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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：
10661849
负责人：
Hua Pan
金额：
$ 43.08万
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/10661849
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Adverse effects Affect Aftercare Amifostine Animals Antineoplastic Agents 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 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 Population Prevention Prognosis Quality of life Regimen Renal function Reperfusion Injury Risk Safety Serum Signal Pathway Signal Transduction Sirolimus Survival Rate Testing Therapeutic Toxic effect Treatment Efficacy Tubular formation United States 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 mortality risk 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.

摘要