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，其疗效和安全性高于标准护理。 通过以下性质：1)针对促凝剂表面的特异性靶向，2)高凝血剂结合部位和 阻断能力，3)通过选择性地仅高度阻断来减小血栓大小的有效和特定的效果 凝血剂部位，4)与目前的抗血小板护理标准相比，降低出血风险，5)立即 起效，以及6)快速清除循环。特定的目标患者队列包括，但可能不是 仅限于新的急性血栓形成、复发的急性血栓形成，尽管有标准的护理，血栓形成的环境 出血风险高，血栓摘除或溶栓后发生缺血再灌注损伤/血栓复发， 包括急性中风和其他不良缺血事件。对这些队列中的每一个人的护理都有所改善 近几十年来很明显，但总体上仍然代表着对 降低凝血风险，而不存在中到重度临床出血的风险，或者在清除血栓的情况下， 随后复发的血栓形成。这是一个重大的未得到满足的临床需求，我们正在寻求 地址。我们的团队已经开发、申请了专利，并彻底测试了一种合成的、高度稳定的单层膜 由1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine组成的脂质体纳米粒(POPC) [C22，22](简写为−-Cy3[22，22]； 暴露脂质体纳米粒)，由我们设计和演示，专门结合促凝剂 高活性促凝血小板膜上的磷脂磷脂酰丝氨酸(PS)， 胞外囊泡等促凝剂PS+细胞膜。我们特别寻求针对患者 抗血栓药物有很高的出血风险，或在预防血栓形成方面不足的队列，如 以上概述-在每种情况下，PS暴露直接由主要不良事件引起 传播凝血和随之而来的凝固性疾病，这在临床上仍然存在问题 管理层。DPAL代表了一种创新的、具体的和有针对性的方法来预防或降低 与当前相比，在降低临床出血风险的同时发生不良心血管事件 抗血栓药，通过选择性和有效靶向促凝血细胞膜。我们强势的预赛 数据表明，DPA暴露脂质体(DPAL)具有必要的性质，以满足 翻译目标。我们将实现以下第一阶段的里程碑目标：1)准备和表征DPAL， 测定DPAL稳定性，评价内皮细胞毒性、损伤和通透性；2)优化DPAL 急性阻断损伤和激动剂诱导的剂量和体内抗凝效果的测定 在小鼠模型中维持止血时的血栓形成。这些基本研究将坚定地为 进一步的翻译研究进入临床试验。