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型抗血栓药物，其疗效和安全性优于护理标准 通过以下特性：1) 特异性靶向促凝血表面，2) 高凝血位点结合和 阻断能力，3) 通过仅高度选择性阻断来减少血块尺寸的有效且特定的效果 凝血部位，4) 与当前抗血小板护理标准相比，降低出血风险，5) 立即 起效，以及 6) 快速从循环中清除。具体目标患者群体包括但可能不是 仅限于新发的急性血栓形成、尽管经过标准护理但复发性急性血栓形成、环境中的血栓形成 高出血风险，以及血栓切除或溶栓后缺血性再灌注损伤/复发性血栓形成， 包括急性中风和其他不良缺血事件。对每个群体的护理都有所改善 近几十年来显着，但总的来说仍然代表着对关键平衡的管理尚未解决。 降低凝血风险，而没有中度至重度临床出血的风险，或者在血栓清除的情况下， 随后血栓复发。这代表了一个重大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、高度稳定的单层材料，并获得了专利并进行了彻底的测试 外观由1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（POPC）组成的脂质体纳米颗粒 暴露 Zn(II)−双-二吡啶胺花青 3 [C22,22]（缩写为 DPA-Cy3[22,22]；一起，DPAL 表示 DPA- 暴露脂质体纳米颗粒），由我们设计并证明可以特异性结合促凝血剂 高度活化的促凝血血小板膜上的磷脂磷脂酰丝氨酸（PS）， 细胞外囊泡和其他促凝血 PS+ 细胞膜。我们专门寻求目标患者 抗血栓药物存在高出血风险或不足以预防血栓形成的人群，如 如上所述 - 在每种情况下，主要不良事件直接引起的 PS 暴露 传播凝血和随后的凝血病，这在临床上继续存在问题 管理。 DPAL 代表了一种创新、具体和有针对性的方法来预防或降低风险 与目前相比，不良心血管事件同时降低临床出血风险 通过选择性和有效地靶向促凝血细胞膜来抗血栓。我们强大的前期 数据表明，暴露 DPA 的脂质体 (DPAL) 具有满足以下要求的必要特性： 转化目标。我们将实现以下第一阶段里程碑目标：1）准备并表征 DPAL， 确定 DPAL 稳定性，并评估内皮毒性、损伤和通透性； 2）优化DPAL 剂量并确定急性阻断损伤和激动剂诱导的体内抗凝功效 在小鼠模型中维持止血的同时抑制血栓形成。这些重要的研究将为 进一步的转化研究转向临床试验。