Phosphatidylserine-blocking nanoparticles as improved anti-thrombotic with reduced bleeding risk

磷脂酰丝氨酸阻断纳米颗粒可改善抗血栓形成并降低出血风险

• 批准号: 10598788
• 负责人: Brian David Gray
• 金额: $ 29.99万
• 依托单位: MOLECULAR TARGETING TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598788
• 关键词: Abbreviations; Acute; Address; Adverse event; Agonist; Anticoagulants; Binding; Binding Sites; Blood Coagulation Disorders; Blood Platelets; Bolus Infusion; Cardiovascular system; Caring; Cell surface; Cellular Membrane; Circulation; Clinical; Clinical Management; Clinical Trials; Coagulants; Coagulation Process; Coupling; Data; Dose; Edema; Endothelial Cells; Endothelium; Equilibrium; Event; Excision; Factor Xa; Fibrinolytic Agents; Hemorrhage; Hemostatic function; Human; In Vitro; Infusion procedures; Injury; Ischemia; Legal patent; Link; Liposomes; Maps; Measurement; Membrane; Methods; Mus; Patients; Permeability; Phase; Phosphatidylserines; Phospholipids; Phosphorylcholine; Plasma; Pre-Clinical Model; Prevention; Production; Property; Recurrence; Reperfusion Injury; Risk; Risk Reduction; Safety; Site; Surface; Testing; Thrombectomy; Thromboplastin; Thrombosis; Thrombus; Time; Toxic effect; acute stroke; antithrombin III-protease complex; clinical risk; clinical translation; cohort; cyanine; design; dosage; extracellular vesicles; high risk; improved; in vivo; innovation; intravenous administration; minimal risk; mouse model; nanoparticle; novel; permissiveness; phase 1 study; prevent; scale up; standard of care; thrombolysis; thrombotic; translational goal; translational study; venous thromboembolism; wound

We propose to develop a novel antithrombotic agent with improved efficacy and safety over standard of care via the following properties: 1) specific targeting to procoagulant surfaces, 2) high coagulant site binding and blocking capacity, 3) potent and specific effects of reducing clot size by selectively blocking only highly coagulant sites, 4) reducing bleeding risk compared with current antiplatelet standard of care, 5) immediate onset, and 6) rapid clearance from circulation. The specific target patient cohorts include, but may not be limited to new acute thrombosis, recurrent acute thrombosis despite standard of care, thrombosis in the setting of high bleeding risk, and ischemic reperfusion injury/recurrent thrombosis after thrombectomy or thrombolysis, including acute stroke and other adverse ischemic events. Care for each of these cohorts has improved markedly in recent decades, but altogether still represents unsolved management of the critical balance of reducing clotting risk without risks of moderate to severe clinical bleeding, or in cases of clot removal, subsequent recurrent thrombosis. This represents a major unmet clinical need, which we are seeking to address. Our team has developed, patented, and thoroughly tested a synthetic, highly stable unilamellar liposome nanoparticle composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) outwardly exposing Zn(II)−bis-dipicolylamine cyanine 3 [C22,22] (abbreviated, DPA-Cy3[22,22]; together, DPAL for DPA- exposing liposome nanoparticles), designed and demonstrated by us to bind specifically the procoagulant phospholipid phosphatidylserine (PS) on the membranes of highly activated procoagulant platelets, extracellular vesicles, and other procoagulant PS+ cellular membranes. We seek specifically to target patient cohorts for which antithrombotics present high risk of bleeding, or are insufficient in preventing thrombosis, as outlined above - in each of these cases, PS exposure induced by the principal adverse event directly propagates coagulation and ensuing coagulopathies which continue to present problems in clinical management. DPAL represent an innovative, specific and targeted approach to preventing or reducing risk for adverse cardiovascular events while simultaneously reducing risk of clinical bleeding compared to current antithrombotics, via selective and potent targeting of procoagulant cellular membranes. Our strong preliminary data demonstrate that DPA-exposing liposomes (DPAL) harbor the necessary properties to fulfill the translational goals. We will achieve the following Phase I milestone aims: 1) prepare and characterize DPAL, determine DPAL stability profile, and evaluate endothelial toxicity, damage and permeability; 2) optimize DPAL dosage and determine in vivo anticoagulant efficacies in acute blockade of injury- and agonist-induced thrombosis while maintaining hemostasis in mouse models. These essential studies will firmly set the stage for further translational studies moving to clinical trials.

我们建议开发一种新的抗血栓药物，其疗效和安全性优于标准治疗 通过以下性质：1）特异性靶向促凝血表面，2）高凝血位点结合， 阻断能力，3）通过选择性地仅高度阻断而减少凝块大小的有效和特异性作用 凝血部位，4）与当前抗血小板标准治疗相比，降低出血风险，5）立即 发作，和6）从循环中快速清除。特定目标患者队列包括但不限于 仅限于新发急性血栓形成、标准治疗后复发的急性血栓形成、环境中血栓形成 血栓切除术或溶栓后高出血风险和缺血再灌注损伤/复发性血栓形成， 包括急性中风和其它不良的局部缺血事件。对这些群体的护理都有所改善 近几十年来，这一问题明显存在，但总体上仍然代表着对关键的 降低凝血风险，无中度至重度临床出血风险，或在凝块清除的情况下， 随后复发性血栓形成。这代表了一个主要的未满足的临床需求，我们正在寻求 地址.我们的团队开发了一种合成的高度稳定的单层膜， 由1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（POPC）组成的脂质体纳米粒 暴露Zn（II）−bis-dipicolylamine cyanine 3 [C22，22]（缩写为DPA-Cy 3 [22，22];合起来，DPAL代表DPA- 暴露的脂质体纳米颗粒），其由我们设计并证明特异性结合促凝血剂 磷脂酰丝氨酸（PS）在高度活化的促凝血血小板的膜上， 细胞外囊泡和其他促凝血PS+细胞膜。我们专门针对患者 抗血栓药物存在高出血风险或不足以预防血栓形成的队列，例如 在这些病例中，主要不良事件直接诱导的PS暴露 传播凝血和随后的凝血病， 管理DPAL代表了一种创新的，具体的和有针对性的方法，以预防或降低风险， 与目前相比，在降低临床出血风险的同时， 抗血栓药，通过选择性和有效的靶向促凝血细胞膜。我们强大的初步 数据表明，DPA暴露脂质体（DPAL）具有实现 翻译目标。我们将实现以下第一阶段的里程碑目标：1）制备和表征DPAL， 测定DPAL的稳定性，并评价内皮毒性、损伤和渗透性; 2）优化DPAL 剂量和确定在损伤和激动剂诱导的急性阻断中的体内抗凝效力 在小鼠模型中，血栓形成同时维持止血。这些重要的研究将为 进一步的转化研究进入临床试验。