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

基本信息

批准号：
10327052
负责人：
Yutong Liu
金额：
$ 19.13万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327052
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 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/antagonist 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

项目摘要

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.

项目概要我们建议开发针对中枢神经系统（CNS）的人类免疫缺陷病毒（HIV）治疗诊断学基于抗逆转录病毒药物的内在化学交换饱和转移（CEST）对比。治疗诊断学是治疗学和诊断学这两个术语的组合，它能够实现生物分布使用体内成像技术（例如磁学）测量靶器官中的抗逆转录病毒药物（ARV）磁共振成像（MRI）。 HIV 治疗诊断学在三个方面有利于抗逆转录病毒治疗的研究。第一的， HIV治疗诊断学将成为开发针对中枢神经系统病毒库的抗逆转录病毒药物的有力工具。二、艾滋病毒治疗诊断学将有助于制定策略，最大限度地减少抗逆转录病毒药物的脱靶效应。三、长寿命活体成像术语 PK 和 BD 对于长效药物的开发至关重要。此外，HIV 治疗诊断学能够实现真正的中枢神经系统药物水平的时间监测使设计适合个人的个性化治疗成为可能患者。与用显像剂标记药物的传统治疗诊断技术相比，CEST 是一种固有特性抗逆转录病毒药物，因此其成像不需要外来化学试剂。这消除了限制与显像剂相关，包括有限的治疗效果和成像敏感性，以及可能的毒性。我们假设药物分子中质子的组合 CEST 效应会产生独特的 CEST 被称为 CEST 指纹的特征，使体内药物检测具有灵敏度和特异性。我们将首先表征一线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。目标 1：表征 ARV 的 CEST 指纹（3TC、ABC、TDF 和 DTG）。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并组合以构建药物的 CEST 指纹。每个的 CEST 指纹将使用人类单核细胞衍生的巨噬细胞（MDM）在细胞中进一步验证和确定药物。目标 2：使用 CEST MRI 测量人源化小鼠体内 ARV 的中枢神经系统生物分布。我们假设 MRI 利用 CEST 指纹为 ARV 体内测量提供灵敏度和特异性。测试假设，MRI数据采集和分析方法将基于ARV CEST指纹开发在目标 1 中进行测量，并针对联合治疗的受感染人源化小鼠体内检测进行了优化抗逆转录病毒治疗（DTG/ABC/3TC 或 DTG/3TC/TDF）。使用液体测量脑组织药物水平色谱质谱法 (LC-MS/MS) 将用于验证 CEST MRI 结果。该研究的一个成功成果是采用无创 MRI 技术测量大脑 ARV 水平。这技术将为开发减轻艾滋病毒中枢神经系统并发症的治疗方法提供强大的工具感染并改善艾滋病毒患者的心理健康结果。