Personalized, high-resolution pharmacokinetic measurements to improve drug dosing

描述（由申请方提供）：药物的患者间药代动力学变量仍然是癌症治疗中一个重要的未解决的问题。作为回应，我在这里建议开发能够实时、连续测量体内药物水平的技术。这种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给药方案转移到基于实际患者特异性的、测量的药代动力学的方案，从而“个性化”药物递送以改善患者结果。为了实现这一目标，我的研究计划侧重于开发一类新的无试剂电化学生物传感器，该传感器支持连续，实时监测体内化疗药物浓度，具有亚分钟的时间分辨率和临床相关的灵敏度，特异性和精度。这种技术将使个性化，超高精度给药成为可能，提高疗效，同时降低毒性。基于电化学适体的传感器可以满足这一需求。这类传感器将电化学检测的选择性和简易性与适体的特异性和多功能性相结合。这些传感器已经支持未稀释血清的定量实时检测，使其成为迄今为止报道的最具选择性的实时生物传感器之一。然而，连续暴露于全血产生信号电流的显著基线漂移。在这个建议中，我概述了两个互补的策略，以减少这种漂移的幅度，并使纠正信号对这种漂移，使这项技术直接用于动物的血管。在体外全血传感成功后，我建议直接在兔耳缘静脉留置阿霉素传感器的体内测试。

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.