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

基本信息

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
项目类别：
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

项目摘要

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。电化学，基于APATMER（EAB）传感器是已经显示的微创技术支持几秒钟分解的实时，体内分子测量，而不论化学反应性如何其目标。也就是说，EAB传感器是唯一的实时分子测量技术类似地（1）可推广到药物和生物标志物以及（2）在体内原位工作。对这些主张的支持，作为初步结果，我们报告了有史以来的第一个秒（甚至是秒）已解决多种药物和蛋白质生物标志物的VIVO内测量。这些测量，这些测量 75 µm直径的传感器原位放在血液（颈）和醒着的组织（大脑，肌肉），自由移动大鼠在数小时内实现临床相关的准确性，精度和特异性。剩下的但是，技术限制仍然排除了EAB传感器的进一步临床测试：比之后在体内〜5 h，apatmer降解开始显着降低EAB的精度。 R21项目在这里描述专注于解决这个问题。具体而言，在这里，我们提出了抗降解的引入，非天然XNA适体进入EAB平台，作为在体内实现多天的手段测量。这项工作的成功结论将为R01规模项目奠定阶段确定例如反馈控制的长期EAB测量值的临床价值在多日治疗课程中提供狭窄的治疗性指数抗生素和实时监测 ICU中的诊断细胞因子在多天的感染过程中，例如败血症和Covid-19中。