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Intraoperative diagnostics and elimination of residual microtumours with plasmonic nanobubbles

Abstract

Failure of cancer surgery to intraoperatively detect and eliminate microscopic residual disease (MRD) causes lethal recurrence and metastases, and the removal of important normal tissues causes excessive morbidity. Here, we show that a plasmonic nanobubble (PNB), a non-stationary laser pulse-activated nanoevent, intraoperatively detects and eliminates MRD in the surgical bed. PNBs were generated in vivo in head and neck cancer cells by systemically targeting tumours with gold colloids and locally applying near-infrared, low-energy short laser pulses, and were simultaneously detected with an acoustic probe. In mouse models, between 3 and 30 residual cancer cells and MRD (undetectable with current methods) were non-invasively detected up to 4 mm deep in the surgical bed within 1 ms. In resectable MRD, PNB-guided surgery prevented local recurrence and delivered 100% tumour-free survival. In unresectable MRD, PNB nanosurgery improved survival twofold compared with standard surgery. Our results show that PNB-guided surgery and nanosurgery can rapidly and precisely detect and remove MRD in simple intraoperative procedures.

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Figure 1: Mechanism of PNB diagnostics of residual microtumours and cancer cells in vivo.
Figure 2: PNBs report even single cancer cells in vitro in transparent medium and in tissue.
Figure 3: Intraoperative non-invasive detection of cancer cells in a surgical bed in vivo with a single laser pulse.
Figure 4: Biodistribution and toxicity in vivo after systemic administration of gold conjugates reveal a safe and efficient accumulation of gold nanoparticles in a tumour.
Figure 5: PNBs intraoperatively detect MRD in a surgical bed and guide its resection in real time with standard surgery.
Figure 6: PNBs improve surgical outcome in both resectable and unresectable MRDs.

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Acknowledgements

The authors thank E.Y. Hanna and R.J. Karni for the discussion of clinical applications of the technology, A. Hurrell, T. Kelley, E. Batres, D. Wagner, A. Aleknavicius and R. Sulcas for help with experimental equipment, and J. Markovits for assistance with veterinary pathology and surgical training and S. Parminter for copy-editing. E.Y.L.H., Y.S.K., B.E.O. and D.O.L. were supported by grants from the Gillson Longenbaugh Foundation, the National Science Foundation (CBET-1341212) and the National Institutes of Health (R01GM094816).

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E.Y.L.H. conducted PNB experiments, prepared the figures and wrote the manuscript. Y.S.K. conducted the animal experiments and collected animal data. I.B., A.M.G., D.O.L., B.E.O. and E.Y.L.H. discussed the experimental design and results, and clinical applications of the technology. B.E.O. contributed to the conceptual experimental design and organized the animal handling and monitoring. D.O.L. developed the technology and research strategy, designed the experimental setup and wrote the manuscript.

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Correspondence to Dmitri O. Lapotko.

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Lukianova-Hleb, E., Kim, YS., Belatsarkouski, I. et al. Intraoperative diagnostics and elimination of residual microtumours with plasmonic nanobubbles. Nature Nanotech 11, 525–532 (2016). https://doi.org/10.1038/nnano.2015.343

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