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On-demand intracellular amplification of chemoradiation with cancer-specific plasmonic nanobubbles

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Abstract

Chemoradiation-resistant cancers limit treatment efficacy and safety. We show here the cancer cell–specific, on-demand intracellular amplification of chemotherapy and chemoradiation therapy via gold nanoparticle– and laser pulse–induced mechanical intracellular impact. Cancer aggressiveness promotes the clustering of drug nanocarriers and gold nanoparticles in cancer cells. This cluster, upon exposure to a laser pulse, generates a plasmonic nanobubble, the mechanical explosion that destroys the host cancer cell or ejects the drug into its cytoplasm by disrupting the liposome and endosome. The same cluster locally amplifies external X-rays. Intracellular synergy of the mechanical impact of plasmonic nanobubble, ejected drug and amplified X-rays improves the efficacy of standard chemoradiation in resistant and aggressive head and neck cancer by 100-fold in vitro and 17-fold in vivo, reduces the effective entry doses of drugs and X-rays to 2–6% of their clinical doses and efficiently spares normal cells. The developed quadrapeutics technology combines four clinically validated components and transforms a standard macrotherapy into an intracellular on-demand theranostic microtreatment with radically amplified therapeutic efficacy and specificity.

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Figure 1: Principle of the quadrapeutics: four components—colloidal gold, encapsulated drugs, low-energy short laser pulses and X-rays—are administered in a simple three-step protocol.
Figure 2: PNB-enhanced intracellular on-demand ejection (release) of encapsulated calcein green dye.
Figure 3: Quadrapeutics mechanisms in vitro.
Figure 4: Quadrapeutics treatment of HNSCC in mouse models.
Figure 5: Evaluation of quadrapeutics for intraoperative real-time diagnosis and treatment of HNSCC MRD.

Change history

  • 18 November 2014

     In the version of this article initially published, the sentence “At the same time, standard photoacoustic imaging of the same animals failed to detect MRD (Supplementary Fig. 5d)” was incorrect. It should have read “At the same time, standard photoacoustic imaging of the same animals was unable to detect even the large primary tumor (Supplementary Fig. 5d).” The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J. Myers (MD Anderson Cancer Center, NOM9 cell line), L. Metelitsa (Texas Children's Hospital, J32 cell line) and J. Ensley (Wayne State University, HN30 and HN31 cell lines) for sharing cell lines, E. Hanna, A. Gillenwater, H. Skinner and M. Kupferman for helpful discussions of head and neck cancer, G. Peng, R. Bouchard and C. Kingsley for technical help, D.S. Wagner for discussing cellular effects of PNBs, G. Mixon, S. Saunders, D. Grayson and M. Martinez for engineering and administrative help, D. Townley for performing transmission electron microscopy and W. Hartner and S. Parminter for editing. This work was supported by US National Institutes of Health (NIH) grant R01GM094816, US National Science Foundation grant CBET-1341212 and Virginia and L.E. Simmons Family Foundation Award (D.O.L.), US NIH grants R01CA128486 (V.P.T.), 5U54151881-012 (V.P.T.) and S10RR026399-01 (confocal microscope).

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E.Y.L.-H.,V.P.T. and D.O.L. discussed the results and wrote the paper; D.O.L. conceived the strategy and designed the experiments; E.Y.L.-H. and D.O.L. performed the experiments; E.Y.L.-H., V.P.T., X.W. and D.O.L. analyzed the data; R.R.S. prepared nanocarriers; and X.W. and X.R. prepared and analyzed the animals.

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Correspondence to Dmitri O Lapotko.

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Supplementary Figures 1–6, Supplementary Methods and Supplementary Table 1 (PDF 1444 kb)

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Lukianova-Hleb, E., Ren, X., Sawant, R. et al. On-demand intracellular amplification of chemoradiation with cancer-specific plasmonic nanobubbles. Nat Med 20, 778–784 (2014). https://doi.org/10.1038/nm.3484

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