Abstract
While chemotherapy is a major mode of cancer therapeutics, its efficacy is limited by systemic toxicities and drug resistance. Recent advances in nanomedicine provide the opportunity to reduce systemic toxicities. However, drug resistance remains a major challenge in cancer treatment research. Here we developed a nanomedicine composed of a phase-change nano-droplet (PCND) and an anti-cancer antibody (9E5), proposing the concept of ultrasound cancer therapy with intracellular vaporisation. PCND is a liquid perfluorocarbon nanoparticle with a liquid–gas phase that is transformable upon exposure to ultrasound. 9E5 is a monoclonal antibody targeting epiregulin (EREG). We found that 9E5-conjugated PCNDs are selectively internalised into targeted cancer cells and kill the cells dynamically by ultrasound-induced intracellular vaporisation. In vitro experiments show that 9E5-conjugated PCND targets 97.8% of high-EREG-expressing cancer cells and kills 57% of those targeted upon exposure to ultrasound. Furthermore, direct observation of the intracellular vaporisation process revealed the significant morphological alterations of cells and the release of intracellular contents.
Highlights
The 9E5 human anti-EREG antibody was selected for active targeting of phase-change nano-droplets (PCNDs)
Fluorescent-labelled 9E5 antibody clearly bound to high-EREG-expressing cells, followed by rapid internalisation into intracellular compartments within a few hours (Supplementary Fig. 1). 9E5 was conjugated to PCNDs using the biotin-streptavidin-biotin binding technique
Antibody-conjugated PCND is a new type of nanomedicine for ultrasound cancer therapy that could be used to treat cancer mechanically by ultrasound with high selectivity
Summary
Epiregulin (EREG), the cell-membrane-expressed ligand of epidermal growth factor receptor, is expressed and integrated into the plasma membrane at relatively high levels in a variety of human cancers, including colorectal and breast cancer[26] This ligand has been intensively investigated as a therapeutic target[26]. The anti-EREG antibody 9E5 was conjugated as the active targeting moiety to submicron particles called phase-change nano-droplets (PCNDs), acoustic droplets composed of a phospholipid shells and liquid perfluorocarbon (PFC) core (Fig. 1a). These nano-sized PFC droplets have attracted attention as multi-modal imaging contrast agents and drug carriers[27,28,29,30] because they vaporise into microbubbles upon exposure to ultrasound[31]. We succeeded in demonstrating the selective targeting and cytotoxic effects in vitro with direct observation of intracellular vaporisation by high-speed imaging
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