Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds

Abstract

Nanoparticle-mediated delivery of chemotherapies has demonstrated enhanced anti-cancer efficacy, mainly through the mechanisms of both passive and active targeting. Herein, we report other than these well-elucidated mechanisms, rationally designed nanoparticles can efficiently deliver drugs to cancer stem cells (CSCs), which in turn contributes significantly to the improved anti-cancer efficacy. We demonstrate that doxorubicin-tethered gold nanoparticles via a poly(ethylene glycol) spacer and an acid-labile hydrazone bond mediate potent doxorubicin delivery to breast CSCs, which reduces their mammosphere formation capacity and their cancer initiation activity, eliciting marked enhancement in tumor growth inhibition in murine models. The drug delivery mediated by the nanoparticles also markedly attenuates tumor growth during off-therapy stage by reducing breast CSCs in tumors, while the therapy with doxorubicin alone conversely evokes an enrichment of breast CSCs. Our findings suggest that with well-designed drug delivery system, the conventional chemotherapeutic agents are promising for cancer stem cell therapy.

Keywords: Breast cancer; Cancer stem cells; Drug delivery; Drug resistance; Gold nanoparticles.