Albumin Nanoparticles Incorporating Piceatannol (PANPs) for ALI/ARDS therapy

含有白皮杉醇 (PANP) 的白蛋白纳米颗粒用于 ALI/ARDS 治疗

• 批准号: 9663231
• 负责人: Prasad V. S. Kanteti
• 金额: $ 86.71万
• 依托单位: NANO BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9663231
• 关键词: Acute Lung Injury; Acute respiratory failure; Admission activity; Adult Respiratory Distress Syndrome; Affect; Albumins; Animal Model; Anti-inflammatory; Bacterial Pneumonia; Cardiovascular Physiology; Cell surface; Cells; Clinic; Clinical; Clinical Data; Clinical Pharmacology; Clinical Trials; Critical Illness; Data; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Effectiveness; Endotoxemia; Endotoxins; Ensure; Environmental air flow; Escherichia coli; Etiology; Family suidae; Funding; Future; Goals; Health Care Costs; Hepatocyte; Host Defense; Human; Immune response; Industry; Inflammatory; Intervention; Investments; Lung; Measurement; Mediating; Modeling; Mus; Pathology; Pathway interactions; Patients; Peritonitis; Phagocytes; Pharmaceutical Preparations; Pharmacotherapy; Phase; Piceatannol; Pneumonia; Preparation; Privatization; Procedures; Protein Tyrosine Kinase; Pseudomonas aeruginosa; Regulatory Pathway; Research Design; Respiratory physiology; Route; Sepsis; Small Business Technology Transfer Research; Syndrome; TNF gene; Testing; Therapeutic Effect; Time; Toxicology; Treatment Efficacy; aging population; base; cecal ligation puncture; combat; commercialization; cytokine; cytokine release syndrome; defense response; drug metabolism; effective therapy; efficacy study; efficacy testing; inhibitor/antagonist; kinase inhibitor; macrophage; monocyte; mortality; mouse model; nanodrug; nanoparticle; neutrophil; particle therapy; polymicrobial sepsis; pre-clinical; preclinical study; response; scale up

Sepsis-induced ALI/ARDS is a devastating syndrome of acute respiratory failure in critically ill patients that accounts for among the highest admission rates in ICU and mortality. During STTR Phase 1, we at Cell Biologics Inc., demonstrated that piceatannol, a naturally occurring anti-inflammatory that selectively inhibits Syk tyrosine kinase, when entrapped in in 150 nm albumin nanoparticles (PANPs) was therapeutically effective in treating experimental ALI and significantly reduced mortality in 3 different mouse sepsis induced ALI/ARDS models such as endotoxemia, cecal ligation puncture (CLP)-induced polymicrobial sepsis, and pneumonia induced by Pseudomonas aeruginosa. This protection was ascribed directly to PANP-mediated delivery of the drug into phagocytic cells and could not be reproduced by injecting the inhibitor alone. Moreover, albumin nanoparticles (ANP), without the drug entrapped, had no therapeutic effect. The nanoparticles were preferentially taken up by cell surface FcRIIIa expressed in activated phagocytic cells such as neutrophils and monocytes/macrophages. Treatment with PANPs suppressed the IL-Iand TNF inflammatory cytokine storm. Importantly, PANP treatment however did not adversely affect the host defense response in the circulating non-adherent phagocytic cells. In normal mice, PANPs were mainly internalized by liver cells whereas they were preferentially in lung microvascular entrapped activated phagocytic cells in endotoxemic mice model substantiating our hypothesis that PANPs target activated phagocytic cells mediating ALI/ARDS. The overreaching goal in STTR Phase II is to generate supporting data to seek FDA ‘IND’ status for PANP therapy of ALI/ARDS. For Phase II, we chose Pig and ex vivo human lung models of sepsis induced ALI/ARDS, as tese are the closest to humans. In specific aim 1, we will undertake the scaling-up of PANPs to meet demands of pig sepsis-induced ALI/ARDS and ex vivo human lung studies. We will ensure stability, potency and storage capabilities of the nanoparticles. Specific aim 2 will determine pharmacokinetic parameters, drug metabolism and early toxicological studies using the pig model. The goal of specific aim 3 will be to establish the efficacy of PANPs in treatment of sepsis-induced ALI/ARDS. As the disease has multiple etiologies, studies in pigs will be made using LPS (endotoxemia), E. coli- induced peritonitis, and polymicrobial sepsis induced by CLP. Studies in the ex vivo human lung model will be made by challenging lungs with bacterial pneumonia (E. coli) delivered by the intra-tracheal route. We will concomitantly implement the detailed commercialization plan we have developed with the help of bio-pharma industry, FDA and clinical consultants. We have established clear time lines of goals to be achieved for submission of IND package to FDA. In addition, we have outlined the necessary regulatory pathway. We have also proposed a PANP based patient intervention plan that will aid us in pursuing future PANP clinical trials. As we make progress validating the efficacy of PANP in pig and ex vivo human lung models of ALI, we will make aggressive efforts to seek commitments from biopharma and investment firms.

脓毒症诱导的ALI/ARDS是危重患者急性呼吸衰竭的破坏性综合征， 占ICU入院率和死亡率的最高比例。在STTR第1阶段，我们在Cell Biologics 股份有限公司、证明了Piceatannol，一种选择性抑制Syk酪氨酸的天然抗炎药， 当包埋在150 nm白蛋白纳米颗粒（PANP）中时， 在3种不同的小鼠脓毒症诱导的ALI/ARDS模型中， 如内毒素血症、盲肠结扎穿孔（CLP）诱导的多微生物败血症和 绿脓杆菌。这种保护作用直接归因于PANP介导的药物递送至 吞噬细胞，并且不能通过单独注射抑制剂来复制。此外，白蛋白纳米颗粒 (ANP)未包封的药物无治疗作用。纳米颗粒优先被 在活化的吞噬细胞如嗜中性粒细胞和单核细胞/巨噬细胞中表达的细胞表面Fc γ RIIIa。 用PANP治疗抑制了IL-1 β和TNF α炎性细胞因子风暴。重要的是，PANP 然而，治疗对循环非粘附吞噬细胞中的宿主防御反应没有不利影响。 细胞在正常小鼠中，PANPs主要被肝细胞内化，而它们优先在肺中内化 内毒素血症小鼠模型中微血管捕获的活化吞噬细胞证实了我们的假设 PANP靶向介导ALI/ARDS的活化吞噬细胞。STTR第二阶段的过度目标 是生成支持性数据，以寻求ALI/ARDS PANP治疗的FDA“IND”状态。第二阶段，我们 选择了猪和离体人肺脓毒症诱导的ALI/ARDS模型，因为它们最接近于人。在 具体目标1，我们将扩大PANP的规模，以满足猪败血症诱导的ALI/ARDS的需求 和离体人肺研究。我们将确保纳米颗粒的稳定性、效力和储存能力。 具体目标2将确定药代动力学参数、药物代谢和早期毒理学研究， 猪的模型具体目标3的目标将是确定PANP在治疗脓毒症诱导的 ALI/ARDS。由于该病有多种病因，因此将使用LPS（内毒素血症）、E.大肠杆菌- 诱导的腹膜炎和CLP诱导的多微生物脓毒症。将在离体人肺模型中进行研究。 通过挑战肺部细菌性肺炎（E。大肠杆菌）通过气管内途径递送。我们将 同时实施我们在生物制药公司的帮助下制定的详细商业化计划 行业、FDA和临床顾问。我们已经制定了明确的目标时间表， 向FDA提交IND包装。此外，我们还概述了必要的监管途径。我们有 还提出了一个基于PANP的患者干预计划，这将有助于我们进行未来的PANP临床试验。作为 我们在证实PANP在猪和离体人肺ALI模型中的功效方面取得了进展， 积极努力寻求生物制药和投资公司的承诺。