Targeted Drug Delivery For Acute Respiratory Distress Syndrome

急性呼吸窘迫综合征的靶向给药

• 批准号: 8982338
• 负责人: Jacob Brenner
• 金额: $ 6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8982338
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adverse effects; Affect; Alveolar; Alveolus; Analytical Chemistry; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Binding; Biological Assay; Blood capillaries; Breathing; Clinical; Conflict (Psychology); Data; Development; Diffuse; Drug Carriers; Drug Delivery Systems; Drug Packaging; Endothelial Cells; Endothelium; Enzymes; Epithelial; FDA approved; Floods; Free Radicals; Functional disorder; Future; Goals; Human; In Vitro; Individual; Infiltration; Inflammatory; Injury; Intravenous; Leukocytes; Lipopolysaccharides; Liposomes; Liquid substance; Lung; Measurement; Mediating; Medical; Mentors; Modeling; Mus; NADPH Oxidase; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Pathway; Nitroprusside; Paper; Pathway interactions; Patients; Peroxonitrite; Pharmaceutical Preparations; Phospholipids; Pneumonia; Population; Positioning Attribute; Problem Solving; Production; Property; Prophylactic treatment; Proteins; Pulmonary alveolar structure; Reactive Oxygen Species; Research Personnel; Role; Route; Sepsis; Serum; Signaling Molecule; Superoxide Dismutase; Superoxides; Target Populations; Technology; Testing; Therapeutic; Therapeutic Effect; Training; Vascular Cell Adhesion Molecule-1; White Blood Cell Count procedure; Work; base; capillary; cytokine; improved; inflammatory lung disease; inflammatory marker; inhaled nitric oxide; inhibitor/antagonist; insight; lung injury; mortality; mouse model; nanocarrier; nanomedicine; nanometer; nanoscale; novel therapeutics; prevent; protein expression; public health relevance; small molecule; tool; transcription factor; translational medicine

 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.

 描述（由申请人提供）：ARDS 是一种急性、弥漫性、炎症性肺损伤，由多种损伤引起，最常见的是肺炎、败血症和误吸1，美国每年约有 200,000 例病例，死亡率约为 40%，且无。批准后，ARDS 代表了一个重大的未满足的医疗需求 2 不幸的是，有十多种药物在 ARDS 临床试验中失败了 3，可能有以下三个原因 4：1）ARDS 患者病情不稳定，因此药物作用较轻。副作用可能会增加死亡率5。2) ARDS 是异质的，因此仅作用于一种途径可能是不够的。3) ARDS 的淹没肺泡严重阻碍了吸入途径5。为此，我们创建了 PEL：肺内皮靶向脂质体，即脂质体（100 纳米球形）。磷脂双分子层）涂有与肺内皮结合的抗体，静脉内 PEL 积聚在肺泡内皮中，从而限制药物作用。但关于其在 ARDS 中的效用的数据一直存在争议，部分冲突是因为吸入的 NO 无法到达淹没的肺泡，而静脉注射 NO 供体药物会导致脱靶。此外，在 ARDS 期间，超氧化物（一种活性氧）增加，并且超氧化物将 NO 转化为促炎性过氧亚硝酸盐。该提案的科学目的是确定 PEL 介导的 NO 向肺内皮的传递是否会减轻脂多糖（LPS）。 ）诱导的急性肺损伤（ALI），与人类 ARDS 类似的小鼠模型，其目的是：1）确定 PEL 介导的 NO 供体药物的递送是否会降低 LPS-。诱导的 ALI，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 2) 确定含有 SOD 的 PEL 是否单独或与 NO 供体 PEL 联合改善 ARDS。该提案的另一个关键目标是在靶向药物输送领域对候选人进行培训，这将影响教学课程、个性化指导和工具实践培训。例如纳米载体生产、分析化学和 ARDS 动物模型。