Efficacy and pharmacokinetic assessment of renal-targeted therapy in a pig model of cisplatin induced acute kidney injury.

项目摘要 急性肾损伤（阿基）是一种常见的临床疾病，与发病率和死亡率增加有关。阿基 约占美国住院人数的2%，医院获得性阿基的年度费用 大约有100亿美元。所有形式阿基的治疗干预仍然不足，部分原因是 低药物特异性和差的药代动力学特征。我们开发了一种新型的纳米级药物输送系统 选择性靶向啮齿动物近端肾小管上皮的平台（威廉姆斯，纳米快报，2015; 威廉姆斯，高血压，2018）。这种策略使药物在小鼠肾脏中的定位效率比在小鼠肾脏中高26倍。 任何其他器官。颗粒在近端和远端小管内释放其药物货物，同时不表现出任何细胞毒性。 对肾脏或其他器官的毒性作用。我们和我们的合作者已经成功地治疗了小鼠模型 顺铂诱导的阿基（CI-AKI）和缺血再灌注诱导的阿基（IR-AKI）。我们特别 施用负载有活性氧（ROS）清除剂依达拉奉的中尺度纳米颗粒， 导致使用剂量约为20 mg/kg的依达拉奉对鼠CI-AKI模型的显著功效， 比先前在啮齿动物模型中全身治疗阿基的剂量低154倍（威廉姆斯，bioRxiv，2020）。 此外，该平台证明了通过递送抗IR-AKI药物或抗IR-AKI药物来有效治疗小鼠中的IR-AKI。 免疫调节寡核苷酸（Han，Kidney International，2020）或NF-κB的肽调节剂（Han，JCI Insight，2020）。我们已发表的研究中提供的数据沿着本提案中的初步数据 证明了这种中尺度纳米颗粒（MNP）平台表现出卓越的临床潜力。整体 我们公司的目标是解决肾脏疾病治疗策略的未满足需求， 批准的和实验性的治疗有效载荷的肾脏。本提案的目的是评估 依达拉奉包封的MNP在顺铂猪模型中的药代动力学、生物分布和疗效- 诱发阿基。我们将追求以下具体目标：目标1：评估药物的药代动力学和生物分布 猪阿基模型中的依达拉奉负载的MNP。我们将评估的药代动力学和生物分布 在猪阿基模型中的依达拉奉负载的中尺度纳米颗粒。目的2：评估 猪阿基模型中的依达拉奉负载的MNP。我们将确定依达拉奉-MNP的疗效和安全性 并在顺铂诱导的猪阿基模型中与可溶性依达拉奉进行比较。第一阶段SBIR的结果 包括依达拉奉-MNP在猪中的生物分布、药代动力学和疗效评估， 最佳表征的大型动物模型，以接近人类肾脏生理学。这项工作将大大提高- 冒着这项技术的风险。它还将使该公司能够启动CMC和IND使能研究，并将为 为阿基患者规划适当的临床试验。

PROJECT SUMMARY Acute kidney injury (AKI) is a common clinical condition associated with increased morbidity and mortality. AKI accounts for approximately 2% of hospital admissions in the US, and the annual costs for hospital-acquired AKI are approximately $10 billion. Therapeutic interventions for all forms of AKI remain inadequate, in part due to low drug specificity and poor pharmacokinetic profiles. We have developed a novel nanoscale drug delivery platform that selectively targets the proximal tubular epithelium in rodents (Williams, Nano Letters, 2015; Williams, Hypertension, 2018). This strategy localizes drugs up to 26-fold more efficiently in mouse kidneys than any other organ. The particles release their drug cargo within the proximal and distal tubules while exhibiting no toxic effects on the kidneys or other organs. We and our collaborators have successfully treated murine models of both cisplatin-induced AKI (CI-AKI) and ischemia-reperfusion-induced AKI (IR-AKI). Specifically, we administered mesoscale nanoparticles loaded with the reactive oxygen species (ROS) scavenger edaravone, resulting in striking efficacy against a murine CI-AKI model using a dose of edaravone that was approximately 154 times lower than that previously shown to treat AKI systemically in a rodent model (Williams, bioRxiv, 2020). Further, the platform demonstrated effective treatment against IR-AKI in mice via delivery of either an immunomodulatory oligonucleotide (Han, Kidney International, 2020) or a peptide modulator of NF-κB (Han, JCI Insight, 2020). The data presented in our published studies along with preliminary data in this proposal demonstrate that this mesoscale nanoparticle (MNP) platform exhibits exceptional clinical potential. The overall goal of our company is to address the unmet need for treatment strategies for renal diseases by targeting both approved and experimental therapeutic payloads to the kidneys. The objective of this proposal is to evaluate the pharmacokinetic, biodistribution and efficacy of edaravone-encapsulated MNPs in a pig model of cisplatin- induced AKI. We will pursue the following specific aims: Aim 1: Assess Pharmacokinetics and Biodistribution of Edaravone-Loaded MNPs in a Porcine AKI Model. We will evaluate the pharmacokinetics and biodistribution of edaravone-loaded mesoscale nanoparticles in a pig model of AKI. Aim 2: Assess Efficacy and Safety of Edaravone-Loaded MNPs in a Porcine AKI Model. We will determine efficacy and safety of edaravone-MNPs and compare with soluble edaravone in a cisplatin-induced pig AKI model. The outcomes of this Phase I SBIR include an assessment of the biodistribution, pharmacokinetics and efficacy of edaravone-MNPs in pigs as the best characterized large-animal model to approximate human renal physiology. This work will substantially de- risk this technology. It will also allow the company to initiate CMC and IND-enabling studies and will set the stage for planning appropriate clinical trials in AKI patients.