provided by applicant): Inflammation in atherosclerotic plaque is a key promoter of acute vascular syndromes (i.e., thrombosis). Panoply of cytokines, growth factors, and immune cellular infiltrates converges to dramatically enhance the local thrombogenic potential of unstable plaques by creating a hypercoagulant, tissue factor-rich milieu that is exposed by either plaque rupture or erosion, which results in vessel occlusion and hypoxic tissue death. The overarching theme of our continuing multidisciplinary translational effort is the development and clinical testing of nanoparticle based approaches for the diagnosis and therapy of thrombotic cardiovascular diseases to detect, treat, and monitor unstable atheroma. The initial phase of the program was devoted to novel molecular imaging strategies that have culminated in FDA approved clinical trials of integrin-targeted nanoparticles for plaque angiogenesis detection. In the next phase of the work, we seek to develop and quantify the efficacy of new nanotherapeutic agents to attenuate plaque inflammation with the clinical goal of reducing the propensity toward thrombosis in acute vascular syndromes. We will evaluate the following overarching hypothesis: anti- inflammatory therapeutic nanoparticles can modulate the hyperthrombotic state in acute vascular syndromes and restore stability in atherosclerotic lesions with benefits over and above conventional therapy. The specific aims are to: I. Design, formulate, and evaluate targeted anti-inflammatory nanotherapies in vitro II. Test therapeutic formulations in vivo in a standardized ApoE -/-mouse thrombosis model III. Test nanoparticle combinations and multiplexed nanoparticles in vivo for synergistic efficacy