Rapid Electronic Detection of Drug Analytes in Blood

描述(由申请人提供)：血液药物浓度实时测量方法的发展将彻底改变当代医疗保健的许多方面。例如，它可以提供一种在运行中调节药物输送(例如……化疗药物)的方法，这反过来又可以极大地提高药物疗效，同时减少过量剂量的潜在毒性后果。拟议研究的目标是使现有的基于电化学适配子(E-AB)的传感技术能够满足这一苛刻的应用。对于这种方法至关重要的是，E-AB平台已经被证明具有灵敏(微摩尔)可重复使用、快速(秒-分钟)、无试剂和足够选择性，可以直接用于血清和其他复杂的临床相关样本矩阵。然而，尽管E-AB传感器在理想的实验室条件下受到尿液、血清和其他复杂材料的挑战时表现良好，但该技术还需要进一步发展，才能实现流动的全血中的临床相关检测。因此，我在此建议开发提高E-AB平台的灵敏度、稳定性和检测置信度的方法，以改进这项技术，使其满足这一雄心勃勃的目标的要求。为此，我将重点关注三个具体目标：1)通过系统研究适配子生物物理和传感器制造对E-AB信号的影响，优化传感器的检测限和响应时间；2)通过合成和应用替代氧化还原标签，提高传感器在全血中的操作性能；3)开发测量和校正E-AB背景电流的方法，从而提高检测的准确性和置信度。这些具体目标中的每一个都包含多种互补的策略，用于表征、修改和优化DMA适配子传感器的生物物理特性，这将显著提高我们对这一潜在重要的新诊断技术的理解。实时监测血液中药物浓度的方法的发展，如治疗学，将使现代医疗保健在护理地点发生革命性的变化。例如，护理点检测可以使反馈控制的药物剂量达到前所未有的精度，并针对患者进行个性化。在这里，我建议开发传感器，最终的目标是能够支持直接在全血中实时定量药物。

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.