Personalized, high-resolution pharmacokinetic measurements to improve drug dosing

描述(由申请人提供)：在癌症治疗中，患者之间的药代动力学变化非常大，仍然是一个重要的未解决的问题。对此，我建议开发能够实时、连续测量体内药物水平的技术。这样的技术将允许临床医生从使用不精确的药代动力学模型计算的剂量方案转移到基于实际患者特定的、测量的药代动力学的方案，从而使药物输送“个性化”，以改善患者的结果。为了实现这一目标，我的研究计划专注于开发一种新型的无试剂电化学生物传感器，支持以亚分钟的时间分辨率和临床相关的灵敏度、特异性和精确度连续、实时地监测体内的化疗药物浓度。这种技术将使个性化、超高精度给药成为可能，在提高疗效的同时降低毒性。基于电化学适配子的传感器可以满足这一需求。这类传感器结合了电化学检测的选择性和易用性与适体的特异性和多功能性。这些传感器已经支持对未稀释的血清进行定量实时检测，使其成为迄今报告的最具选择性的实时生物传感器之一。然而，持续暴露在全血中会产生信号电流的显著基线漂移。在这项提议中，我概述了两种互补的策略，以减少这种漂移的幅度，并能够针对这种漂移校正信号，从而使这项技术能够直接用于动物的血管。在全血体外传感成功后，我提议将阿霉素传感器直接留置在兔的耳缘静脉中进行体内测试。

DESCRIPTION (provided by applicant): Drastically variable inter-patient pharmacokinetics remain a significant, unsolved problem in cancer treatment. In response, I propose here the development of technology enabling the real-time, continuous measurement of in vivo drug levels. Such a technology would allow clinicians to move from dosing regimens calculated using imprecise models of pharmacokinetics to regimens based on actual patient-specific, measured pharmacokinetics, thereby "personalizing" drug delivery to improve patient outcomes. Towards this goal, my research program focuses on the development of a new class of reagentless, electrochemical biosensors that supports the continuous, real-time monitoring of chemotherapeutic concentrations in vivo with sub-minute time resolution and clinically relevant sensitivity, specificity and precision. Such a technology would enable personalized, ultra-high-precision dosing possible, enhancing efficacy while decreasing toxicity. Electrochemical aptamer-based sensors can meet this need. This class of sensors couples the selectivity and ease of electrochemical detection with the specificity and versatility of aptamers. These sensors already support quantitative, real-time detection in undiluted blood serum, placing them among the most selective real-time biosensors reported to date. However, continuous exposure to whole blood produces a significant baseline drift of the signaling current. In this proposal, I outline two complementary strategies to reduce the magnitude of this drift and enable correcting signal against this drift to enable this technology for use directly in the blood vessel of an animal. Upon successful in vitro sensing in whole blood, I propose the in vivo testing of an indwelling doxorubicin sensor directly in the marginal ear vein of a rabbit.