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: 10597045
• 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/10597045
• 关键词: Abbreviations; Acute Renal Failure with Renal Papillary Necrosis; Address; Adjuvant; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Attenuated; Benchmarking; 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; 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; Periodicals; Peritoneal; Pharmaceutical Preparations; Pharmacology; Polyesters; Prevention; Public Health; Reactive Oxygen Species; Regimen; Renal function; Research; Resistance; Rodent; Safety; Speed; Surface; Syndrome; System; TFRC gene; Testing; Therapeutic; Tissues; Transferrin; Tubular formation; Unresectable; Work; age related; cancer cell; cancer therapy; canine model; chemotherapy; clinical translation; combination cancer therapy; comparative; cost; density; design; dosage; effective therapy; glomerular filtration; improved; intestinal barrier; microbial; mortality; mouse model; nanoparticle; nanopolymer; neuroinflammation; novel therapeutic intervention; particle; pet animal; receptor; research clinical testing; side effect; success; therapeutic nanoparticles; 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.

项目摘要 急性肾脏损伤（AKI）的病因是一种常见疾病，可以是多因素的，目前没有FDA- 批准了预防或治疗的药物。实验室和临床研究的新兴证据 提示发病机理涉及活性氧（ROS）产生，炎症激活和 凋亡途径；因此，规范这些途径提供了保护。鉴于抗氧化剂 尿素A（UA）的炎症和抗凋亡作用，肠道肠道微生物代谢产物，目的是 该项目是探索AKI中UA的治疗潜力。但是，UA的治疗潜力是 受生物利用度差的限制。以前的发现启用了该工作，其中的口服交付是 通过利用靶向肠道表达的表面共轭配体的可生物降解的纳米颗粒实现 转铁蛋白受体。 UA的纳米颗粒封装导致口服的〜7倍和〜6倍 与健康的啮齿动物和狗中的本机UA相比，生物利用度分别。用纳米颗粒UA处理 还显着削弱了顺铂诱导的AKI的组织病理学标志，并降低了死亡率 鼠标模型中有63％。该项目将进一步发展为治疗AKI的潜在治疗方法， 考虑到仅在癌症患者中使用顺铂的事实 诊所的剂量。总体目标将通过追求以下独立的特定目标来实现。 AIM 1将定义分娩系统的结构元素和病理生理学的程度 影响UA生物利用度。 AIM 2，将评估最可生物利用形式的UA的保护益处 剂量和依赖年龄的顺铂引起的AKI，以及UA的所需和不希望的效应 癌症中的顺铂。 AIM 3将建立对健康犬中替铂诱导的AKI的疗效 （非癌性），在研究结束时将被重新归为宠物。在拟议的研究结束时，我们 将理解并完全能够描述有效分娩的影响UA的药理学，并与 关于小鼠和狗模型的所需效果和不希望的效果。获得的知识将是有价值的 在开发UA时，不仅是针对AKI的口服治疗，以及其他血管和神经炎症性的治疗方法 普通UA表现出一些好处的疾病，但也作为组合疗法的辅助疗法 癌症治疗，可以在狗（癌症患者）中立即进行临床测试。