Enhanced Delivery of Thrombolytic Carriers for Empyema

增强溶栓载体治疗脓胸的效果

基本信息

批准号：
10686862
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
项目类别：
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/10686862
关键词：
3-Dimensional Acute Address Affinity Age Animals Biochemical Biophysics Chemicals Chest 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 Pneumonia Probability Regimen Research Resistance Risk Sampling Sepsis Site Solid Streptococcus pneumoniae Technology Testing Therapeutic Thoracic Surgical Procedures Thrombolytic Therapy Tissues Translational Research Treatment Protocols Ultrasonography United States Urokinase X-Ray Computed Tomography bench to bedside commercialization comorbidity design early phase clinical trial effusion experience human old age (65+)improved improved outcome indexing innovation liposomal delivery liposome vector male mortality nanomolar novel novel strategies older patient risk mitigation sex sound success targeted delivery therapy outcome ultrasound

项目摘要

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.

项目摘要脓胸（EMP）在全球频率上增加，与死亡率高达20％有关年龄超过65岁的患者。治疗EMP的胸外科手术具有侵入性，许多患者患有合并症这阻止了它的使用。出血仍然是一个主要问题，发生在多达5-15％的EMP患者中胸膜纤维蛋白水解疗法（IPFT）。这些因素为识别更有效的前提提供了前提易耐受的IPFT形式，可以更好地解决有关胸膜内纤维蛋白溶解的分子机制，特别是在高级EMP中。需要更高效，创新的IPFT表示差距在该项目中高度重视并解决的领域中。我们研究的目的是确定新颖使用针对纤维蛋白的递送来改善EMP受试者治疗结果的干预措施在经过验证的模型中结合了超声Sonobibrinsylysylysylysylysy（US）的封装纤溶酶原激活剂（PAS）肺炎链球菌诱导兔子的EMP。带有单链（SC）组织（SCTPA）的脂质体载体和尿激酶（SCUPA），并且对纤溶酶原激活剂抑制剂1“分子笼”类型的复合物具有抗性将测试α-巨球蛋白（αM/UPA）。我们的初步数据表明（i）经胸化或sctpa- 基于纳摩尔亲和力对纤维蛋白的基于脂质体（talip）改善了否则的治疗结果无效的纤维纤维蛋白剂量；（ii）US促进αM/UPA的胸膜内形成，这与成功相关胸膜损伤中的IPFT。我们的假设是，将低剂量的纤维蛋白蛋白蛋白的胸膜内递送结合用超声Sonodbroinsylysy溶解构成纤维蛋白靶向载体，将添加增加纤溶酶原活化剂的胸膜胸膜半衰期和纤维蛋白溶解速率，提高了IPFT的效率慢性肺炎链球菌诱导EMP。该假设将以三个特定目的进行检验：1。回声脂质体载体的最小有效剂量（MED）用于治疗肺炎链球菌兔子中的emp。 2。确定优化结果的超声机械指数和治疗时间表脑肺炎链球菌诱导EMP的兔子中的IPFT。 3。使用经胸超声和纤维蛋白的添加性靶向载体输送以提高肺炎链球菌诱导EMP的IPFT效率。我们的项目团队由两个具有翻译研究专业知识的小组组成，IPFT，EMP管理，治疗商业化以及脂质体载体配方和交付。通过应用最先进的生化，生物物理，生理，组织分析和成像技术，我们将完成研究计划解决脓乳治疗中当前的差距，并扩展我们对声学机制的理解。如果正如预期的那样，该项目成功，是一个新的，耐受的，更有效，更有效和临床上的范式 IPFT将出现，最终可能会改善脓肿患者的预后。