Chemoprotection and imaging for aminoglycoside and chemotherapy toxicities

许多常用治疗药物的毒副作用可导致药物剂量减少或 停用，限制这些有效且廉价的药物在临床上的使用。保护免受剂量伤害 限制毒性将改善患者的生活质量，并有可能通过以下方式改善治疗结果 提高对治疗方案的依从性，并允许增加治疗次数和剂量。使用 在过去的退伍军人管理局资助中，我们一直在研究减少或消除以下毒副作用的机制 癌症化疗已有20年的历史，并已从基础研究进入第三阶段临床试验。我们的 研究表明，延迟给予硫醇化学保护剂硫代硫酸钠 乙酰半胱氨酸(STS)和N-乙酰半胱氨酸(NAC)是一种有效的减少耳蜗、肾脏和骨髓的策略 铂类化疗药物顺铂和卡铂的毒性及抗肿瘤作用 肿瘤疗效。这项提案将把我们的化学保护策略扩展到氨基糖苷类抗生素，这些抗生素 常用于VA患者人群的严重感染治疗。此外，我们还将测试 认为激活耳蜗内天然免疫反应后的炎症会增强的假说 顺铂化疗和氨基糖苷类抗生素的耳毒性副作用。为了调查 毒性和化学保护的潜在机制，我们将测试新的磁共振成像(MRI) 使用氧化铁纳米颗粒造影剂阿魏酸甲酯的技术。阿魏酸甘油酯被 巨噬细胞和激活的小胶质细胞在24小时的过程中，提供了一种非侵入性标记 发炎的组织。我们假设阿魏酸甘油酯在mri上的增强将提供一个可量化的生物标记物。 为了测量耳蜗炎症和炎症对耳毒性刺激的影响，以及 化学保护对这些过程的影响。在目标1中，我们将评估先天免疫系统增强 全身炎症与局限性急性神经炎对比研究顺铂耳毒性。我们 将评估耳毒性的大小和耳蜗炎性细胞的渗透，并确定 硫醇化学保护是否阻断顺铂增强的毒性。我们将研究高分辨率核磁共振 用阿魏酸甲酯评估炎症反应和顺铂的耳毒性，并确定STS和NAC对耳毒性的影响 这些过程。在目标2中，我们将评估内毒素血症增强型氨基糖苷类药物的化学保护作用。 耳毒性。我们将使用阿魏酸甘油酯MRI来评估耳蜗血管的通透性和炎症。我们的整体 目标是开发针对治疗和成像的副作用的化学保护策略 改善炎症检测和管理的生物标志物，最终改善长期结果 对退伍军人症患者来说。

The toxic side effects of many commonly used therapeutic agents can result in drug dose reduction or discontinuation, limiting the use of these effective and inexpensive agents in the clinic. Protecting against dose limiting toxicities would improve patient quality of life and has the potential to improve therapeutic outcomes by increasing compliance with treatment regimens and allowing increased treatment times and doses. With previous VA funding, we have been investigating mechanisms to decrease or eliminate the toxic side effects of cancer chemotherapy for two decades and have moved from basic research to Phase III clinical trials. Our research has demonstrated that delayed administration of the thiol chemoprotective agents sodium thiosulfate (STS) and N-acetylcysteine (NAC) is an effective strategy to reduce the cochlear, renal and bone marrow toxicities of the platinum-based chemotherapy agents cisplatin and carboplatin without decreasing their anti- tumor efficacy. This proposal will expand our chemoprotection strategy to aminoglycoside antibiotics that are commonly used in the VA patient population for the treatment of serious infections. Additionally, we will test the hypothesis that inflammation following activation of the innate immune response in the cochlea will enhance the ototoxic side effects of cisplatin chemotherapy and aminoglycoside antibiotics. To investigate the mechanisms underlying toxicity and chemoprotection, we will test novel magnetic resonance imaging (MRI) techniques using the iron oxide nanoparticle contrast agent ferumoxytol. Ferumoxytol is taken up by macrophages and activated microglial cells over the course of 24 hours, providing a non-invasive marker of inflamed tissues. We hypothesize that ferumoxytol enhancement on MRI will provide a quantifiable biomarker to measure inflammation in the cochlea and the impact of inflammation on ototoxic stimuli, as well as the impact of chemoprotection on these processes. In Aim 1 we will evaluate innate immune system enhancement of cisplatin ototoxicity using generalized systemic inflammation versus localized acute neuroinflammation. We will evaluate the magnitude of ototoxicity and inflammatory cell infiltration into the cochlea, and determine whether thiol chemoprotection blocks the enhanced cisplatin toxicity. We will investigate high-resolution MRI with ferumoxytol to assess inflammation and cisplatin ototoxicity and determine the impact of STS and NAC on these processes. In Aim 2 we will assess chemoprotection for endotoxemia-potentiated aminoglycoside ototoxicity. We will use ferumoxytol MRI to assess cochlear vessel permeability and inflammation. Our overall goals are to develop chemoprotection strategies against the side effects of therapeutics and imaging biomarkers to improve detection and management of inflammation, ultimately improving long-term outcomes for VA patients.