Delivery of Anti-thrombotic Drugs by Blood Cells

描述（由申请人提供）：血栓形成在许多病理条件下引起发病率和死亡率。抗凝剂和抗血小板药物的预防和纤溶性纤溶酶原激活剂的治疗溶栓，PA的疗效有限，并因出血和脑损伤而受损。我们的团队：i)提出与载体红细胞（RBC）偶联将改善纤溶性PA的药代动力学，使其具有预防作用；ii)通过在动物中重新输注红细胞/tPA偶联物，证明了有效和安全的血栓预防原理（Nature Biotech 2003）；iii)通过抗红细胞/tPA偶联物在体内设计循环红细胞的安全负载。为了将这个有希望的原型转化为临床可接受的实用性、安全性和特异性的血栓预防，我们现在设计了一系列由凝血酶激活的抗红细胞scFv/PA融合前药。为了测试这个平台对红细胞载体上的抗血栓药物的递送，我们将描述：i)抗红细胞scFv/PA前药的活性、药代动力学和凝血酶调节（目的1）；ii)对小鼠静脉和动脉血栓形成模型的影响（目的2）；iii)安全性：对红细胞的潜在危害、出血、全身效应和中枢神经系统的不良反应（Aim 3）。这笔拨款的实施将为这种潜在的革命性的安全有效的血栓预防新方法转化为临床领域提供基础。我们设计了一种新的预防血栓形成的策略，该策略基于纤溶前药物重组融合结构的偶联，可以安全地结合载体红细胞（RBC）。我们将在小鼠血栓模型中描述药物的活性和药代动力学调节、疗效和安全性。这项转译资助的实施将为这种潜在的革命性血栓预防新方法的临床开发提供坚实的基础。

DESCRIPTION (provided by applicant): Thrombosis causes morbidity and mortality in many pathological conditions. Prevention by anticoagulants and anti-platelet agents and therapeutic thrombolysis by fibrinolytic plasminogen activators, PA have limited efficacy and marred by bleeding and brain injury. Our team: i) proposed that coupling to carrier red blood cells (RBC) will improve pharmacokinetics of fibrinolytic PA, permitting their preventive utility; ii) demonstrated a proof of principle for effective and safe thromboprophylaxis attained by re-infusion of RBC/tPA conjugates in animals (Nature Biotech 2003); and, iii) designed safe loading of circulating RBC by anti-RBC/tPA conjugates in vivo. In order to translate this promising prototype into clinically applicable thromboprophylaxis with clinically acceptable utility, safety and specificity, we now designed a series of anti-RBC scFv/PA fusion pro-drugs activated by thrombin. To test this platform for delivery of anti-thrombotic agents loaded on RBC carriers, we shall characterize: i) activities, pharmacokinetics and thrombin regulation of the anti-RBC scFv/PA pro-drugs (Aim 1); ii) their efficacy in mouse models of venous and arterial thrombosis (Aim 2); and, iii) safety: potential harm to RBC, bleeding, systemic effects and adverse effects in the CNS (Aim 3). Implementation of this grant will provide a basis for translation into the clinical domain of this potentially revolutionizing novel approach for safe and effective thromboprophylaxis. PUBLIC HEALTH RELEVANCE we have designed a new strategy for prophylaxis of thrombosis based on coupling of fibrinolytic pro-drug recombinant fusion constructs that safely bind to carrier red blood cells (RBC). We shall characterize activities and pharmacokinetics regulation of the drugs, efficacy and safety in mouse models of thrombosis. Implementation of this translational grant will provide a solid basis for clinical development of this potentially revolutionizing novel approach for thromboprophylaxis.