Abstract 5693: Guided intracellular drug delivery and release with plasmonic nanobubbles in drug-resistant cancer cells
Authors: Lukianova-Hleb Ekaterina , Ren Xiaoyang , Belyanin Andrey , Zasadzinski Joseph A. , Wu Xiangwei , Lapotko Dmitri O. 
Published: August 2012

Abstract
Chemotherapies are often impeded by drug resistance of cancer cells, high non-specific toxicity and low selectivity and efficacy of drug delivery. We developed a platform for the selective, fast, guided intracellular delivery of drugs into cancer cells with new cell-specific agents, plasmonic nanobubbles (PNBs). PNBs are not particles but transient events, vapor nanobubbles, induced by a short laser pulse around gold nanoparticles. Therapeutic effects of PNBs have a localized mechanical, non-thermal, nature and can be dynamically tuned in cancer cells to support non-invasive imaging, disruption of endosomes and drug carriers, injection of drug and mechanical cell ablation with single cell selectivity in a heterogeneous tissue. Simultaneous treatment of a bulk tissue activates those functions only in cancer cells while leaving adjacent normal cells intact. Optical and acoustical properties of PNBs provide a real time guidance of therapeutic effect. PNB mechanisms were evaluated for intracellular delivery of free and encapsulated doxorubicin into drug-resistant oral cavity squamous cell carcinoma (OCSCC) cells mixed in a co-culture with normal cells. Gold nanoshells were conjugated with Panitumumab antibody to target EGFR that is overexpressed by OCSCC. Receptor-endocytotic targeting resulted in cancer cell-specific clusters of nanoshells. These clusters selectively generated PNBs only in cancer cells while normal cells did not produce PNBs under simultaneous treatment with a single, short near-infrared laser pulse of low, biologically safe, energy. PNBs selectively delivered free extracellular drug only to cancer cells by creating transient nano-holes in cellular membranes and inbound nanojets that brought the extracellular drug into the cytoplasm. Thus PNBs worked as nano-injector of extracellular drug. Compared to a standard treatment with doxorubicin alone, PNB injection improved therapeutic efficacy by 12-fold and at the same time reduced drug dose by 10-fold and non-specific toxicity by 3-fold. Plasmonic nanobubble-enhanced endosomal escape (PNBEE) provided intracellular delivery of the liposome-encapsulated drug, Doxil, that was administered separately with gold nanoshells through a self-assembly of mixed nanoshell-Doxil nanoclusters by cancer cells. Small PNBs generated in these nanoclusters disrupted both liposomes and endosomes and ejected the released doxorubicin into cytoplasm. Cancer cell-specific generation of PNBs in a mixed co-culture of OCSCC and normal cells increased the therapeutic efficacy of Doxil by 31-fold and at the same time reduced drug dose by 20-fold, treatment time by 3-fold and non-specific toxicity by 10-fold. The described mechanisms of nano-injection and PNBEE are universal, can be applied to various cancers and provide a guided intracellular drug delivery in heterogeneous tissues through the application of plasmonic nanobubbles.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5693. doi:1538-7445.AM2012-5693