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

Multidrug and radiation resistance, as well as nonspecific toxic effects of some drugs, currently limit some cancer therapies. Ekaterina Lukianova-Hleb and colleagues address this with the development of an intracellular drug release system using plasmonic nanobubbles for the on-demand release of the encapsulated payload from nanocarriers, achieving high target cell specificity and intracellular concentration and enhanced therapeutic efficacy of both drugs and X-rays. Validation is shown in aggressive and multidrug resistant head and neck squamous cell carcinoma using encapsulated doxorubicin and paclitaxel. 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....