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 我们建议开发中枢神经系统（CNS）的人类免疫缺陷病毒（HIV）疗法 基于抗逆转录病毒药物的内在化学交换饱和转移（CEST）对比。 疗法是术语和诊断术语的组合，可以实现生物分布 使用体内成像技术（例如磁性）的目标器官中抗逆转录病毒（ARV）的测量 共振成像（MRI）。艾滋病毒治疗学以三种方式使抗逆转录病毒疗法的研究受益。第一的， HIV Theranostics将是针对CNS病毒储层的ARV开发的强大工具。第二，艾滋病毒 Theranostics将有助于制定策略，以最大程度地减少ARV的脱靶效应。第三，长长的体内成像 PK和BD术语对于长效药物的开发至关重要。此外，艾滋病毒疗法可以实现 CNS药物水平的时间监测使设计为个人量身定制的个性化治疗 患者。 与传统的疗法技术相比，将药物标记为成像剂，CEST是一种内在特性 在ARV中，因此不需要外部化学剂才能成像。这消除了限制 与成像剂有关，包括有限的治疗有效性和成像敏感性，并可能 毒性。我们认为，药物分子中质子的联合CEST效应会产生独特的Cest 特征被称为CEST指纹，可以使体内药物检测具有敏感性和特异性。我们 将首先描述一线HIV ARV的CEST指纹，并基于药物开发MRI方法 用于体内检测的CEST指纹。 目的1：表征ARV的CEST指纹（3TC，ABC，TDF和DTG）。我们假设这一点 这些药物的可兑换质子产生独特的CEST指纹。质子在 药物分子将进行测量并组合以构建药物的CEST指纹。每个指纹的指纹 使用人单核细胞衍生的巨噬细胞（MDMS），将在细胞中进一步验证药物。 目标2：测量使用CEST MRI在人源化小鼠中对ARV的体内生物分布。我们认为MRI 利用CEST指纹具有对ARV体内测量的敏感性和特异性。测试 假设，将根据ARV CEST指纹开发MRI数据获取和分析方法 在AIM 1中测量，并针对被感染的人源性小鼠进行了优化 抗逆转录病毒疗法（DTG/ABC/3TC或DTG/3TC/TDF）。使用液体测量的脑组织药物水平 色谱质谱法（LC-MS/MS）将用于验证CEST MRI结果。 该研究的成功结果是一种无创的MRI技术，可测量脑ARV水平。这 技术将为开发减轻艾滋病毒并发症的治疗方法提供强大的工具 感染并改善HIV患者的心理健康结果。