Enhanced Delivery of Thrombolytic Carriers for Empyema

增强溶栓载体治疗脓胸的效果

• 批准号: 10450841
• 负责人: MELVIN E KLEGERMAN
• 金额: $ 62.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450841
• 关键词: 3-Dimensional; Acute; Address; Affinity; Age; Animals; Biochemical; Biophysics; Chemicals; Chronic; Clinical; Coagulation Process; Complex; Complication; Data; Disease; Dose; Drug Kinetics; Elderly; Empyema; Encapsulated; Fibrin; Fibrinolysis; Formulation; Foundations; Frequencies; Functional disorder; Half-Life; Health Care Costs; Hemorrhage; Histologic; Imaging Techniques; In Vitro; Incidence; Injury; Intervention; Liposomes; Liquid substance; Macroglobulins; Measurement; Mechanics; Modeling; Molecular; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Patients; Pharmaceutical Preparations; Physiological; Plasma; Plasmin; Plasminogen; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Pleural; Probability; Regimen; Research; Resistance; Risk; Sampling; Sepsis; Site; Solid; Streptococcus pneumoniae; Testing; Therapeutic; Thoracic Surgical Procedures; Thrombolytic Therapy; Tissues; Translational Research; Treatment Protocols; Ultrasonography; United States; Urokinase; X-Ray Computed Tomography; base; bench to bedside; commercialization; comorbidity; design; early phase clinical trial; effusion; experience; improved; improved outcome; indexing; innovation; liposomal delivery; liposome vector; male; mortality; nanomolar; novel; novel strategies; older patient; sex; sound; success; targeted delivery; therapy outcome; ultrasound

PROJECT SUMMARY Empyema (EMP) is increasing in frequency worldwide and is associated with a mortality rate of up to 20% in patients older than 65 years. Thoracic surgery for treating EMP is invasive and many patients have co-morbidities that preclude its use. Bleeding remains a major concern and occurs in up to about 5-15% of EMP patients treated with intrapleural fibrinolytic therapy (IPFT). These factors offer a premise for the identification of more effective, well-tolerated forms of IPFT that better address the molecular mechanisms governing intrapleural fibrinolysis, particularly in advanced-stage EMP. The need for more efficacious, innovative forms of IPFT represents a gap in the field that is of high priority and addressed in this project. The objective of our study is to identify novel interventions that improve therapeutic outcomes in subjects with EMP using a fibrin-targeted delivery of encapsulated plasminogen activators (PAs) combined with ultrasound sonofibrinolysis (US) in a validated model of Streptococcus pneumoniae induced EMP in rabbits. Liposomal carriers with single chain (sc) tissue (sctPA) and urokinase (scuPA), and resistant to plasminogen activator inhibitor 1 “molecular cage” type complexes with α-macroglobulin (αM/uPA) will be tested. Our preliminary data demonstrate that (i) transthoracic US or sctPA- based liposomes (TELIP) with nanomolar affinity to fibrin improve therapeutic outcomes of an otherwise ineffective dose of fibrinolysin; (ii) US promotes intrapleural formation of αM/uPA, which correlates with success of IPFT in pleural injury. Our hypothesis is that combining intrapleural delivery of low doses of a fibrinolysin encapsulated within fibrin targeted carriers with ultrasound sonofibrinolysis will additively increase the intrapleural half-life of plasminogen activators and rate of fibrinolysis, enhancing the efficacy of IPFT in acute and chronic S. pneumoniae induced EMP. The hypothesis will be tested in three Specific Aims: 1. Determine the minimal effective doses (MEDs) of echogenic liposomal carriers for treatment of S. pneumoniae induced EMP in rabbits. 2. Identify the ultrasound mechanical index and treatment schedule that optimizes outcomes of IPFT in rabbits with S. pneumoniae induced EMP. 3. Use the additivity of transthoracic ultrasound and fibrin- targeted carrier delivery to increase the efficacy of IPFT in S. pneumoniae induced EMP. Our project team consists of two groups with expertise in translational research, IPFT, management of EMP, therapeutic commercialization, and liposomal carrier formulation and delivery. By applying state-of-the-art biochemical, biophysical, physiologic, tissue analysis and imaging techniques, we will accomplish the Research Plan to address the current gaps in empyema treatment and expand our understanding of sonochemical mechanisms. If, as expected, this project succeeds, a new, well-tolerated, more effective and clinically tractable paradigm for IPFT will emerge that may ultimately improve outcomes in patients with empyema.

项目总结 脓胸(EMP)在全球范围内频率正在增加，并与#年高达20%的死亡率有关 65岁以上的患者。胸部手术治疗电磁脉冲是侵入性的，许多患者并存。 这就排除了它的使用。出血仍然是一个主要问题，在接受治疗的电磁脉冲患者中，出血的发生率高达5%-15%。 采用胸腔内纤溶治疗(IPFT)。这些因素为鉴定更有效的， 耐受性良好的IPFT形式，更好地解决了胸腔内纤溶的分子机制， 特别是在晚期电磁脉冲中。对更有效、更创新的IPFT形式的需求是一个缺口 在这一项目中涉及的具有高度优先地位的领域。我们研究的目的是找出小说 使用纤维蛋白靶向递送改善EMP患者治疗结果的干预措施 微囊化纤溶酶原激活剂(PAS)与超声超声纤溶(US)联合应用的验证模型 肺炎链球菌诱导兔电磁脉冲。单链组织脂质体载体(SctPA) 和尿激酶(ScuPA)，以及对纤溶酶原激活物抑制物1的抗药性。 将检测α-巨球蛋白(αM/uPA)。我们的初步数据表明：(I)经胸US或sctPA- 与纤维蛋白有纳摩尔亲和力的脂质体(TELIP)可改善其他疾病的治疗结果 无效剂量的纤溶酶；(Ii)US促进胸腔内αM/uPA的形成，这与成功相关 IPFT在胸膜损伤中的应用。我们的假设是，联合胸腔内注射低剂量的纤溶酶 包裹在纤维蛋白靶向载体内的超声超声纤溶将额外增加 胸腔内纤溶酶原激活物的半衰期和纤溶速率，提高IPFT治疗急性胸腔积液的疗效 慢性肺炎链球菌诱导的EMP。这一假设将在三个具体目标上进行检验：1.确定 回声脂质体载体治疗肺炎链球菌的最小有效剂量 兔的电磁脉冲。2.确定超声机械指数和治疗计划，以优化治疗结果 肺炎链球菌感染兔的IPFT诱导的电磁脉冲。3.利用经胸超声和纤维蛋白的可加性- 靶向载体传递提高IPFT治疗肺炎链球菌EMP的疗效。我们的项目组 由两个小组组成，具有翻译研究、IPFT、EMP管理、治疗方面的专业知识 商业化，脂质体载体制剂和递送。通过应用最先进的生物化学， 生物物理学、生理学、组织分析和成像技术，我们将完成研究计划以 解决目前脓胸治疗方面的空白，扩大我们对声化学机制的理解。 如果这个项目如预期的那样成功，一个新的、耐受性好的、更有效的和临床上易于处理的范例 IPFT将会出现，最终可能会改善脓胸患者的预后。