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.
Pharmacokinetic models used to estimate drug dosing are notoriously poor, and current measurement techniques require successive timed blood draws, significant sample preparation, and complex equipment. This proposal outlines the development of an indwelling sensor for the precise, continuous measurement of chemotherapeutics in real time. Such a device would enable truly personalized, effective dosing, reducing toxicity and improving patient outcomes.
|Idili, Andrea; Amodio, Alessia; Vidonis, Marco et al. (2014) Folding-upon-binding and signal-on electrochemical DNA sensor with high affinity and specificity. Anal Chem 86:9013-9|