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

Nature Biomedical Engineering volume 1, pages 654–666 (2017)Cite this article

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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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Authors and Affiliations

  1. Department of Molecular Physiology, Niigata University School of Medicine, Niigata, 951-8510, Japan

    Genki Ogata, Fumiaki Nin, Takamasa Yoshida, Taiga Higuchi, Seishiro Sawamura, Takeru Ota, Karin Hori & Hiroshi Hibino

  2. Center for Transdisciplinary Research, Niigata University, Niigata, 950-2181, Japan

    Genki Ogata, Fumiaki Nin & Hiroshi Hibino

  3. Department of Chemistry, Faculty of Science and Technology, Keio University, Yokohama, 223-8522, Japan

    Yuya Ishii, Kai Asai & Yasuaki Einaga

  4. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan

    Yamato Sano, Kazuya Maeda & Hiroyuki Kusuhara

  5. Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Takamasa Yoshida & Shizuo Komune

  6. Division of Otolaryngology—Head and Neck Surgery, Yuaikai Oda Hospital, Kashima, Saga, 849-1311, Japan

    Shizuo Komune

  7. Department of Otolaryngology, Kindai University Faculty of Medicine, Osaka, 589-8511, Japan

    Katsumi Doi

  8. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, 113–8656, Japan

    Madoka Takai

  9. Laboratoire des Cellules Cardiaques et Vasculaires, CNRS ERL 7368, Faculté des Sciences, Université François-Rabelais, Tours, 37200, France

    Ian Findlay

  10. JST-ACCEL, Tokyo, 812-8582, Japan

    Yasuaki Einaga

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Contributions

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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