Targeted Drug Delivery For Acute Respiratory Distress Syndrome

 描述（由申请人提供）：ARDS是一种急性、弥漫性、炎性肺损伤，由多种损伤引起，最常见的是肺炎、脓毒症和吸入1。美国每年约有200，000例病例，死亡率约为40%，并且没有批准的药物，ARDS代表了一个主要的未满足的医疗需求2。不幸的是，十几种药物在ARDS临床试验中失败3，可能有三个原因4：1）ARDS患者不稳定，因此副作用轻微的药物可能会增加死亡率5。2)ARDS是异质性的，因此作用于一个通路可能是不够的。3)吸入途径严重受阻于ARDS 5的淹没肺泡。我们的目标是通过创造纳米级的药物载体来解决这些问题，这些药物载体可以将多种药物特异性地输送到受影响的肺泡。为此，我们创建了PELs：肺内皮靶向脂质体，这是一种脂质体（100纳米球形磷脂双层），涂有结合肺内皮的抗体。静脉注射的PEI在肺泡内皮中积聚，使药物作用局部化。我们现在建议用调节一氧化氮（NO）通路的药物装载PEL。一氧化氮是一种强有力的抗炎剂，但其在急性呼吸窘迫综合征（ARDS）中的作用一直存在争议.冲突的部分原因是吸入的NO不能到达被淹没的肺泡，而IV NO供体药物会导致脱靶效应。此外，在ARDS期间，超氧化物（活性氧物质）增加，并且超氧化物将NO转化为促炎性过氧亚硝酸盐。这项建议的科学目的是确定是否PEL介导的NO输送到肺内皮细胞加重脂多糖（LPS）诱导的急性肺损伤（ALI），一种类似于人类ARDS的小鼠模型。因此，目标是：1）基于肺泡蛋白渗漏和白细胞计数以及血清细胞因子水平的测定，确定N0供体药物的PEL介导的递送是否降低LPS诱导的ALI。2)确定含有SOD的PEL单独或与NO供体PEL组合是否改善ARDS。这些研究可能提供一种新的治疗方法，并将有助于了解NO在ARDS中的作用。该提案的另一个关键目标是在靶向药物输送领域培训候选人。这将损害教学课程，个性化的指导，并在纳米载体生产，分析化学和ARDS动物模型等工具的实践培训。

 DESCRIPTION (provided by applicant): ARDS is an acute, diffuse, inflammatory lung injury caused by a variety of insults, most commonly pneumonia, sepsis, and aspiration1. With ~200,000 US cases per year, a mortality of ~40%, and no approved drugs, ARDS represents a major unmet medical need2. Unfortunately, more than a dozen drugs have failed in ARDS clinical trials3, perhaps for three reasons4: 1) ARDS patients are unstable, so drugs with mild side effects may increase mortality5. 2) ARDS is heterogeneous, so acting on one pathway may be insufficient. 3) The inhaled route is severely hampered by the flooded alveoli of ARDS5. We aim to solve these problems by creating nano-scale drug carriers that deliver multiple drugs specifically to affected alveoli. Towards that end, we created PELs: pulmonary endothelium-targeted liposomes, which are liposomes (100-nanometer spherical phospholipid bilayers) coated with antibodies that bind the pulmonary endothelium. Intravenous PELs accumulate in the alveolar endothelium, localizing drug effects. We now propose to load PELs with drugs that modulate the nitric oxide (NO) pathway. NO is a powerful anti- inflammatory, but data have been conflicting on its utility in ARDS. Part of the conflict is because inhaled NO does not reach flooded alveoli and IV NO donor drugs cause off-target effects. Additionally, during ARDS superoxide (a reactive oxygen species) is increased, and superoxide converts NO into pro-inflammatory peroxynitrite. The scientific objective of this proposal is to determine if PEL-mediated delivery of NO to the pulmonary endothelium alleviates lipopolysaccharide (LPS)-induced acute lung injury (ALI), a mouse model similar to human ARDS. The Aims are thus: 1) Determine if PEL-mediated delivery of NO donor drugs decreases LPS- induced ALI, based on assays of alveolar protein leak and leukocyte count, and serum cytokine levels. 2) Determine if PELs containing SOD ameliorate ARDS, alone or in combination with NO donor PELs. These studies may provide a new therapeutic, and will give insight into NO's role in ARDS. The proposal's other key objective is to train the candidate in the field of targeted drug delivery. Ths will compromise didactic coursework, individualized mentoring, and hands-on training in tools such as nanocarrier production, analytical chemistry, and animal models of ARDS.