Urolithin A nanoparticle therapy for acute kidney injury

项目摘要 急性肾损伤（阿基）是一种常见疾病，其病因可能是多因素的，目前FDA还没有明确的诊断标准。 用于预防或治疗的药物。来自实验室和临床研究的新证据 表明发病机制涉及活性氧（ROS）的产生，炎症和 凋亡途径;因此，调节这些途径提供保护。考虑到抗氧化剂，抗- 尿石素A（UA），鞣花酸的肠道微生物代谢产物的炎症和抗凋亡作用，目的是 本项目旨在探索UA在阿基中的治疗潜力。然而，UA的治疗潜力是 受生物利用度差的限制。这项工作是由以前的研究结果，其中口服尿酸是 通过生物可降解的纳米颗粒实现，所述纳米颗粒利用表面缀合的配体靶向肠道表达的 转铁蛋白受体UA的纳米颗粒包封导致口腔中的~7和~6倍增强， 分别在健康啮齿动物和狗中与天然UA相比的生物利用度。纳米颗粒UA治疗 还显着减弱了顺铂诱导的阿基的组织病理学特征，并降低了死亡率， 63%的小鼠模型。该项目将进一步开发UA作为治疗阿基的潜在治疗药物， 考虑到顺铂仅用于重复低剂量给药的癌症个体， 剂量在诊所。总体目标将通过追求以下独立的具体目标来实现。 目的1，将定义输送系统的结构元件和病理生理学可以 影响UA生物利用度。目标2，将评估最具生物利用度的UA形式在 剂量和年龄依赖性顺铂诱导的阿基，以及UA联合 顺铂在癌症治疗中的应用目的3将在健康犬中确定UA对顺铂诱导的阿基的疗效 （非癌症），在研究结束时将作为宠物重新回家。在研究结束时，我们 将理解并完全能够描述有效的交付如何影响UA的药理学， 关于小鼠和狗模型中的期望和不期望的作用。获得的知识将是有价值的 在开发UA不仅作为阿基和其他血管和神经炎性疾病的口服治疗中， 普通UA已经显示出一些益处的疾病，但也可作为联合治疗的辅助剂， 癌症治疗，可以立即在狗（癌症患者）身上进行临床试验。

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.