Rapid Electronic Detection of Drug Analytes in Blood

描述（由申请人提供）：开发实时测量血液药物水平的方法将彻底改变当代医疗保健的许多方面。例如，它可以提供一种实时调节药物递送（例如....化疗药物）的方法，这反过来又可以大大提高药物功效，同时减少过量使用的潜在毒性后果。提出的研究目标是适应现有的基于电化学适体（E-AB）的传感技术，以满足这种苛刻的应用。对于这种方法至关重要的是，E-AB平台已经被证明具有足够的灵敏度（微摩尔）可重复使用、快速（秒-分钟）、无试剂和选择性，可以直接用于血清和其他复杂的、临床相关的样品基质。然而，尽管在理想的实验室条件下，E-AB传感器在尿液、血清和其他复杂材料的挑战下表现良好，但该技术需要进一步发展，才能在流动的全血中实现临床相关的检测。因此，我在此提出了提高E-AB平台的灵敏度、稳定性和检测置信度的方法，以改进该技术，使其满足这一雄心勃勃的目标的需求。为此，我将重点关注三个具体目标：1)通过系统研究适体生物物理学和传感器制造对E-AB信号的影响来优化传感器的检测极限和响应时间；2)通过合成和应用替代氧化还原标签来提高传感器在全血中运行的性能；3)开发测量和纠正E-AB背景电流的方法，从而提高检测精度和信心。在这些特定目标中包含了多种互补的策略，用于表征、修饰和优化DMA适体传感器的生物物理特性，这将大大提高我们对这一潜在重要的新诊断技术的理解。开发实时监测血液中药物水平的方法，如治疗药物，将彻底改变现代医疗保健的护理点。例如，即时检测可以使患者个性化的反馈控制药物剂量达到前所未有的精度。在这里，我建议发展传感器，如果雄心勃勃，最终目标是能够支持全血中药物的实时定量。

DESCRIPTION (provided by applicant): The development of real-time methods for the measurement of blood drug levels would revolutionize many aspects of contemporary healthcare. It could, for example, provide a means of regulating drug delivery (e.g....chemotherapeutics) on-the-fly which, in turn, could greatly improve drug efficacy while reducing the potentially toxic consequences of over-dosage. The goal of the proposed research is to adapt an existing, electrochemical aptamer-based (E-AB) sensing technology to meet this demanding application. Critical to this approach, the E-AB platform has already proven sensitive (micromolar) reusable, rapid (seconds - minutes), reagentless, and selective enough to employ directly in blood serum and other complex, clinically relevant sample matrices. However, while E-AB sensors perform well when challenged with urine, blood serum and other complex materials under ideal laboratory conditions, the technology requires further development before it will achieve clinically-relevant detection in flowing, whole blood. Thus motivated, I hereby propose the development of methods to improve the sensitivity, stability and detection confidence of the E-AB platform in order to improve this technology such that it meets the demands of this ambitious goal. To do so I will focus on three specific aims: 1) optimize sensor detection limits and response times via a systematic study of the effect of aptamer biophysics and sensor fabrication on E-AB signaling, 2) improve sensor performance for operation in whole blood via the synthesis and application of alternative redox tags, and 3) develop methods to measure and correct E-AB background current thus improving detection accuracy and confidence. Contained within each of these specific aims are multiple, complimentary strategies for characterization, modification and optimization of the biophysical properties of DMA aptamer sensors that should significantly improve our understanding of this potentially important new diagnostic technology. The development of real-time methods for monitoring drug levels, such as therapeutics, in flowing blood would revolutionize modern healthcare at the point-of-care. Point-of-care detection could, for example, enable feedback controlled drug dosage of unprecedented precision that is individualized to the patient. Here I propose the development of sensors, with the ultimate, if ambitious, goal of being capable of supporting the real-time quantification of drugs directly in whole blood.