Biostable nucleic acid aptamers for long-duration, in vivo molecular monitoring

用于长时间体内分子监测的生物稳定核酸适体

• 批准号: 10430240
• 负责人: Kevin W Plaxco
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430240
• 关键词: Acute Respiratory Distress Syndrome; Aminoglycosides; Animal Model; Antibiotics; Binding; Biological Markers; Biotechnology; Blood; Brain; COVID-19; Chemicals; Clinical; Communicable Diseases; Continuous Glucose Monitor; Creatinine; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diameter; Disease; Dose; Dose Limiting; Drug Kinetics; Electrodes; Electron Transport; Elements; Engineering; Exhibits; Feedback; Glucose; Goals; Health; Health Status; Hormones; Hour; In Situ; In Vitro; Infection; Measurable; Measurement; Measures; Medical Research; Molecular; Monitor; Muscle; Nucleic Acids; Oligonucleotides; Outcome; Output; Oxidation-Reduction; Patients; Performance; Pharmaceutical Preparations; Preclinical Testing; Process; Rattus; Renal function; Reporter; Reporting; Research; Resistance; Safety; Sepsis; Signal Transduction; Site; Solid; Specificity; Surface; Technology; Therapeutic; Therapeutic Index; Time; Tissues; Tobramycin; Toxic effect; Vancomycin; Vertebral column; Whole Blood; Widow; Widowhood; Work; aptamer; awake; clinical practice; clinically actionable; clinically relevant; cytokine; diagnostic biomarker; drug efficacy; fabrication; falls; improved; in vitro testing; in vivo; in vivo evaluation; in vivo monitoring; innovation; meter; minimally invasive; monolayer; oxidation; precision drugs; protein biomarkers; real time monitoring; research clinical testing; self assembly; sensor; temporal measurement; treatment duration

Summary. Electrochemical, aptamer-based (EAB) sensors are a minimally invasive technology already shown to support seconds-resolved, real-time, in vivo molecular measurements irrespective of the chemical reactivity of its targets. That is, EAB sensors are the only real-time molecular measurement technology that is simultaneously (1) generalizable to drugs and biomarkers and (2) demonstrated to work in situ in the body. In support of these claims, as preliminary results we have reported the first ever seconds- (and even sub-second) resolved, in-vivo measurements of multiple drugs and protein biomarkers. These measurements, which employ 75-µm-diameter sensors placed in situ in the blood (jugular) and tissues (brain, muscle) of awake, freely moving rats, achieve clinically relevant accuracy, precision and specificity over the course of hours. A remaining technological limitation, however, still precludes the further clinical testing of EAB sensors: after more than after ~5 h in vivo, aptamer degradation begins to reduce EAB precision significantly. The R21 project described here is focused on solving this problem. Specifically, here we propose the introduction of degradation-resistant, non-natural XNA aptamers into the EAB platform as a means achieving multi-day in vivo molecular measurements. Successful conclusion of this work would set the stage for R01-scale projects aimed at ascertaining the clinical value of long-duration EAB measurements in, for example, the feedback-controlled delivery of narrow-therapeutic-index antibiotics over multi-day treatment courses and the real-time monitoring of diagnostic cytokines in the ICU over the multi-day clinical course of infections, such as in sepsis and COVID-19.

概括。基于电化学适配体 (EAB) 的传感器是一种已经展示的微创技术 支持秒级解析、实时体内分子测量，无论化学反应性如何 其目标。也就是说，EAB 传感器是唯一一种实时分子测量技术 同时（1）可推广到药物和生物标志物，（2）被证明可以在体内原位发挥作用。在 支持这些说法，作为初步结果，我们报告了有史以来第一秒（甚至亚秒） 多种药物和蛋白质生物标志物的解析体内测量。这些测量采用 直径 75 µm 的传感器原位放置在清醒、自由活动的血液（颈静脉）和组织（大脑、肌肉）中 大鼠，在数小时内达到临床相关的准确性、精密度和特异性。剩余一个 然而，技术限制仍然阻碍了 EAB 传感器的进一步临床测试： 在体内约 5 小时，适体降解开始显着降低 EAB 精度。这里描述的 R21 项目 正致力于解决这个问题。具体来说，在这里我们建议引入抗降解、 将非天然 XNA 适体引入 EAB 平台作为实现多天体内分子生物学的手段 测量。这项工作的成功完成将为 R01 规模的项目奠定基础，旨在 确定长时间 EAB 测量的临床价值，例如，反馈控制 在多天的治疗过程中提供窄治疗指数抗生素并实时监测 ICU 中感染的多天临床过程中的诊断细胞因子，例如脓毒症和 COVID-19。