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Delivery of Anti-thrombotic Drugs by Blood Cells

血细胞输送抗血栓药物

基本信息

批准号：
7689747
负责人：
Vladimir R Muzykantov
金额：
$ 39.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-22 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7689747
关键词：
Acute Adverse effects Animal Model Animals Antibodies Anticoagulants Antigens Behavior Binding Biocompatible Blood Blood Cells Blood Circulation Blood Platelets Brain Injuries Chemicals Clinical Coagulation Process Complement Receptor Type 1 Complex Coupling Cytolysis Development Diffusion Drug Delivery Systems Drug Kinetics Effectiveness Erythrocytes Event Fc Immunoglobulins Fibrinolysis Fibrinolytic Agents Glycophorin A Goals Grant Hemorrhage Hemostatic Agents Immunoglobulin Fragments In Vitro Infusion procedures Injection of therapeutic agent Laboratories Morbidity - disease rate Mus Nature Operative Surgical Procedures Patients Peptide Hydrolases Pharmaceutical Preparations Planet Mars Plasma Plasminogen Activator Platelet Inhibitors Prevention Preventive Prodrugs Prophylactic treatment Recombinants Regulation Resistance Risk Safety Series Solid Specificity Testing Thrombin Thrombolytic Therapy Thrombosis Thrombus Time Tissues Transfusion Translating Translations Urokinase Validation Variant Venous base biomaterial compatibility central nervous system injury clinical practice design drug efficacy flexibility high risk improved in vivo inhibitor/antagonist mortality mouse model novel novel strategies pre-clinical prevent prophylactic prototype public health relevance thrombolysis

项目摘要

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.

描述（由申请人提供）：血栓形成在许多病理状况下导致发病和死亡。通过抗凝剂和抗血小板剂进行预防以及通过纤溶纤溶酶原激活剂 PA 进行治疗性溶栓治疗的效果有限，并且会因出血和脑损伤而受到损害。我们的团队： i) 提出与载体红细胞 (RBC) 偶联将改善纤溶 PA 的药代动力学，从而使其具有预防作用； ii) 证明了通过在动物体内重新输注 RBC/tPA 结合物可实现有效且安全的血栓预防的原理证明（Nature Biotech 2003）； iii) 设计通过体内抗 RBC/tPA 缀合物安全装载循环 RBC。为了将这一有前途的原型转化为临床上适用的血栓预防药物，具有临床可接受的效用、安全性和特异性，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。为了测试该平台用于在 RBC 载体上递送抗血栓药物，我们应表征： i) 抗 RBC scFv/PA 前药的活性、药代动力学和凝血酶调节（目标 1）； ii) 它们在小鼠静脉和动脉血栓模型中的功效（目标 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（目标 3）。这项资助的实施将为将这种潜在的革命性新方法转化为临床领域提供基础，以实现安全有效的血栓预防。公共卫生相关性我们设计了一种预防血栓形成的新策略，该策略基于与载体红细胞 (RBC) 安全结合的纤溶前药重组融合构建体的偶联。我们将表征药物在血栓形成小鼠模型中的活性和药代动力学调节、功效和安全性。这项转化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。