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）。细胞因子、生长因子和免疫细胞浸润的集合通过产生高凝性、富含组织因子的环境而显著增强不稳定斑块的局部血栓形成潜力，所述高凝性、富含组织因子的环境通过斑块破裂或侵蚀而暴露，这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 开发和临床测试基于纳米颗粒的方法，用于血栓性心血管疾病的诊断和治疗，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FDA批准了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药物减轻斑块炎症的疗效，临床目标是减少急性血管综合征中血栓形成的倾向。我们将评估以下总体假设：抗炎治疗性纳米颗粒可以调节急性血管综合征中的高血栓状态，并恢复动脉粥样硬化病变的稳定性，其益处超过常规治疗。具体目标是：一。设计，制定和评估体外靶向抗炎纳米疗法。在标准化ApoE -/-小鼠血栓形成模型III中体内测试治疗制剂。在体内测试纳米颗粒组合和多重纳米颗粒的协同功效

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