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.

项目概要 脓胸 (EMP) 在全球范围内的发病率不断增加，并且与高达 20% 的死亡率相关 65岁以上的患者。治疗 EMP 的胸外科手术是侵入性的，许多患者有合并症 这妨碍了它的使用。出血仍然是一个主要问题，在接受治疗的 EMP 患者中，出血率高达 5-15% 胸膜腔内纤溶治疗（IPFT）。这些因素为识别更有效的、 耐受性良好的 IPFT 形式可以更好地解决控制胸膜内纤维蛋白溶解的分子机制， 特别是在高级电磁脉冲中。对更有效、创新形式的 IPFT 的需求存在差距 在本项目中高度优先并解决的领域。我们研究的目的是确定新颖的 使用纤维蛋白靶向递送来改善 EMP 受试者的治疗结果的干预措施 在经过验证的模型中封装纤溶酶原激活剂 (PA) 与超声纤溶酶 (US) 相结合 肺炎链球菌诱导家兔电磁脉冲的研究。具有单链 (sc) 组织 (sctPA) 的脂质体载体 和尿激酶 (scuPA)，并抵抗纤溶酶原激活剂抑制剂 1“分子笼”型复合物 将测试 α-巨球蛋白 (αM/uPA)。我们的初步数据表明 (i) 经胸超声或 sctPA- 具有纳摩尔级纤维蛋白亲和力的脂质体 (TELIP) 可改善其他药物的治疗效果 纤溶酶剂量无效； (ii) US 促进胸膜内 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，结合胸腔内输送低剂量的纤溶酶 封装在纤维蛋白靶向载体内，通过超声波超声纤溶作用将进一步增加 纤溶酶原激活剂的胸膜内半衰期和纤维蛋白溶解率，增强 IPFT 在急性期的疗效 和慢性肺炎链球菌诱导的电磁脉冲。该假设将在三个具体目标中进行检验： 1. 确定 回声脂质体载体治疗肺炎链球菌引起的最小有效剂量（MED） 电磁脉冲对兔子的作用。 2. 确定超声机械指标和治疗方案以优化结果 肺炎链球菌诱导 EMP 兔子的 IPFT。 3.利用经胸超声和纤维蛋白的相加性 靶向载体递送以提高 IPFT 在肺炎链球菌诱导的 EMP 中的功效。我们的项目团队 由两个在转化研究、IPFT、EMP 管理、治疗 商业化、脂质体载体配制和递送。通过应用最先进的生化技术， 生物物理、生理学、组织分析和成像技术，我们将完成研究计划 解决目前脓胸治疗方面的差距并扩大我们对声化学机制的理解。 如果正如预期的那样，该项目成功，将为患者提供一种新的、耐受性良好、更有效且临床上易于处理的范例 IPFT 的出现可能最终改善脓胸患者的预后。