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.
Subscribe to Journal
Get full journal access for 1 year
We are sorry, but there is no personal subscription option available for your country.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Meier, J. D., Oliver, D. A. & Varvares, M. A. Surgical margin determination in head and neck oncology: current clinical practice. The results of an International American Head and Neck Society Member Survey. Head Neck 27, 952–958 (2005).
de Carvalho, A. C. et al. Clinical significance of molecular alterations in histologically negative surgical margins of head and neck cancer patients. Oral. Oncol. 48, 240–248 (2012).
Loree, T. R. & Strong, E. W. Significance of positive margins in oral cavity squamous carcinoma. Am. J. Surg. 160, 410–414 (1990).
Looser, K. G., Shah, J. P. & Strong, E. W. The significance of ‘positive’ margins in surgically resected epidermoid carcinomas. Head Neck Surg. 1, 107–111 (1978).
Vikram, B., Strong, E. W., Shah, J. P. & Spiro, R. Failure at the primary site following multimodality treatment in advanced head and neck cancer. Head Neck Surg. 6, 720–723 (1984).
Leemans, C. R., Braakhuis, B. J. & Brakenhoff, R. H. The molecular biology of head and neck cancer. Nature Rev. Cancer 11, 9–22 (2011).
Haddad, R. I. & Shin, D. M. Recent advances in head and neck cancer. N. Engl. J. Med. 359, 1143–1154 (2008).
Calabrese, L. et al. Future challenges in head and neck cancer: from the bench to the bedside? Crit. Rev. Oncol. Hematol. 84, e90–e96 (2012).
Langendijk, J. A. et al. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J. Clin. Oncol. 26, 3770–3887 (2008).
Radosevich, J. A. (Ed.) Head and Neck Cancer: Current Perspectives, Advances and Challenges (Springer, 2013).
Vermorken, J. B. et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N. Engl. J. Med. 357, 1695–1704 (2007).
Wang, L. V. Multiscale photoacoustic microscopy and computed tomography. Nature Photon. 3, 503–509 (2009).
Jathoul, A. P. et al. Deep in vivo photoacoustic imaging of mammalian tissues using a tyrosinase-based genetic reporter. Nature Photon. 9, 239–246 (2015).
Kaiplavil, S. & Mandelis, A. Truncated-correlation photothermal coherence tomography for deep subsurface analysis. Nature Photon. 8, 635–642 (2014).
Lo Celso, C. et al. Live-animal tracking of individual haemotapoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009).
Upile, T. et al. Head and neck optical diagnostics: vision of the future of surgery. Head Neck Oncol. 1, 25 (2009).
Thorek, D. L., Ogirala, A., Beattie, B. J. & Grimm, J. Quantitative imaging of disease signatures through radioactive decay signal conversion. Nature Med. 19, 1345–1350 (2013).
Nguyen, Q. T. & Tsien, R. Y. Fluorescence-guided surgery with live molecular navigation—a new cutting edge. Nature Rev. 13, 653–662 (2013).
van Dam, G. M. et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate reseptor-α targeting: first in-human results. Nature Med. 17, 1315–1319 (2011).
Vahmeijer, A. L., Hutteman, M., van de Vorst, J. R., van de Velde, C. J. H. & Frangioni, J. V. Image-guided cancer surgery using near-infrared fluorescence. Nature Rev. Clin. Oncol. 10, 507–518 (2013).
Holt, D. et al. Intraoperative near-infrared imaging can distinguish cancer from normal tissue but not inflammation. PLoS ONE 9, e103342 (2014).
Troyan, S. L. et al. The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann. Surg. Oncol. 16, 2943–2952 (2009).
Qiu, L. et al. Multispectral scanning during endoscopy guides biopsy of dysplasia in Barrett's esophagus. Nature Med. 16, 603–606 (2010).
Ntziachristos, V. Clinical translation of optical and optoacoustic images. Phil. Trans. R. Soc. A. 369, 4666–4678 (2011).
De Boer, E. et al. Optical innovations in surgery. Br. J. Surg. 105, e56–e72 (2015).
Taruttis, A. & Ntziachristos, V. Advances in real-time multispectral optoacoustic imaging and its applications. Nature Photon. 9, 219–227 (2015).
Lukianova-Hleb, E. Y. et al. On-demand intracellular amplification of chemoradiation with cancer-specific plasmonic nanobubbles. Nature Med. 20, 778–784 (2014).
Hleb, E. Y. et al. LANTCET: elimination of solid tumor cells with photothermal bubbles generated around clusters of gold nanoparticles. Nanomedicine 3, 647–667 (2008).
Lukianova-Hleb, E. et al. Plasmonic nanobubbles as transient vapor nanobubbles generated around plasmonic nanoparticles. ACS Nano 4, 2109–2123 (2010).
Lukianova-Hleb, E. Y., Volkov, A. N., Wu, X. & Lapotko, D. O. Transient enhancement and spectral narrowing of the photothermal effect of plasmonic nanoparticles under pulsed excitation. Adv. Mater. 25, 772–776 (2013).
Kitz, M. et al. Vapor bubble generation around gold nano-particles and its application to damaging of cells. Biomed. Opt. Express 2, 291–304 (2011).
Pitsillides, C. M., Joe, E. K., Wei, X., Anderson, R. R. & Lin, C. P. Selective cell targeting with light-absorbing microparticles and nanoparticles. Biophys. J. 84, 4023–4032 (2003).
Lapotko, D. et al. Photothermal microscopy and laser ablation of leukemia cells targeted with gold nanoparticles. Proc. SPIE 5697, 82–89 (2005).
Lukianova-Hleb, E. Y., Hanna, E. Y., Hafner, J. H. & Lapotko, D. O. Tunable plasmonic nanobubbles for cell theranostics. Nanotechnology 21, 085102 (2010).
Lukianova-Hleb, E. Y. et al. Improved cellular specificity of plasmonic nanobubbles versus nanoparticles in heterogeneous cell systems. PLoS ONE 7, e34537 (2012).
Lukianova-Hleb, E. Y. et al. Plasmonic nanobubbles rapidly detect and destroy drug-resistant tumors. Theranostics 2, 976–987 (2012).
Pilot Study of AuroLase(TM) Therapy in Refractory and/or Recurrent Tumors of the Head and Neck (Nanospectra Biosciences, 2015); https://clinicaltrials.gov/ct2/show/NCT00848042?term=aurolase%28tm%29&rank=1
Merchant, B. Gold, the noble metal and the paradoxes of its toxicology. Biologicals 26, 49–59 (1998).
Kean, W. F. & Kean, I. R. L. Clinical pharmacology of gold. Inflammopharmacology 16, 112–125 (2008).
Goldstein, N. I., Prewett, M., Zuklys, K., Rockwell, P. & Mendelsohn, J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin. Cancer Res. 1, 1311–1318 (1995).
Wagner, D. S. et al. The in vivo performance of plasmonic nanobubbles as cell theranostic agents in zebrafish hosting prostate cancer xenografts. Biomaterials 31, 7567–7574 (2010).
Chen, H. & Diebold, G. Chemical generation of acoustic waves: a giant photoacoustic effect. Science 250, 963–966 (1995).
Lin, C. P. & Kelly, M. W. Cavitation and acoustic emission around laser-heated microparticles. Appl. Phys. Lett. 72, 2800 (1998).
Lukianova-Hleb, E. Y., Volkov, A. N. & Lapotko, D. O. Laser pulse duration is critical for the generation of plasmonic nanobubbles. Langmuir 30, 7425–7434 (2014).
Reuveni, T., Motiei, M., Romman, Z. & Popovtzer, R. Targeted gold nanoparticles enable molecular CT imaging of cancer: an in vivo study. Int. J. Nanomed. 6, 2859–2864 (2011).
Sano, D. et al. Disruptive TP53 mutation is associated with aggressive disease characteristics in an orthotopic murine model of oral tongue cancer. Clin. Cancer Res. 17, 6658–6670 (2011).
Sharafinski, M. E., Ferris, R. L., Ferrone, S. & Grandis, J. R. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck 32, 1412–1421 (2010).
Maeda, H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 41, 189–207 (2001).
Weissleder, R. A clearer vision for in vivo imaging. Nature Biotechnol. 19, 316–317 (2001).
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).
The authors declare no competing financial interests.
About this article
Cite this article
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
Antifouling Dendrimer-Entrapped Copper Sulfide Nanoparticles Enable Photoacoustic Imaging-Guided Targeted Combination Therapy of Tumors and Tumor Metastasis
ACS Applied Materials & Interfaces (2021)
Near-infrared small molecule coupled with rigidness and flexibility for high-performance multimodal imaging-guided photodynamic and photothermal synergistic therapy
Nanoscale Horizons (2021)
Advanced Healthcare Materials (2021)
Photoacoustic Cavitation‐Ignited Reactive Oxygen Species to Amplify Peroxynitrite Burst by Photosensitization‐Free Polymeric Nanocapsules
Angewandte Chemie International Edition (2021)