Chemoprotection and imaging for aminoglycoside and chemotherapy toxicities

氨基糖苷类和化疗毒性的化学保护和成像

• 批准号: 10046284
• 负责人: EDWARD A. NEUWELT
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046284
• 关键词: Acetylcysteine; Acute; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Animals; Auditory Brainstem Responses; Basic Science; Biological; Biological Markers; Bone Marrow; Brain; Brain Neoplasms; CD14 Antigen; Carboplatin; Cell Survival; Cells; Chemoprotection; Chemoprotective Agent; Chemotherapy-Oncologic Procedure; Cisplatin; Clinic; Cochlea; Contrast Media; DNA Intercalation; Detection; Dose; Dose-Limiting; Ear; Endotoxemia; Free Radical Formation; Free Radicals; Funding; Gentamicins; Glutathione; Goals; Hair Cells; Hearing; Hour; Image; Imaging Techniques; Immunohistochemistry; Infection; Infiltration; Inflammation; Inflammatory; Injections; Innate Immune Response; Innate Immune System; Intravenous; Kidney; Knock-out; Lesion; Lipopolysaccharides; Magnetic Resonance Imaging; Measures; Mediating; Microglia; Molecular; Monitor; Neutrophil Infiltration; Outcome; Pathway interactions; Patients; Pattern; Permeability; Pharmaceutical Preparations; Phase III Clinical Trials; Platinum; Process; Protein Synthesis Inhibition; Quality of life; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Regimen; Reproducibility; Research; Resolution; Risk; Signal Transduction; Solid Neoplasm; Stimulus; Sulfhydryl Compounds; Testing; Therapeutic Agents; Therapeutic Uses; Time; Tissues; Toxic effect; Toxicity due to chemotherapy; Treatment Protocols; aminoglycoside-induced ototoxicity; base; cell injury; chemotherapeutic agent; chemotherapy; ferumoxytol; hearing impairment; imaging biomarker; immune activation; improved; iron oxide nanoparticle; macromolecule; macrophage; middle ear disorder; monocyte; nephrotoxicity; neuroimaging; neuroinflammation; neutrophil; novel; otoacoustic emission; ototoxicity; pathogen; patient population; peroxidation; preclinical study; side effect; sodium thiosulfate; systemic inflammatory response; therapeutic biomarker; therapy outcome; tool; tumor

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.

许多常用治疗药物的毒副作用可能导致药物剂量减少或 停药，限制了这些有效且廉价的药物在临床上的使用。预防剂量 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时间和剂量。和 在之前的 VA 资助中，我们一直在研究减少或消除毒副作用的机制 癌症化疗已有二十年历史，已从基础研究转向三期临床试验。我们的 研究表明，延迟施用硫醇化学保护剂硫代硫酸钠 (STS) 和 N-乙酰半胱氨酸 (NAC) 是减少耳蜗、肾脏和骨髓的有效策略 铂类化疗药物顺铂和卡铂的毒性，但不降低其抗肿瘤作用 肿瘤疗效。该提案将把我们的化学保护策略扩展到氨基糖苷类抗生素 常用于 VA 患者群体，用于治疗严重感染。此外，我们将测试 假设耳蜗先天免疫反应激活后炎症会增强 顺铂化疗和氨基糖苷类抗生素的耳毒性副作用。为了调查 为了了解毒性和化学保护的机制，我们将测试新型磁共振成像 (MRI) 使用氧化铁纳米颗粒造影剂 ferumoxytol 的技术。 Ferumoxytol 被吸收 24 小时内巨噬细胞和活化的小胶质细胞，提供非侵入性标记物 发炎的组织。我们假设 MRI 上的 Ferumoxytol 增强将提供可量化的生物标志物 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的增强 使用全身性炎症与局部急性神经炎症比较顺铂耳毒性。我们 将评估耳毒性和炎症细胞浸润耳蜗的程度，并确定 硫醇化学保护是否可以阻止增强的顺铂毒性。我们将研究高分辨率 MRI 与 ferumoxytol 一起评估炎症和顺铂耳毒性，并确定 STS 和 NAC 对 这些过程。在目标 2 中，我们将评估内毒素血症强化氨基糖苷类药物的化学保护作用 耳毒性。我们将使用 Ferumoxytol MRI 来评估耳蜗血管通透性和炎症。我们的整体 目标是制定针对治疗和成像副作用的化学保护策略 生物标志物可改善炎症的检测和管理，最终改善长期结果 对于 VA 患者。

项目成果

Ferumoxytol-Enhanced MRI Is Not Inferior to Gadolinium-Enhanced MRI in Detecting Intracranial Metastatic Disease and Metastasis Size.

Ferumoxytol 增强 MRI 在检测颅内转移性疾病和转移灶大小方面并不逊色于钆增强 MRI。

• 发表时间: 2020
• 作者: Hamilton, Bronwyn E;Barajas, Ramon;Nesbit, Gary M;Fu, Rongwei;Ambady, Prakash;Taylor, Matthew;Neuwelt, Edward A
• 通讯作者: Neuwelt, Edward A

Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses.

颈动脉内高渗甘露醇打开血脑屏障可诱导无菌炎症和先天免疫反应。

• 发表时间: 2021
• 影响因子: 11.1
• 作者: Burks, Scott R;Kersch, Cymon N;Witko, Jaclyn A;Pagel, Michael A;Sundby, Maggie;Muldoon, Leslie L;Neuwelt, Edward A;Frank, Joseph A
• 通讯作者: Frank, Joseph A

Toll-like Receptor 4 Signaling and Downstream Neutrophilic Inflammation Mediate Endotoxemia-Enhanced Blood-Labyrinth Barrier Trafficking.

Toll 样受体 4 信号传导和下游中性粒细胞炎症介导内毒素血症增强的血迷路屏障贩运。

• DOI: 10.1097/mao.0000000000002447
• 发表时间: 2024-09-13
• 期刊: Otology & Neurotology
• 影响因子: 2.1
• 作者: Z. Urdang;Jessica L. Bills;David Y. Cahana;L. Muldoon;E. Neuwelt
• 通讯作者: E. Neuwelt