title: Co-delivery of thioridazine and doxorubicin using polymeric micelles for targeting both cancer cells and cancer stem cells.
abstract: In this study, thioridazine (THZ), which was reported to kill cancer stem cells, was used in a combination therapy with doxorubicin (DOX) to eradicate both cancer cells and DOX-resistant cancer stem cells to mitigate the reoccurrence of the disease. Both THZ and DOX were loaded into micelles with sizes below 100 nm, narrow size distribution and high drug content. The micelles were self-assembled from a mixture of acid-functionalized poly(carbonate) and poly(ethylene glycol) diblock copolymer (PEG-PAC) and urea-functionalized poly(carbonate) (PUC) and PEG diblock copolymer (PEG-PUC). The drug-loaded mixed micelles (MM) were used to target both cancer cells and stem cells via co-delivery. Cancer stem cells were sorted by a side population assay from BT-474 and MCF-7 human breast cancer cell lines, and identified by CD44+/CD24- phenotype. The cytotoxicity of various formulations was evaluated on the sorted cancer stem cells (side population SP cells), sorted non-stem-like cancer cells (non-side population NSP cells) and unsorted cancer cells. Antitumor activity was also evaluated on BT-474 xenografts in nude mice. As compared with NSP cells, DOX suppressed SP cell growth less effectively, while THZ and THZ-MM were more effective in the inhibition of SP cells. A stronger inhibitory effect was observed on SP cells with the co-delivery of free DOX and THZ or DOX-MM and THZ-MM as compared to free DOX or DOX-MM. THZ and THZ-MM were capable of lowering the population of SP cells in unsorted cells. In the BT-474 xenografts, the co-delivery of DOX-MM and THZ-MM produced the strongest antitumor efficacy, and both THZ and THZ-MM showed strong activity against cancer stem cells. This combination therapy may provide a promising strategy for breast cancer treatment by targeting both cancer cells and cancer stem cells.
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore; NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
authors.forename: Xi-Yu
authors.initials: XY
authors.lastname: Ke
authors.forename: Victor Wee
authors.initials: VW
authors.lastname: Lin Ng
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Gao
authors.forename: Yen Wah
authors.initials: YW
authors.lastname: Tong
authors.forename: James L
authors.initials: JL
authors.lastname: Hedrick
authors.forename: Yi Yan
authors.initials: YY
authors.lastname: Yang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D018492:Dopamine Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011076:Polycarboxylate Cement / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D013881:Thioridazine / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D018492:Dopamine Antagonists; D004337:Drug Carriers; D008823:Micelles; D011076:Polycarboxylate Cement; C005506:polycarbonate; D011092:Polyethylene Glycols; D004317:Doxorubicin; D013881:Thioridazine
keywords: Cancer stem cells; Co-delivery; Doxorubicin; Polycarbonates; Polymeric micelles; Thioridazine