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

脓毒症引起的ALI/ARDS是危重病患者急性呼吸衰竭的一种破坏性综合征， 占重症监护室入院率和死亡率最高的之一。在STTR第1阶段，我们在细胞生物学 Inc.证明了Piceat注l，一种选择性抑制Syk酪氨酸的天然抗炎药物 包埋在150 nm白蛋白纳米粒(PANPS)中的激酶在治疗上有效 3种不同脓毒症诱导的ALI/ARDS模型的实验性ALI和显著降低死亡率 如内毒素血症，盲肠结扎穿刺术(CLP)引起的多菌败血症，以及由 铜绿假单胞菌。这种保护直接归因于PANP介导的药物传递到 并不能通过单独注射抑制剂进行复制。此外，白蛋白纳米粒 未包埋药物的心钠素(ANP)没有治疗作用。纳米粒子优先被 细胞表面FcRIIIa表达于活化的吞噬细胞，如中性粒细胞和单核/巨噬细胞。 PANPS可抑制IL-I和肿瘤坏死因子的炎性细胞因子风暴。重要的是，PANP 然而，治疗并没有对循环中的非粘附性吞噬细胞的宿主防御反应产生不利影响。 细胞。在正常小鼠中，PANP主要由肝细胞内化，而在肺中优先内化 内毒素血症小鼠模型微血管包裹活化吞噬细胞证实了我们的假设 PANPS靶向活化的吞噬细胞介导ALI/ARDS。STTR第二阶段的超额目标 是生成支持数据，为ALI/ARDS的PANP治疗寻求FDA的“IND”地位。对于第二阶段，我们 选用猪和体外人肺脓毒症模型诱发ALI/ARDS，Tese是最接近人类的模型。在……里面 具体目标1，我们将扩大PANPs的规模，以满足猪脓毒症诱导的ALI/ARDS的需求 和体外人体肺脏研究。我们将确保纳米颗粒的稳定性、效力和储存能力。 特定目标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的目标是确定PANPS在治疗败血症中的疗效。 ALI/ARDS。由于这种疾病有多种病因，将在猪身上进行内毒素血症(内毒素血症)、大肠杆菌- 致腹膜炎和CLP引起的多菌败血症。体外人肺模型的研究将是 通过气管内传播的细菌性肺炎(E.Coli)攻击肺部而制成。我们会 同时执行我们在生物制药的帮助下制定的详细的商业化计划 行业、FDA和临床顾问。我们已经确定了要实现的目标的明确时间表 向FDA提交IND包装。此外，我们还概述了必要的调控途径。我们有 还提出了一个基于PANP的患者干预计划，将帮助我们进行未来的PANP临床试验。AS 我们在验证PANP在猪和体外人肺ALI模型中的有效性方面取得了进展，我们将 积极努力寻求生物制药和投资公司的承诺。

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.