Real-time measurement of small molecules directly in awake, ambulatory animals
Edited by Jack W. Szostak, Massachusetts General Hospital, Boston, MA, and approved December 5, 2016 (received for review August 12, 2016)
Significance
The ability to monitor arbitrary molecules directly in living subjects as they undergo their daily routines remains one of the “holy grails” of bioanalytical chemistry. Such a technology would, for example, vastly improve our knowledge of physiology, pharmacokinetics, and toxicology by allowing the high-precision measurement of drugs and metabolites under realistic physiological conditions. Real-time molecular measurements would also provide an unparalleled window into health status (e.g., kidney function) and would facilitate “therapeutic drug monitoring,” in which dosing is personalized to the specific metabolism of each individual patient. Finally, the ability to measure molecules in the body in real time would provide unprecedented new routes by which drugs with dangerously narrow therapeutic windows could be safely and efficiently administered.
Abstract
The development of a technology capable of tracking the levels of drugs, metabolites, and biomarkers in the body continuously and in real time would advance our understanding of health and our ability to detect and treat disease. It would, for example, enable therapies guided by high-resolution, patient-specific pharmacokinetics (including feedback-controlled drug delivery), opening new dimensions in personalized medicine. In response, we demonstrate here the ability of electrochemical aptamer-based (E-AB) sensors to support continuous, real-time, multihour measurements when emplaced directly in the circulatory systems of living animals. Specifically, we have used E-AB sensors to perform the multihour, real-time measurement of four drugs in the bloodstream of even awake, ambulatory rats, achieving precise molecular measurements at clinically relevant detection limits and high (3 s) temporal resolution, attributes suggesting that the approach could provide an important window into the study of physiology and pharmacokinetics.
Acknowledgments
The authors thank Yanxian Lin for the code used in real-time data tracking and Dr. Martin Kurnik for providing the molecular graphics used in Fig. 1A. These studies were supported by a grant from the W. M. Keck Foundation and by the Institute for Collaborative Biotechnologies through US Army Research Office Grant W911NF-09-0001. J.S. is supported by National Institutes of Health National Cancer Institute Grant NRSA F31CA183385. N.A.-C. is supported by the Otis Williams Postdoctoral Fellowship of the Santa Barbara Foundation.
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Published online: January 9, 2017
Published in issue: January 24, 2017
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Acknowledgments
The authors thank Yanxian Lin for the code used in real-time data tracking and Dr. Martin Kurnik for providing the molecular graphics used in Fig. 1A. These studies were supported by a grant from the W. M. Keck Foundation and by the Institute for Collaborative Biotechnologies through US Army Research Office Grant W911NF-09-0001. J.S. is supported by National Institutes of Health National Cancer Institute Grant NRSA F31CA183385. N.A.-C. is supported by the Otis Williams Postdoctoral Fellowship of the Santa Barbara Foundation.
Notes
This article is a PNAS Direct Submission.
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Competing Interests
Conflict of interest statement: K.W.P. discloses service on the scientific advisory boards of Diagnostic Biochips Inc., Ilumi Health, and Eccrine Systems. N.A.-C., J.S., and K.W.P. have filed a provisional patent based on the work presented in this paper.
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Real-time measurement of small molecules directly in awake, ambulatory animals, Proc. Natl. Acad. Sci. U.S.A.
114 (4) 645-650,
https://doi.org/10.1073/pnas.1613458114
(2017).
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