Urolithin A nanoparticle therapy for acute kidney injury

尿石素A纳米颗粒治疗急性肾损伤

• 批准号: 10193296
• 负责人: Meenakshi Arora
• 金额: $ 32.32万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10193296
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adjuvant; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Attenuated; Benchmarking; Bioavailable; Biological Availability; Blood Vessels; Cancer Patient; Canis familiaris; Carbon; Carcinoma; Characteristics; Cisplatin; Clinic; Clinical; Clinical Research; Cytotoxic agent; Data; Development; Disease; Dose; Drug Kinetics; Elements; Ellagic Acid; Encapsulated; Etiology; Excretory function; FDA approved; Formulation; Functional disorder; Generations; Goals; Home; Human; Impairment; Individual; Inflammatory; Kidney Diseases; Knowledge; Laboratory Study; Length; Length of Stay; Ligands; Literature; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Methods; Modeling; Morbidity - disease rate; Mus; Neoplasm Metastasis; Nucleosome Core Particle; Oncology; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Performance; Periodicity; Peritoneal; Pharmaceutical Preparations; Pharmacology; Polyesters; Polymers; Prevention; Public Health; Reactive Oxygen Species; Regimen; Renal function; Research; Resistance; Rodent; Safety; Speed; Structure; Surface; Syndrome; System; TFRC gene; Testing; Therapeutic; Tissues; Transferrin; Tubular formation; Unresectable; Work; age related; cancer cell; cancer therapy; chemotherapy; clinical translation; combination cancer therapy; comparative; cost; density; design; dosage; effective therapy; glomerular filtration; improved; intestinal barrier; microbial; mortality; mouse model; nanoparticle; neuroinflammation; novel therapeutic intervention; particle; pet animal; receptor; research clinical testing; side effect; success; therapeutic target; therapy outcome; tumor; uptake; urinary

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.

项目概要 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 FDA 尚无 批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、炎症和炎症的激活 细胞凋亡途径；因此，调节这些途径可以提供保护。鉴于抗氧化剂，抗 尿石素 A (UA)（一种鞣花酸的肠道微生物代谢物）的炎症和抗细胞凋亡作用，其目的 该项目旨在探索 UA 在 AKI 中的治疗潜力。然而，UA 的治疗潜力是 受到生物利用度差的限制。这项工作是由之前的研究结果促成的，其中口服 UA 是 通过可生物降解的纳米颗粒实现，该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 纳米颗粒封装导致口服效果提高约 7 倍和约 6 倍 分别与健康啮齿动物和狗的天然 UA 的生物利用度进行比较。纳米粒子UA治疗 还显着减弱了顺铂诱导的 AKI 的组织病理学特征，并降低了死亡率 小鼠模型中为 63%。该项目将进一步开发 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要素和病理生理学可以达到的程度 影响UA的生物利用度。目标 2，将评估生物利用度最高的 UA 形式的保护作用 顺铂引起的 AKI 的剂量和年龄依赖性，以及 UA 联合用药的预期和不良影响 顺铂在癌症治疗中的应用。目标 3 将确定 UA 对健康犬顺铂诱导的 AKI 的功效 （非癌症），研究结束后将被重新安置为宠物。在拟议的研究结束时，我们 将理解并完全能够描述有效递送如何影响 UA 的药理学， 关于小鼠和狗模型中期望和不期望的效果。获得的知识将是有价值的 开发 UA 不仅作为 AKI 以及其他血管和神经炎症的口服治疗药物 普通 UA 已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，可以立即对狗（癌症患者）进行临床测试。