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

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

doi:10.1039/c9sc01495k

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

Chem Sci. 2019 Jul 22;10(35):8164-8170. doi: 10.1039/c9sc01495k. eCollection 2019 Sep 21.

Authors

Andrea Idili^{1

2}, Netzahualcóyotl Arroyo-Currás³, Kyle L Ploense^{1

2

4}, Andrew T Csordas^{1

2}, Masayasu Kuwahara⁵, Tod E Kippin^{4

6

7}, Kevin W Plaxco^{1

2}

Affiliations

¹ Department of Chemistry and Biochemistry , University of California, Santa Barbara , Santa Barbara , CA 93106 , USA . Email: kwp@ucsb.edu.
² Center for Bioengineering , University of California, Santa Barbara , Santa Barbara , CA 93106 , USA.
³ Department of Pharmacology and Molecular Sciences , Johns Hopkins School of Medicine , Baltimore , Maryland 21205 , USA.
⁴ Department of Psychological and Brain Sciences , University of California, Santa Barbara , Santa Barbara , CA 93106 , USA.
⁵ Graduate School of Integrated Basic Sciences , Nihon University , 3-25-40 Sakurajosui, Setagaya-ku , Tokyo 156-8550 , Japan.
⁶ Department of Molecular Cellular and Developmental Biology , University of California, Santa Barbara , Santa Barbara , CA 93106 , USA.
⁷ Department of Neuroscience Research Institute , University of California, Santa Barbara , Santa Barbara , CA 93106 , USA.

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.