Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body.

Andrea Idili,Masayasu Kuwahara,Netzahualcóyotl Arroyo-Currás,Tod E Kippin,Andrew T Csordas,Kyle L Ploense,Kevin W Plaxco

doi:10.1039/c9sc01495k

Abstract

The ability to measure drugs in the body rapidly and in real time would advance both our understanding of pharmacokinetics and our ability to optimally dose and deliver pharmacological therapies. To this end, we are developing electrochemical aptamer-based (E-AB) sensors, a seconds-resolved platform technology that, as critical for performing measurements in vivo, is reagentless, reversible, and selective enough to work when placed directly in bodily fluids. Here we describe the development of an E-AB sensor against irinotecan, a member of the camptothecin family of cancer chemotherapeutics, and its adaptation to in vivo sensing. To achieve this we first re-engineered (via truncation) a previously reported DNA aptamer against the camptothecins to support high-gain E-AB signaling. We then co-deposited the modified aptamer with an unstructured, redox-reporter-modified DNA sequence whose output was independent of target concentration, rendering the sensor's signal gain a sufficiently strong function of square-wave frequency to support kinetic-differential-measurement drift correction. The resultant, 200 μm-diameter, 3 mm-long sensor achieves 20 s-resolved, multi-hour measurements of plasma irinotecan when emplaced in the jugular veins of live rats, thus providing an unprecedentedly high-precision view into the pharmacokinetics of this class of chemotherapeutics.

Highlights

The goal of personalized medicine is to precisely tailor treatment to the individual.[1,2] To this end, an ability to measure drugs in the living body with seconds resolution would allow clinicians to de ne drug dosing based on high-precision, patient-speci c pharmacokinetic measurements rather than on indirect predictors of drug metabolism such as age, body mass, or pharmacogenetics.[3,4] the ability to measureelectrochemical aptamer-based (E-AB) sensors employ an electrode-bound, redox-reportermodi ed aptamer as their recognition element (Fig. 1A)
We describe the development of an E-AB sensor against irinotecan, a member of the camptothecin family of cancer chemotherapeutics, and its adaptation to in vivo sensing
The resultant, 200 mm-diameter, 3 mm-long sensor achieves 20 s-resolved, multi-hour measurements of plasma irinotecan when emplaced in the jugular veins of live rats, providing an unprecedentedly high-precision view into the pharmacokinetics of this class of chemotherapeutics

Summary

Introduction

The goal of personalized medicine is to precisely tailor treatment to the individual.[1,2] To this end, an ability to measure drugs in the living body with seconds resolution would allow clinicians to de ne drug dosing based on high-precision, patient-speci c pharmacokinetic measurements rather than on indirect predictors of drug metabolism such as age, body mass, or pharmacogenetics.[3,4] the ability to measureE-AB sensors employ an electrode-bound, redox-reportermodi ed aptamer as their recognition element (Fig. 1A). We co-deposited the modified aptamer with an unstructured, redox-reporter-modified DNA sequence whose output was independent of target concentration, rendering the sensor's signal gain a sufficiently strong function of square-wave frequency to support kinetic-differential-measurement drift correction.

Results

Conclusion