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An integrated magneto-electrochemical device for the rapid profiling of tumour extracellular vesicles from blood plasma

Nature Biomedical Engineering volume 5, pages 678–689 (2021)Cite this article

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Abstract

Assays for cancer diagnosis via the analysis of biomarkers on circulating extracellular vesicles (EVs) typically have lengthy sample workups, limited throughput or insufficient sensitivity, or do not use clinically validated biomarkers. Here we report the development and performance of a 96-well assay that integrates the enrichment of EVs by antibody-coated magnetic beads and the electrochemical detection, in less than one hour of total assay time, of EV-bound proteins after enzymatic amplification. By using the assay with a combination of antibodies for clinically relevant tumour biomarkers (EGFR, EpCAM, CD24 and GPA33) of colorectal cancer (CRC), we classified plasma samples from 102 patients with CRC and 40 non-CRC controls with accuracies of more than 96%, prospectively assessed a cohort of 90 patients, for whom the burden of tumour EVs was predictive of five-year disease-free survival, and longitudinally analysed plasma from 11 patients, for whom the EV burden declined after surgery and increased on relapse. Rapid assays for the detection of combinations of tumour biomarkers in plasma EVs may aid cancer detection and patient monitoring.

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Fig. 1: HiMEX approach for clinical EV analyses.
Fig. 2: HiMEX assay optimization and characterization.
Fig. 3: EV profiling for CRC detection.
Fig. 4: Analyses of prospective cohorts for CRC diagnosis.
Fig. 5: HiMEX analyses of longitudinal samples from patients with CRC.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw patient datasets generated and analysed during the study are available from the corresponding authors on reasonable request, subject to approval from the Institutional Review Board of the Kyungpook National University Hospital. For initial marker selection, we used the public databases, the Human Protein Atlas (https://www.proteinatlas.org) and UniProt (https://www.uniprot.org). Source data are provided with this paper.

Code availability

Source codes for the marker selection are available at https://csb.mgh.harvard.edu/bme_software.

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Acknowledgements

We thank X. O. Breakefield (Massachusetts General Hospital) for discussions. This work was supported in part by grants from the V-Foundation for Cancer Research (R. Weissleder, C.M.C.); the American Cancer Society (C.M.C.); the Robert Wood Johnson Foundation/Amos Medical Faculty Development Program (C.M.C.); US National Institutes of Health (NIH) grant numbers R01CA229777 (H. Lee), R21DA049577 (H. Lee), R01CA204019 (R. Weissleder), U01CA233360 (H. Lee, C.M.C.), TR000931 (B.S.C.), U01CA230697 (B.S.C., L.B.), R01CA239078 (H. Lee, B.S.C.), R01CA237500 (H. Lee, B.S.C.) and CA069246 (B.S.C.); US DOD-W81XWH1910199 (H. Lee) and DOD-W81XWH1910194 (H. Lee); MGH Scholar Fund (H. Lee), MGH Fund for Medical Discovery Fellowship (H.-Y.L.); and Basic Science Research Program grants NRF-2019R1C1C1008792 (J.P.), NRF-2020R1A4A1016093 (J.P.), and NRF-2017M3A9G8083382 (J.S.P.) from the Ministry of Education, South Korea.

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Author notes

  1. These authors contributed equally: Jongmin Park, Jun Seok Park.

Authors and Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jongmin Park, Jun Seok Park, Chen-Han Huang, Ala Jo, Hsing-Ying Lin, Jan Van Deun, Huiyan Li, Jouha Min, Cesar M. Castro, Ralph Weissleder & Hakho Lee

  2. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jongmin Park, Jun Seok Park, Chen-Han Huang, Ala Jo, Hsing-Ying Lin, Jan Van Deun, Huiyan Li, Jouha Min, Ralph Weissleder & Hakho Lee

  3. Department of Chemistry, Kangwon National University, Chuncheon, Korea

    Jongmin Park

  4. Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea

    Jun Seok Park & Gyu-Seog Choi

  5. Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan

    Chen-Han Huang

  6. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Kaitlyn Cook & Rui Wang

  7. Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, USA

    Rui Wang

  8. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Lan Wang, Bob S. Carter & Leonora Balaj

  9. Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea

    Ghilsuk Yoon

  10. Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Cesar M. Castro

  11. Department of Systems Biology, Harvard Medical School, Boston, MA, USA

    Ralph Weissleder

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Contributions

J.P., J.S.P., C.M.C., R. Weissleder and H. Lee designed the study, prepared the figures and wrote the manuscript. J.S.P. and G.-S.C. collected patient samples. G.Y. performed tissue immunohistochemistry staining. C.-H.H. developed the HiMEX system. J.P., A.J., H.-Y.L., J.V.D., H. Li and J.M. performed research and analysed data. L.W., L.B. and B.S.C. guided mRNA analysis. J.S.P., G.-S.C., C.M.C. and R. Weissleder analysed clinical data. K.C., R. Wang and H. Lee performed statistical analyses.

Corresponding authors

Correspondence to Ralph Weissleder or Hakho Lee.

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Competing interests

The authors declare the filing of a patent (US20190346434A1) that was assigned to and handled by Massachusetts General Hospital. The following disclosures are not related to the subject matter of this work. R.Weissleder is a consultant to ModeRNA, Tarveda Pharmaceuticals, Lumicell, Seer, Earli, Alivio Therapeutics, Aikili Biosystems and Accure Health. H. Lee is a consultant to Exosome Diagnostics, Accure Health and Aikili Biosystems.

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Peer review information Nature Biomedical Engineering thanks Tony Hu, Philip Stahl and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Park, J., Park, J.S., Huang, CH. et al. An integrated magneto-electrochemical device for the rapid profiling of tumour extracellular vesicles from blood plasma. Nat Biomed Eng 5, 678–689 (2021). https://doi.org/10.1038/s41551-021-00752-7

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