Ultrasound-mediated thrombolysis for MVO and PAO treatment.

用于 MVO 和 PAO 治疗的超声介导溶栓。

基本信息

批准号：
10447822
负责人：
Emmanuelle Joelle Meuillet
金额：
$ 35.02万
依托单位：
MICROVASCULAR THERAPEUTICS, LLC
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：
2021-07-09 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447822
关键词：
Acoustics Acute Acute myocardial infarction Affinity Animal Model Back Pain Binding Biochemical Blood Platelets Blood Vessels Caliber Cell Nucleus Charge Clinical Clinical Research Coagulation Process Consumption Contrast Media Coronary Data Definity Detection Development Diagnostic Effectiveness Electron Microscopy Electrostatics Excipients Excision Exploratory/Developmental Grants Phase II FDA approved Feasibility Studies Fibrin Formulation Gas Chromatography Gases Generations Goals Grant Hemorrhage Hindlimb In Vitro International Ischemic Stroke Laboratories Legal patent Ligands Lipids Lytic Measurement Mechanics Mediating Microbubbles Modeling Molecular Target Outcome Particle Size Pathway interactions Peptides Peripheral Pharmacologic Substance Physical condensation Physiologic pulse Process Production Progress Reports Publishing Raman Spectrum Analysis Rattus Reaction Refrigeration Reperfusion Therapy Research Personnel Risk Safety Site Spottings Structure System Temperature Testing Therapeutic Thrombectomy Thrombus Time Transmission Electron Microscopy Ultrasonography Universities artery occlusion base clinical development clinical efficacy design efficacy testing efficacy validation improved in vitro Model in vivo in vivo Model indexing molecular imaging nanoDroplet nanosized novel phase change porcine model preclinical development pressure product development programs research clinical testing side effect stem thrombolysis ultrasound

项目摘要

ABSTRACT Encouraging results have been obtained with microbubble (MB) enhanced sonothrombolysis (SL) to treat vascular occlusions in acute ST elevation MI (STEMI), peripheral arterial occlusions (PAO) and ischemic stroke. However, there is no approved MB for these indications. Thrombi are porous structures composed variably of RBC’s, fibrin and platelets. MB are micron sized structures and probably too large to effectively permeate thrombi. Efforts to remove occlusive thrombi via thrombectomy, mechanical disruption, and/or biochemical dissolution have demonstrated efficacy; however, these are time consuming, show mixed results in improving clinical outcomes, and are accompanied by substantial risk of hemorrhagic complications. Efforts to enhance the safety and efficacy of thrombus removal have high potential clinical impact. Ultrasound (US) has been shown to disrupt thrombi and MB can locally amplify and accelerate US-enhanced thrombolysis at a lower energy level. A caveat to the use of MB stems from their size (1-3 microns), which may limit their access to the interior of the microthrombi responsible for MVO and PAO. Smaller acoustically active materials, including phase change nanodroplets (ND, ~100-200 nm), should more easily penetrate thrombus to increase sonothrombolytic efficiency and clinical efficacy. Microvascular Therapeutics (MVT) has developed a safe and more stable lipid- based MB (MVT-100) less likely to induce anaphylactoid reactions as compared to Definity® and is developing MVT-100 via the 505(b)(2) pathway. Moreover, MVT has subsequently made ND from MVT-100 (Patent, US 9,427,410B2; herein referred as MVT-101) and conjugated ND with a peptide ligand with high affinity for fibrin (FTND). Electron microscopy of fibrin clots shows that FTND permeate clot > non-targeted ND >> FTMB>MB. Preliminary studies performed in our laboratory as well as by our collaborators at the University of Pittsburgh Center for Ultrasound Molecular Imaging and Therapeutics in an in vitro model of MVO show that fibrin micro- clots are disrupted by US with ND >> MB. Finally, our international co-Investigator was able to show in a recent clinical study of SL in acute PAO that Definity® plus US shortened the time to reperfusion compared to standard lytic therapy along. In this R33 Catalyze Program, our combined groups propose to formulate and characterize fibrin targeted MB (FTMB) and ND (FTND) and evaluate their effectiveness in vivo in disrupting the microvascular thrombi in biologically relevant models reflective of MVO during acute myocardial infarction and PAO. After production of bioconjugate and FTND/FTMB, we will evaluate their binding to the fibrin target. We hypothesize that FTND will improve fibrin clot detection and achieve superior dissolution of thrombi upon US activation as compared to MB and FTMB. The overall goal of this program is to obtain in vivo results in both animal models for the usage of FTNDs and perform feasibility studies which will, if successful, support further preclinical development and IND-enabling studies of ND for either PAO or MVO therapeutic indication.

抽象的通过微泡（MB）增强的Sonothrombolysy（SL）获得了令人鼓舞的结果以治疗急性ST升高MI（STEMI），周围动脉闭塞（PAO）和缺血性中风中的血管闭塞。但是，这些迹象没有批准的MB。血栓是多孔结构的多变结构 RBC的纤维蛋白和血小板。 MB是微米尺寸的结构，可能太大而无法有效渗透血栓。通过血栓切除术，机械破坏和/或生化去除闭塞性血栓的努力溶解已表现出效率；但是，这些很耗时，表现出不同的结果临床结果，是通过出血并发症的重大风险来实现的。努力增强安全性和清除血栓的易于性具有很高的潜在临床影响。超声（美国）已显示在较低的能量下，破坏血栓和MB可以局部扩增和加速美国增强的溶栓等级。警告使用MB的大小（1-3微米），这可能会限制其进入内部负责MVO和PAO的微骨。较小的声学材料，包括相变纳米条（nd，〜100-200 nm），应更容易穿透血栓以增加Sonothothrolbolytic 效率和临床效率。微血管疗法（MVT）开发了一种安全，更稳定的脂质与Definity®相比，基于MB（MVT-100）诱导过敏反应的可能性较小，并且正在发展 MVT-100通过505（b）（2）途径。此外，MVT随后从MVT-100（美国专利，美国专利）制作了ND 9,427,410b2;以下称为MVT-101），并与具有高亲和力的肽配体共轭ND （ftnd）。纤维蛋白凝块的电子显微镜表明，FTND渗透凝块>未靶向ND >> FTMB> MB。在我们的实验室以及匹兹堡大学的合作者中进行的初步研究在MVO的体外模型中，超声分子成像和治疗中心表明纤维蛋白微 - 凝块被ND >> MB破坏了。最后，我们的国际共同投资者能够在最近的一个与标准相比裂解疗法。在此R33催化程序中，我们的组合小组提出了制定和表征的建议纤维蛋白靶向MB（FTMB）和ND（FTND），并评估其在破坏微血管的体内有效性在急性心肌梗塞和PAO期间反映了与生物学相关的模型中的血栓。后生物轭和FTND/FTMB的产生，我们将评估它们与纤维蛋白靶标的结合。我们假设该FTND将改善纤维蛋白凝块检测并在我们激活时实现血栓的优势溶解与MB和FTMB相比。该程序的总体目标是获得两种动物模型的体内结果用于使用FTND并进行可行性研究，如果成功，将支持进一步的临床前 PAO或MVO治疗指示的ND的开发和成分研究。