A microsensing system for the in vivo real-time detection of local drug kinetics

Real-time recording of the kinetics of systemically administered drugs in in vivo microenvironments may accelerate the development of effective medical therapies. However, conventional methods require considerable analyte quantities, have low sampling rates and do not address how drug kinetics correlate with target function over time. Here, we describe the development and application of a drug-sensing system consisting of a glass microelectrode and a microsensor composed of boron-doped diamond with a tip of around 40 μm in diameter. We show that, in the guinea pig cochlea, the system can measure—simultaneously and in real time—changes in the concentration of bumetanide (a diuretic that is ototoxic but applicable to epilepsy treatment) and the endocochlear potential underlying hearing. In the rat brain, we tracked the kinetics of the drug and the local field potentials representing neuronal activity. We also show that the actions of the antiepileptic drug lamotrigine and the anticancer reagent doxorubicin can be monitored in vivo. Our microsensing system offers the potential to detect pharmacological and physiological responses that might otherwise remain undetected.

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Fig. 1: Measurement of bumetanide using a BDD microsensor in vitro.
Fig. 2: Electrochemical properties of native perilymph in the guinea pig cochlea.
Fig. 3: In vivo detection of bumetanide and measurement of EP in the guinea pig cochlea.
Fig. 4: Quantification of the bumetanide concentration in the cochlea.
Fig. 5: Simultaneous recording of bumetanide and neuronal activity in the rat brain.
Fig. 6: Simultaneous recording of lamotrigine and neuronal activity in the rat brain.
Fig. 7: Simultaneous in vivo measurement of doxorubicin and EP in the guinea pig.

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Acknowledgements

We thank P. Bredeloux for comments on the experimental results, and Y. Takahashi and H. Shiku for technical advice. This study was partially supported by the following research grants: Grant-in-Aid for Scientific Research B 25293058 (to H.H.); Grant-in-Aid for Scientific Research C 15K10770 (to K.D.); and Grants-in-Aid for Young Scientists B 25870248 (to F.N.) and 26870210 (to G.O.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and JST-ACCEL (to Y.E.). In addition, funds were provided by the Nakatani Foundation (to H.H.), Takeda Science Foundation (to F.N.), Uehara Memorial Foundation (to F.N.) and Astellas Foundation for Research on Metabolic Disorders (to F.N.).

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G.O., F.N., H.K., T.Y., Y.E. and H.H. designed the experiments. G.O. and K.D. developed the experimental setup. F.N., T.Y. and S.K. were involved in developing the surgical procedures. Y.I., K.A. and Y.E. prepared the BDD electrodes. Y.I., K.A., Y.E. and M.T. contributed to establishing the protocol for the electrochemical experiments. G.O. performed the electrochemical experiments. T.H., T.O. and K.H. supported the data collection. Y.S., K.M. and H.K designed the LC–MS/MS experiments. Y.S. performed the LC–MS/MS experiments. G.O., S.S., T.O. and I.F. analysed the results. G.O., T.O., I.F. and H.H. wrote the paper. All authors edited the paper.

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Correspondence to Yasuaki Einaga or Hiroshi Hibino.

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Ogata, G., Ishii, Y., Asai, K. et al. A microsensing system for the in vivo real-time detection of local drug kinetics. Nat Biomed Eng 1, 654–666 (2017). https://doi.org/10.1038/s41551-017-0118-5

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