Enhanced Delivery of Thrombolytic Carriers for Empyema

项目摘要 脓胸（EMP）在世界范围内的发生率正在增加， 65岁以上的患者。胸外科手术治疗电磁脉冲是侵入性的，许多患者有合并症 排除其使用。出血仍然是一个主要问题，发生在高达约5-15%的EMP患者治疗 胸膜腔内纤溶治疗（IPFT）。这些因素为确定更有效的、 耐受性良好的IPFT形式，更好地解决了胸膜内纤维蛋白溶解的分子机制， 尤其是在高级电磁脉冲中对更有效、创新形式的IPFT的需求代表了一个差距 在本项目中高度优先和涉及的领域。我们研究的目的是确定新的 使用纤维蛋白靶向递送的干预措施改善EMP受试者的治疗结果 包封纤溶酶原激活剂（PA）联合超声纤溶（US）的有效模型 肺炎链球菌诱发的兔EMP。具有单链（sc）组织（sctPA）的脂质体载体 和尿激酶（scuPA），并耐纤溶酶原激活物抑制剂1“分子笼”型复合物， 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- 基于脂质体（TELIP）与纤维蛋白具有纳摩尔亲和力，改善了治疗结果，否则 纤溶酶的无效剂量;（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胸腔内注射低剂量纤溶酶 包封在纤维蛋白靶向载体内的超声声纤溶将额外增加 纤溶酶原激活物的胸膜内半衰期和纤溶速率，增强急性肺损伤患者IPFT的疗效 和慢性S. pneumoniae诱发EMP。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链球菌的最小有效剂量（MED）。肺炎诱导 兔子的EMP 2.确定超声机械指数和治疗方案，优化结果 用S. pneumoniae诱发EMP。3.利用经胸超声和纤维蛋白的叠加性- 靶向载体递送以增加IPFT在S. pneumoniae诱发EMP。我们的项目团队 由两个小组组成，他们在转化研究、IPFT、EMP管理、治疗 商业化以及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，组织分析和成像技术，我们将完成研究计划， 解决目前脓胸治疗的差距，扩大我们对声化学机制的理解。 如果像预期的那样，这个项目成功了，一个新的，耐受性好的，更有效的和临床上易处理的范例， IPFT的出现可能最终改善脓胸患者的结局。

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.