Platelet-inspired Delivery System for Targeted Thrombolytic Therapy

用于靶向溶栓治疗的血小板启发输送系统

基本信息

批准号：
9127360
负责人：
Anirban Sen Gupta
金额：
$ 46.5万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127360
关键词：
Adverse effects Affect Aftercare Age Albumins Alteplase Binding Biocompatible Blood Platelets Blood Vessels Blood flow Caliber Carotid Artery Thrombosis Catheters Charge Chromogenic Substrates Clinic Clinical Clinical Research Coagulation Process Cues Drug Delivery Systems Drug effect disorder Drug vehicle Embolism Engineering Excision Fibrinogen Fibrinolytic Agents Fluorescence Fluorescence Microscopy Goals Half-Life Health Hemorrhage Imagery In Vitro Injectable Injury Integrins Ischemic Stroke Isoelectric Point Kinetics Label Ligands Mechanics Mediating Microscopy Modeling Morbidity - disease rate Mus Myocardial Infarction P-Selectin P-selectin ligand protein Particulate Pathology Peptides Perfusion Peripheral arterial disease Pharmaceutical Preparations Pharmacologic Substance Physiological Plasma Plasminogen Activator Platelet aggregation Procedures Property Research Risk Shapes Site Spectrophotometry Stroke Surface System Technology Testing Therapeutic Thrombolytic Therapy Thrombus Tissues Treatment Efficacy Vascular Diseases aqueous base blood flow measurement controlled release density design drug distribution flexibility hemodynamics high risk in vitro testing in vivo innovation interest intravital microscopy microscopic imaging mimetics mortality mouse model particle prevent receptor restoration stem targeted treatment tegrin thrombolysis

项目摘要

DESCRIPTION: In occlusive vascular diseases, dissolution of thrombus and rapid restoration of blood flow is critical in preventing tissue morbidity and mortality. To this end, current clinicl `clot-busting' strategies using intravascular systemic administration of thrombolytic drugs like tPA present issues of plasma-induced drug deactivation, short plasma half-life of drugs, rapid drug washout, reduced drug availability at target site, and systemic hemorrhagic side effects. These issues can be potentially resolved by controlled release of the drugs from injectable delivery vehicles that can selectively accumulate at the clot site under hemodynamic flow. For this, it is necessary for the vehicles to (i) actively bind to the clot site, (ii) stay retained uner flow, and (iii) allow localized drug release for site-selective action. For designing such a vehicl, natural platelets provide an excellent paradigm, since platelets have the innate capability to marginate towards the vascular wall, bind actively to clot via specific ligand-receptor interactions, and release cytoplasmic contents to modulate clot activities. The margination of platelets towards the vascular wall is facilitated by their discoid shape, ~2 µ diameter size and ~25-50 kPa modulus, while their active binding at the thrombus site is mediated via ligands fibrinogen (Fg) and PSGL-1 binding to platelet surface integrin GPIIb-IIIa and P-selectin respectively. Inspired by these physico-mechanical and biointeractive cues of natural platelets, we propose to engineer vehicles that will have (i) platelet-mimetic shape, size and modulus to facilitate enhanced margination towards the vascular wall, and (ii) heteromultivalent surface-decoration with GPIIb-IIIa- and P-selectin-binding peptide ligands to enable thrombus-selective anchorage and retention under hemodynamic flow. Our central hypothesis is that controlled release of thrombolytic drugs from such platelet-inspired vehicles anchoring at the thrombus site will enhance the site-specific therapeutic efficacy, while minimizing systemic drug distribution and side-effects. To test this, we will fabricate albumin-based platelet-inspired discoid flexible vehicles, modify their surface heteromultivalently with the active platelet-targeting ligands and evaluate their thrombus anchoring capability in vitro and in vivo (Aim1). In parallel, we will cationically modify tPA (mtPA) to facilitate its loading into the albumin particles since albumin i negatively charged at physiological pH, and characterize the loading and release of mtPA from these particles in vitro (Aim 2). After optimizing the platelet-inspired thrombus- anchoring mechanisms and the mtPA loading/release kinetics via these two synergistic yet independent aims, we will integrate them to create mtPA-loaded platelet-inspired vehicles which will be evaluated for targeted thrombolysis efficacy in vitro and in vivo (Aim 3). Our principal innovation is the design of a delivery vehicle that combines key physico-mechanical and biointeractive parameters inspired by platelets for enhanced thrombus-anchoring ability. The current application will test this technology for targeted thrombolytic therapy. The technology also holds the promise to become a platform for other targeted therapies in vascular diseases.

描述：在闭塞性血管疾病中，血栓溶解和血流快速恢复对于预防组织发病和死亡至关重要。为此，目前使用血管内全身施用 tPA 等溶栓药物的临床“溶栓”策略存在血浆问题。诱导的药物失活、药物血浆半衰期短、药物快速洗脱、靶点药物利用率降低以及全身出血副作用这些问题可以通过控释来解决。来自注射输送载体的药物可以在血流动力学流动下选择性地积聚在凝块部位，为此，载体必须（i）主动结合到凝块部位，（ii）在流动下保持保留。）允许局部药物释放以进行位点选择性作用，为了设计这样的载体，天然血小板提供了一个很好的范例，因为血小板具有向血管壁边缘移动的先天能力，通过特定的配体受体主动结合到凝块上。血小板的盘状形状、约 2 µ 直径大小和约 25-50 kPa 模量促进了血小板向血管壁的边缘化，而它们在血栓部位的主动结合是通过介导的。配体纤维蛋白原 (Fg) 和 PSGL-1 分别与血小板表面整合素 GPIIb-IIIa 和 P-选择素结合受到这些物理机械的启发。和天然血小板的生物交互线索，我们建议设计具有（i）血小板模拟形状、尺寸和模量的载体，以促进增强血管壁边缘化，以及（ii）用 GPIIb-IIIa- 和 P- 进行异多价表面装饰选择素结合肽配体能够在血流动力学流动下实现血栓选择性锚定和保留，我们的中心假设是溶栓药物从这种血小板激发的锚定载体中受控释放。为了测试这一点，我们将制造基于白蛋白的血小板启发的盘状柔性载体，并通过活性血小板靶向对其表面进行异多价修饰。同时，我们将阳离子修饰 tPA (mtPA)，以促进其装载到白蛋白颗粒中，因为白蛋白在生理条件下带负电。通过这两个协同但独立的目标优化血小板启发的血栓锚定机制和 mtPA 加载/释放动力学后，我们将它们整合到体外。创建装载 mtPA 的血小板启发载体，对其进行体外和体内靶向溶栓功效评估（目标 3）。是一种受血小板启发而设计的结合了关键物理机械和生物交互参数的药物，以增强血栓锚定能力。目前的应用将测试该技术的血栓靶向治疗能力。该技术也有望成为其他药物的平台。血管疾病的靶向治疗。