Mitigate cisplatin induced acute kidney injury through preservation of vasculature and proximal tubule

通过保护脉管系统和近端小管减轻顺铂引起的急性肾损伤

• 批准号: 10209816
• 负责人: Hua Pan
• 金额: $ 42.4万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10209816
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adverse effects; Affect; Aftercare; Amifostine; Animals; Apoptosis; Autophagocytosis; Biodistribution; Blood Vessels; Brain; Cancer Patient; Cancer Survivor; Cells; Chemotherapy-Oncologic Procedure; Chronic; Chronic Kidney Failure; Cisplatin; Clinical Trials; Cytoplasm; Disease; Dose; Drug Interactions; Drug Kinetics; Drug or chemical Tissue Distribution; Early Diagnosis; Endothelium; Evaluation; Event; Exhibits; FRAP1 gene; Face; Failure; Fluorocarbons; Follow-Up Studies; Hydration status; Hypoxia; Impairment; In Vitro; Incidence; Individual; Inflammation; Injury; Injury to Kidney; Intervention; Kidney; Magnesium; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Medical; Molecular; Morbidity - disease rate; Mus; Organ; Oxidative Stress; Patients; Penicillins; Pharmaceutical Preparations; Pharmacodynamics; Platinum; Prevention; Prognosis; Quality of life; Regimen; Renal function; Reperfusion Injury; Risk; Safety; Signal Pathway; Signal Transduction; Sirolimus; Survival Rate; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Tubular formation; Warm Ischemia; adaptive immune response; anti-cancer; anticancer treatment; base; cancer therapy; cell injury; chemotherapy; childhood cancer survivor; clinical translation; early phase clinical trial; effective therapy; efficacy evaluation; hypoperfusion; imaging modality; improved; improved outcome; in vivo; injured; kidney vascular structure; mortality; nanoparticle; nanoparticle delivery; nephrotoxicity; ovarian neoplasm; preclinical study; preservation; prevent; quantitative imaging; side effect; statistics; success; targeted agent; therapeutic evaluation; tumor; tumor growth; uptake; vascular injury; wasting

Abstract Since its discovery about five decades ago, cisplatin has been proven to be one of the most effective treatments for a variety of cancers and is still a widely used chemotherapy drug subscribed to 10-20% of the cancer patients. Along with its potent anti-cancer efficacy, well recognized is the toxic side effects associated with cisplatin/platinum-based chemotherapy. Cisplatin induced nephrotoxicity, as known since its early clinical trials, is not only prevalent but also severe with long lasting adverse effects. Acute kidney injury has been observed in 30% of cancer patients receiving a single dose of cisplatin chemotherapy and in 50-70% of patients receiving multiple doses. Besides disrupting effective anti-cancer treatment, cisplatin induced acute kidney injury affects those patients even after switching to other anticancer regimens. They still face increased risks of chronic kidney injury, poor prognosis, and higher mortality. Therefore, it is essential to address this unmet medical need by developing effective preventions and interventions to mitigate cisplatin induced acute kidney injury. In the kidney, cisplatin causes both vascular and proximal tubule damages through molecular events of elevated oxidative stress, inflammation, excessive wastes accumulation in cytoplasm, and apoptosis. Our preliminary results demonstrated that rapamycin perfluorocarbon (PFC) nanoparticles simultaneously enhance autophagy to facilitate clearance of wastes in cytoplasm and inhibit inflammation through mTOR-NF-κB signaling. With the rapamycin PFC nanoparticles treatment, renal function is protected, and survival rate is significantly improved in the mice receiving cisplatin. Moreover, rapamycin PFC nanoparticles have favorable pharmacokinetics and biodistribution. Comparing to free rapamycin, rapamycin PFC nanoparticles significantly reduced systemic exposure of rapamycin and its accumulation in the vital organs, such as brain. Accordingly, in this proposed study, our central hypothesis is that cisplatin induced acute kidney injury could be mitigated by preserving renal vasculature and proximal tubule through simultaneously inhibition of inflammation and enhancement of autophagy via mTOR-NF-κB signaling pathway. Therefore, following three specific aims are proposed to test the hypothesis for potential clinical translation. Specific Aim 1 will further validate the therapeutic efficacy of rapamycin PFC nanoparticles both in vitro and in vivo with regard to elucidate the molecular mechanism of therapy with regard to mTOR-NF-κB signaling pathway; Specific Aim 2 will evaluate integrated 19F and 1H BOLD MRI for non-invasive therapeutic evaluation of cisplatin induced AKI by simultaneously quantifying renal vascular injury and hypoxia. In Specific Aim 3, we will rigorously examine the safety of rapamycin PFC nanoparticles, pharmacokinetics/pharmacodynamics, clearance, and biodistribution in both control and tumor-bearing mice for clinical translation. Also, the effect of rapamycin PFC nanoparticles on tumor growth will be investigated.

摘要 自从大约50年前发现顺铂以来，已被证明是最有效的药物之一。 目前仍是一种广泛使用的化疗药物，认购比例为10-20% 癌症患者。除了其强大的抗癌效果外，公认的是与之相关的毒副作用 以顺铂/铂为基础的化疗。顺铂引起的肾毒性，从其早期临床就已知 试验，不仅普遍，而且严重，具有长期的不良影响。急性肾损伤已经 30%接受单剂顺铂化疗的癌症患者和50%-70%的患者观察到 接受多次注射。除了扰乱有效的抗癌治疗外，顺铂还会导致急性肾损伤 即使在切换到其他抗癌方案后也会影响这些患者。他们仍然面临着慢性疾病风险的增加 肾脏损伤，预后差，死亡率高。因此，解决这一未得到满足的医疗需求至关重要。 通过制定有效的预防和干预措施来减轻顺铂引起的急性肾损伤。在 肾，顺铂通过升高的分子事件引起血管和近端小管损伤 氧化应激、炎症、细胞质内废物过度堆积和细胞凋亡。我们的预赛 结果显示雷帕霉素全氟碳纳米粒(PFC)同时增强自噬。 通过mTOR-NF-κB信号通路促进胞浆内废物的清除，抑制炎症反应。与 雷帕霉素PFC纳米粒治疗后，肾功能得到保护，存活率显著提高 接受顺铂治疗的小鼠。此外，雷帕霉素PFC纳米粒具有良好的药代动力学 生物分布。与游离雷帕霉素相比，雷帕霉素PFC纳米粒显著降低全身性 暴露于雷帕霉素及其在重要器官，如大脑中的蓄积。因此，在本提议中， 研究中，我们的中心假设是顺铂引起的急性肾损伤可以通过保留肾脏来减轻。 血管系统和近端小管通过同时抑制炎症和增强 自噬通过mTOR-NF-κB信号通路实现。因此，提出了以下三个具体目标来测试 潜在临床翻译的假说。特异性靶点1将进一步验证其治疗效果 雷帕霉素PFC纳米粒的体内外研究进展 关于mTOR-NF-κB信号通路的治疗；特定目标2将评估整合的19F和1H BOLD 磁共振同时定量肾血管评价顺铂致急性肾损伤的无创性治疗 损伤和缺氧。在具体目标3中，我们将严格检查雷帕霉素PFC纳米粒的安全性， 阿司匹林在对照和荷瘤小鼠中的药代动力学/药效学、清除性和生物分布 临床翻译。此外，还将研究雷帕霉素PFC纳米粒对肿瘤生长的影响。