CNS HIV Theranostics Based on Intrinsic CEST Contrasts of Antiretroviral Drugs

基于抗逆转录病毒药物内在 CEST 对比的 CNS HIV 治疗诊断

• 批准号: 10455622
• 负责人: Yutong Liu
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455622
• 关键词: AIDS dementia; Affect; Amplifiers; Anti-Retroviral Agents; Biodistribution; Brain; Cells; Central Nervous System Agents; Characteristics; Chemical Agents; Chemicals; Clinical Research; Data; Data Analyses; Detection; Development; Diagnostic; Drug Kinetics; Effectiveness; Fingerprint; Frequencies; Fumarates; HIV; HIV Infections; HIV antiretroviral; HIV therapy; HIV-1; HIV-associated neurocognitive disorder; Human; Image; Imaging Techniques; Infection; Integrase; Lamivudine; Life; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Mental Health; Methods; Monitor; Mus; Neuraxis; Neurocognitive Deficit; Neuroimmune; Nucleosides; Organ; Outcome; Outcome Study; Patients; Persons; Pharmaceutical Preparations; Property; Protons; Research; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Signal Transduction; Techniques; Technology; Tenofovir; Testing; Therapeutic; Tissues; Toxic effect; Treatment Protocols; Viral; Viral Load result; Viral reservoir; Water; abacavir; antiretroviral therapy; base; brain tissue; clinical implementation; data acquisition; design; drug testing; humanized mouse; imaging agent; imaging detection; imaging modality; in vivo; in vivo imaging; individual patient; individualized medicine; inhibitor; liquid chromatography mass spectrometry; macrophage; medication compliance; monocyte; nanoparticle; neurocognitive disorder; personalized medicine; prevent; real time monitoring; theranostics; therapy development; tool; tool development; viral transmission

Project Summary We propose to develop human immunodeficiency virus (HIV) theranostics for the central nervous system (CNS) based on the intrinsic chemical exchange saturation transfer (CEST) contrasts of antiretroviral drugs. Theranostics is a combination of the terms therapeutics and diagnostics that enables the biodistribution measurements of antiretrovirals (ARVs) in target organs using in vivo imaging techniques such as magnetic resonance imaging (MRI). HIV theranostics benefits the research of antiretroviral therapy in three ways. First, HIV theranostics will be a powerful tool for the development of ARVs targeting CNS viral reservoirs. Second, HIV theranostics will help develop strategies to minimize the off-target effects of ARVs. Third, In vivo imaging of long term PK and BD is critical for the development of long-acting drugs. Moreover, HIV theranostics enables real- time monitoring of CNS drug levels making it possible to design personalized treatments tailored for individual patients. Compared to traditional theranostic technologies that tag drugs with imaging agents, CEST is an intrinsic property of an ARV, therefore no extrinsic chemical agents are required for its imaging. This eliminates the limitations associated with imaging agents including limited therapy effectiveness and imaging sensitivity, and possible toxicity. We posit that the combined CEST effects of the protons in a drug molecule generate a unique CEST characteristic termed as CEST fingerprint that enables in vivo drug detection with sensitivity and specificity. We will first characterize the CEST fingerprints of first-line HIV ARVs, and develop MRI methods based on the drug CEST fingerprints for in vivo detection. Aim 1: To characterize the CEST fingerprints of ARVs (3TC, ABC, TDF and DTG). We hypothesize that exchangeable protons of the drugs generate unique CEST fingerprints. The CEST effects of the protons in a drug molecule will be measured and combined to build the drug's CEST fingerprint. The CEST fingerprint of each drug will be further validated and determined in cells using human monocyte-derived macrophages (MDMs). Aim 2: To measure in vivo CNS biodistribution of ARVs in humanized mice using CEST MRI. We posit that MRI utilizing CEST fingerprints offer sensitivity and specificity for in vivo measurements of ARVs. To test the hypothesis, MRI data acquisition and analysis methods will be developed based on the ARV CEST fingerprints measured in Aim 1, and optimized for in vivo detection in infected humanized mice that treated with combined antiretroviral therapy (DTG/ABC/3TC or DTG/3TC/TDF). Brain tissue drug levels measured using liquid chromatography mass spectrometry (LC-MS/MS) will be used to validate CEST MRI results. A successful outcome of the study is a noninvasive MRI technique that measures brain ARV levels. The technique will provide a powerful tool for the development of treatments that mitigate CNS complications of HIV infection and ameliorate the mental health outcomes of HIV patients.

项目摘要 我们建议开发人类免疫缺陷病毒（HIV）治疗诊断学的中枢神经系统（CNS） 基于抗逆转录病毒药物固有的化学交换饱和转移（CEST）对比。 治疗诊断学是术语治疗学和诊断学的组合， 使用体内成像技术，例如磁共振成像， 磁共振成像（MRI）。HIV治疗诊断学从三个方面促进了抗逆转录病毒治疗的研究。第一、 HIV治疗诊断学将成为开发靶向CNS病毒库的ARV的有力工具。第二，艾滋病毒 治疗诊断学将有助于制定战略，尽量减少抗逆转录病毒药物的脱靶效应。第三，在体内成像的长 长期PK和BD对于长效药物的开发至关重要。此外，艾滋病毒治疗诊断学使真实的- 时间监测CNS药物水平，使得有可能设计针对个体的个性化治疗 患者 与传统的用显像剂标记药物的治疗诊断技术相比，CEST是一种固有的性质， 因此，其成像不需要外源性化学试剂。这消除了限制 与成像剂相关，包括有限的治疗有效性和成像灵敏度，以及可能的 毒性我们认为，药物分子中质子的CEST效应组合产生了独特的CEST 这种特征被称为CEST指纹，能够以灵敏度和特异性进行体内药物检测。我们 将首先描述一线HIV抗逆转录病毒药物的CEST指纹，并开发基于该药物的MRI方法 用于体内检测的CEST指纹。 目的1：研究抗逆转录病毒药物（3 TC、ABC、TDF和DTG）的CEST指纹图谱。我们假设 药物的可交换质子产生独特的CEST指纹。质子的CEST效应 药物分子将被测量和组合，以建立药物的CEST指纹。每个人的指纹 将使用人单核细胞衍生的巨噬细胞（MDM）在细胞中进一步验证和测定药物。 目的2：利用CEST MRI测量ARV在人源化小鼠中的体内CNS生物分布。我们把核磁共振成像 利用CEST指纹为抗逆转录病毒药物的体内测量提供了灵敏度和特异性。测试 假设，MRI数据采集和分析方法将根据ARV CEST指纹开发 在Aim 1中测量，并优化用于在用组合抗病毒药物治疗的感染人源化小鼠中的体内检测。 抗逆转录病毒治疗（DTG/ABC/3 TC或DTG/3 TC/TDF）。使用液体测量脑组织药物水平 将使用色谱质谱法（LC-MS/MS）验证CEST MRI结果。 这项研究的一个成功成果是一种测量大脑ARV水平的非侵入性MRI技术。的 这项技术将为开发减轻HIV中枢神经系统并发症的治疗方法提供有力的工具 艾滋病毒感染和改善艾滋病毒患者的心理健康结果。