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Extracellular vesicle drug occupancy enables real-time monitoring of targeted cancer therapy

Nature Nanotechnology volume 16, pages 734–742 (2021)Cite this article

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Abstract

Current technologies to measure drug–target interactions require complex processing and invasive tissue biopsies, limiting their clinical utility for cancer treatment monitoring. Here we develop an analytical platform that leverages circulating extracellular vesicles (EVs) for activity-based assessment of tumour-specific drug–target interactions in patient blood samples. The technology, termed extracellular vesicle monitoring of small-molecule chemical occupancy and protein expression (ExoSCOPE), utilizes bio-orthogonal probe amplification and spatial patterning of molecular reactions within matched plasmonic nanoring resonators to achieve in situ analysis of EV drug dynamics. It measures changes in drug occupancy and protein composition in molecular subpopulations of EVs. When used to monitor various targeted therapies, the ExoSCOPE revealed EV signatures that closely reflected cellular treatment efficacy. We further applied the technology for clinical cancer diagnostics and treatment monitoring. Using a small volume of blood, the ExoSCOPE accurately classified disease status and rapidly distinguished between targeted treatment outcomes, within 24 h after treatment initiation.

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Fig. 1: ExoSCOPE for activity-based analysis of EV drug dynamics.
Fig. 2: Design and evaluation of click probes.
Fig. 3: Multiparametric analysis of EV drug occupancy.
Fig. 4: Multiplexed ExoSCOPE for longitudinal drug analysis.
Fig. 5: Clinical profiling of lung cancer patients.

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Data availability

Full gels and blots shown in Fig. 2c and Supplementary Figs. 1b,d,e; 8a,b; 13c,e; and 16a are provided as a source data file at https://doi.org/10.6084/m9.figshare.13565096. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Code used for the statistical analyses is available on reasonable request.

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Acknowledgements

We thank J. B. S. Mohamed and S. S. Chen for assistance with clinical sample collection and the National University Hospital Tissue Repository for providing the clinical samples and de-identified patient health information. Funding: this work was supported in part by funding from the National University of Singapore (NUS), NUS Research Scholarship, Ministry of Education, National Medical Research Council, Institute for Health Innovation & Technology, IMCB Independent Fellowship and NUS Early Career Research Award.

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Author notes

  1. These authors contributed equally: Sijun Pan, Yan Zhang.

Authors and Affiliations

  1. Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore

    Sijun Pan, Yan Zhang, Auginia Natalia, Carine Z. J. Lim, Nicholas R. Y. Ho, Tze Ping Loh & Huilin Shao

  2. Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore

    Yan Zhang, Auginia Natalia, Carine Z. J. Lim & Huilin Shao

  3. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore

    Nicholas R. Y. Ho & Huilin Shao

  4. Clinical Pharmacology Laboratory, National Cancer Centre Singapore, Singapore, Singapore

    Balram Chowbay

  5. Centre for Clinician-Scientist Development, Duke-NUS Medical School, Singapore, Singapore

    Balram Chowbay

  6. Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore

    Balram Chowbay

  7. Department of Laboratory Medicine, National University Hospital, Singapore, Singapore

    Tze Ping Loh

  8. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    John K. C. Tam & Huilin Shao

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Contributions

S.P., Y.Z. and H.S. designed the study. S.P., Y.Z., A.N., C.Z.J.L. and N.R.Y.H. performed the research. B.C., T.P.L. and J.K.C.T. provided the de-identified clinical samples and health information. S.P., Y.Z., A.N. and H.S. analysed the data and wrote the manuscript. All the authors contributed to the manuscript.

Corresponding author

Correspondence to Huilin Shao.

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The authors declare no competing interests.

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Peer review information Nature Nanotechnology thanks John Gooding, Matt Trau and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–21, Table 1 and methods.

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Pan, S., Zhang, Y., Natalia, A. et al. Extracellular vesicle drug occupancy enables real-time monitoring of targeted cancer therapy. Nat. Nanotechnol. 16, 734–742 (2021). https://doi.org/10.1038/s41565-021-00872-w

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