title: Co-Eradication of Breast Cancer Cells and Cancer Stem Cells by Cross-Linked Multilamellar Liposomes Enhances Tumor Treatment.
abstract: The therapeutic limitations of conventional chemotherapeutic drugs have emerged as a challenge for breast cancer therapy; these shortcomings are likely due, at least in part, to the presence of the cancer stem cells (CSCs). Salinomycin, a polyether antibiotic isolated from Streptomyces albus, has been shown to selectively inhibit cancer stem cells; however, its clinical application has been hindered by the drug's hydrophobility, which limits the available administration routes. In this paper, a novel drug delivery system, cross-linked multilamellar liposomal vesicles (cMLVs), was optimized to allow for the codelivery of salinomycin (Sal) and doxorubicin (Dox), targeting both CSCs and breast cancer cells. The results show that the cMLV particles encapsulating different drugs have similar sizes with high encapsulation efficiencies (>80%) for both Dox and Sal. Dox and Sal were released from the particles in a sustained manner, indicating the stability of the cMLVs. Moreover, the inhibition of cMLV(Dox+Sal) against breast cancer cells was stronger than either single-drug treatment. The efficient targeting of cMLV(Dox+Sal) to CSCs was validated through in vitro experiments using breast cancer stem cell markers. In accordance with the in vitro combination treatment, in vivo breast tumor suppression by cMLV(Dox+Sal) was 2-fold more effective than single-drug cMLV treatment or treatment with the combination of cMLV(Dox) and cMLV(Sal). Thus, this study demonstrates that cMLVs represent a novel drug delivery system that can serve as a potential platform for combination therapy, allowing codelivery of an anticancer agent and a CSC inhibitor for the elimination of both breast cancer cells and cancer stem cells.
authors.affiliation: †Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Yu Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: ‡Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: †Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Si
authors.initials: S
authors.lastname: Li
authors.affiliation: §Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rohrs
authors.affiliation: §Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Zhang
authors.affiliation: ‡Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: †Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, United States.|‡Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States.|§Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States.
authors.forename: Pin
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008081:Liposomes / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011714:Pyrans / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000095662:Polyether Polyketides
chemical_list: D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D004317:Doxorubicin; D008081:Liposomes; D011714:Pyrans; D012333:RNA, Messenger; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: breast cancer stem cells (CSC); colocalized delivery; cross-linked multilamellar liposomal vesicle; doxorubicin; nanomedicine; salinomycin