Urolithin A nanoparticle therapy for acute kidney injury

项目摘要 急性肾损伤(AKI)是一种常见疾病，其病因可能是多因素的，目前还没有FDA- 用于预防或治疗该病的经批准的药物。来自实验室和临床研究的新证据 提示其发病机制涉及活性氧物种(ROS)的产生，炎症和 凋亡通路；因此，调节这些通路可提供保护。考虑到抗氧化剂，抗- 鞣花酸的肠道微生物代谢物尿液A(UA)的炎症和抗细胞凋亡作用 本课题旨在探讨尿酸在急性肾损伤中的治疗潜力。然而，UA的治疗潜力是 受制于生物利用度差。以前的研究结果使这项工作成为可能，其中口服尿酸是 通过利用表面共轭配体靶向肠道表达的可生物降解纳米颗粒实现 转铁蛋白受体。纳米粒包裹尿酸在口腔中的~7倍和~6倍增强 在健康啮齿动物和狗身上分别与天然尿酸进行生物利用度比较。纳米尿酸颗粒的治疗 还可显著减轻顺铂诱导的急性KI的组织病理学特征，并通过以下方式降低死亡率 在小鼠模型中为63%。该项目将进一步发展UA作为治疗AKI的潜在疗法， 考虑到顺铂仅用于重复低剂量给药的癌症患者 诊所里的剂量。总体目标将通过追求以下独立的具体目标来实现。 目标1将定义输送系统的结构元素和病理生理学可以在多大程度上 影响尿酸的生物利用度。目标2，将评估生物可利用度最高的尿酸形式在 顺铂诱导的AKI的剂量和年龄依赖性，以及UA联合UA的预期和不良影响 顺铂在癌症治疗中的应用。目的3确定尿酸对健康犬顺铂诱导的急性心肌梗死的疗效 (非癌症)，它们将在研究结束时作为宠物被送回家。在建议的研究结束时，我们 将理解并完全能够描述有效的递送如何影响尿酸的药理学， 关于小鼠和狗模型的期望和不期望的影响。所获得的知识将是有价值的 UA不仅是治疗AKI和其他血管和神经炎性疾病的口服药物 普通尿酸在这些疾病中显示出一些好处，但也在联合治疗中作为佐剂 癌症治疗，可以在狗(癌症患者)身上立即进行临床测试。

Project Summary The etiology of acute kidney injury (AKI), a common disease, can be multifactorial and currently has no FDA- approved drugs for its prevention or treatment. Emerging evidence from laboratory and clinical studies suggests the pathogenesis involves reactive oxygen species (ROS) generation, activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offer protection. Given the antioxidant, anti- inflammatory and antiapoptotic effects of urolithin A (UA), a gut microbial metabolite of ellagic acid, the aim of this project is to explore the therapeutic potential of UA in AKI. However, UA's therapeutic potential is constrained by poor bioavailability. The work enabled by previous findings, in which oral delivery of UA was achieved by biodegradable nanoparticles that utilize a surface conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a ~7 and ~6-fold enhancement in oral bioavailability compared to native UA in healthy rodents and dogs respectively. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. This project will further develop UA as a potential therapeutic for treating AKI, considering the fact that cisplatin is utilized only in individuals with cancer who are administered repeated low doses in the clinic. The overall goal will be accomplished by pursuing the following independent specific aims. Aim 1, will define the extent to which structural elements of the delivery system and the pathophysiology can influence UA bioavailability. Aim 2, will assess the protective benefits of the most bioavailable form of UA in dose and age dependent cisplatin-induced AKI, as well as desired and undesired effects of UA combined with cisplatin in cancer setting. Aim 3 will establish efficacy of UA against cisplatin-induced AKI in healthy dogs (non-cancerous), who will be re-homed as pets at the end of the study. At the end of the proposed studies, we will understand and fully be able to describe how effective delivery influences the pharmacology of UA, with regards to both desired and undesired effects in mice and dog models. The knowledge gained will be valuable in developing UA as not only an oral therapeutic for AKI and for other vascular and neuroinflammatory diseases in which plain UA has shown some benefit, but also as an adjuvant in combination therapies for cancer treatment, where immediate clinical testing in dogs (cancer patients) can be carried out.