权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

BC-mediated delivery of thromboprophylaxis

BC 介导的血栓预防

基本信息

批准号：
10475755
负责人：
Vladimir R Muzykantov
金额：
$ 66.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10475755
关键词：
Abnormal Red Blood Cell Acute Address Adhesions Adhesiveness Animal Model Animals Antiinflammatory Effect Benign Binding Biodistribution Biological Products Biomechanics Blood Blood Cells Blood Circulation Blood Platelets Blood Vessels Brain Injuries COVID-19 Cell physiology Cells Clinic Clinical Clinical Research Coagulation Process Complement Activation Complex Coupled Coupling Cytolysis Data Development Disease Dose Drug Delivery Systems Drug Kinetics Embolism Endothelium Endotoxemia Epitopes Erythrocytes Fibrinolysis Fibrinolytic Agents Glycoproteins Goals Hemorrhage Hemostatic Agents Hour Human Immobilization Impairment Inflammation Inflammatory Injections Intravenous infusion procedures Kinetics Lead Leg Life Lung Mediating Mediator of activation protein Medical Microfluidics Modeling Modification Molecular Mus Operative Surgical Procedures Outcome Pathologic Patients Phagocytes Pharmaceutical Preparations Physicians Pilot Projects Plasminogen Activator Postoperative Period Primates Prophylactic treatment Regimen Regional Perfusion Regulation Rhesus Risk Safety Site Source Structure Surgical Hemostasis System Testing Therapeutic Thrombin Thrombomodulin Thromboplastin Thrombosis Thrombus Time Transgenic Mice Transgenic Organisms Trauma Urokinase Vascular Diseases Vascular Endothelium Venous Thrombosis Work activated Protein C base biomaterial compatibility clinical application clinical translation design high risk in vivo in vivo Model insight interest mouse model mutant novel novel strategies off-target site pre-clinical preservation prevent prophylactic prototype risk benefit ratio targeted agent thromboinflammation translational study uptake

项目摘要

No anti-thrombotic agent (ATA) is safe and effective in the many patients at a combined risk of acute thrombosis and bleeding, e.g., in the early post-surgery period. To address this unmet need, we develop drug delivery systems (DDS) executing two main functions: A) Block access of ATA to off- target sites, e.g., hemostatic plugs formed after surgery, while B) Optimize pharmacokinetics and deliver ATA into subsequent thrombi, where ATA is activated by thrombin. ATA fused with single- chain fragments (scFv) targeted to red blood cells (RBC) bind to these carriers that execute dual blocking/delivering function. Proof-of-concept is emerging in models of pre-existing and nascent clots in animals. Here we devise humanized scFv/ATA targeted to human RBC and will test them in a humanized microfluidic system (HMF), in transgenic (TG) mice expressing humanized target epitopes on blood cells, and in the perfusion of isolated human lungs. We will pursue three aims. Aim 1. RBC loading. We will characterize scFv/ATA loading onto RBC: A) Binding (copies/cell, on/off kinetics); B) Effect on RBC functionality, biocompatibility and biomechanics; and, B) Regulation of distribution of scFv/ATA between RBC in circulation. We also will characterize biomechanical factors modulating RBC/ATA delivery and effect on clot dynamics and structure, in particular, impact of RBC rigidification, caused by either drug loading or by intrinsic pathophysiological changes in patient's blood. Aim 2. Mechanistic insights. We will interrogate previously unrecognized yet critically aspects of the RBC/ATA workings, in particular their interaction with vascular endothelium and transfer of the drug cargo to these and other vascular cells. In this Aim we will use standard mouse in vivo models, microfluidic model and perfusion of isolated human lungs model. Aim 3. Appraisal of benefit/risk ratio. We are developing TM mice expressing human RBC determinants in mouse EBC, in order to study scFv/ATA loaded on "human RBC" in vivo: A) PK/BD, complement activation, phagocyte uptake and vascular adhesion of RBC/ATA in TG mice; B) Define the time window/extent of anti-thrombotic effect of human RBC/ATA in models of arterial vs venous thrombosis in TG mice; B) Affirm the safety of RBC/ATA. We will detect adversities of scFv/ATA including abnormalities of RBC. To defuse potential issues, if necessary, we will use more benign loading regimen. Together, these studies will advance mechanistic insights and clinical translation of a novel way to mitigate thrombosis in currently unprotected patients by providing a new and tractable approach to understanding thrombus development and a rational approach to deliver cell-directed therapeutics

没有抗血栓药物（ATA）是安全有效的许多患者在合并风险