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

基本信息

批准号：
10644372
负责人：
Hua Pan
金额：
$ 41.17万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644372
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

项目摘要

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.

抽象的自大约五十年前发现以来，顺铂已被证明是最有效的药物之一治疗多种癌症，仍然是一种广泛使用的化疗药物，占到 10-20% 的份额除了其强大的抗癌功效外，人们也认识到其相关的毒副作用。顺铂/铂类化疗引起的肾毒性，从其早期临床就已知。试验中，急性肾损伤不仅普遍存在，而且严重且具有长期持续的不良影响。在 30% 接受单剂量顺铂化疗的癌症患者和 50-70% 的患者中观察到接受多次剂量的顺铂除了破坏有效的抗癌治疗外，还会引起急性肾损伤。即使在改用其他抗癌疗法后，这些患者仍然面临着慢性风险增加。因此，解决这一未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。在肾脏中，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、细胞质中过多的废物积累和细胞凋亡。结果表明，雷帕霉素全氟化碳（PFC）纳米颗粒同时增强自噬促进细胞质中废物的清除并通过 mTOR-NF-κB 信号传导抑制炎症。雷帕霉素PFC纳米粒治疗，肾功能得到保护，生存率显着提高此外，雷帕霉素 PFC 纳米颗粒具有良好的药代动力学和与游离雷帕霉素相比，雷帕霉素PFC纳米颗粒显着降低了全身性。雷帕霉素的暴露及其在重要器官（例如大脑）中的积累因此，在此提出。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功能来减轻通过同时抑制炎症和增强血管系统和近端小管因此，提出以下三个具体目标来测试 mTOR-NF-κB 信号通路。潜在临床转化的假设将进一步验证治疗效果。雷帕霉素 PFC 纳米颗粒在体外和体内阐明了其分子机制有关 mTOR-NF-κB 信号通路的治疗；具体目标 2 将评估整合的 19F 和 1H BOLD MRI 通过同时量化肾血管对顺铂诱导的 AKI 进行无创治疗评估在具体目标3中，我们将严格检查雷帕霉素PFC纳米颗粒的安全性，对照小鼠和荷瘤小鼠的药代动力学/药效学、清除率和生物分布此外，还将研究雷帕霉素 PFC 纳米颗粒对肿瘤生长的影响。