Effective treatment of drug resistant recurrent breast tumors harboring cancer stem-like cells by staurosporine/epirubicin co-loaded polymeric micelles

• Published in: Journal of controlled release Vol. 264; pp. 127 - 135
• Main Authors: Zhang, Juanjuan, Kinoh, Hiroaki, Hespel, Louise, Liu, Xueying, Quader, Sabina, Martin, John, Chida, Tsukasa, Cabral, Horacio, Kataoka, Kazunori
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.10.2017; Elsevier
• Subjects: Aldehyde Dehydrogenase; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer stem-like cells; Cell Line, Tumor; Chemical Sciences; Drug Resistance, Neoplasm - drug effects; Drug-resistance; Epirubicin; Epirubicin - administration & dosage; Female; Mice, Inbred BALB C; Micelles; Neoplastic Stem Cells; Polymeric micelles; Polymers - administration & dosage; Staurosporine; Staurosporine - administration & dosage; Tumor Burden - drug effects; Breast cancer; Epirubicin; Drug-resistance; Cancer stem-like cells; Staurosporine; Polymeric micelles
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.08.025

Breast cancer recurrence and resistance are associated with cancer stem-like cell (CSC) sub-populations. As conventional therapies fail to treat CSCs, institution of novel therapeutic strategies capable of eradicating both cancer cells and CSCs is central for achieving effective treatments with long-term survival. Here, we studied the ability of polymeric micelles cooperatively loading the cytotoxic drug epirubicin (Epi) and the CSC inhibitor staurosporine (STS) to treat breast tumors, particularly when tumors relapsed after chemotherapy. The STS/Epi-loaded micelles (STS/Epi/m) demonstrated potent therapeutic efficacy against both naïve orthotopic 4T1-luc breast tumors and their recurrent Epi-resistant counterparts, significantly prolonging survival. This efficacy enhancement of STS/Epi/m was correlated with the ability of the micelles to suppress the CSC-associated sub-populations of breast cancer, i.e. the aldehyde dehydrogenase-positive (ALDH+) population and the CD44+/CD24− fraction, in Epi-resistant cells and tumors. These results demonstrated STS/Epi/m as a promising strategy for effective management of breast cancer. [Display omitted]