(227l) Co-Delivery of Salinomycin and Doxorubicin to Target Both Breast Cancer and Cancer Stem Cells Via Crosslinked Multilamellar Liposomal Vesicles (cMLVs)

Breast cancer is the most frequently diagnosed cancer in women of all female cancer. Chemotherapy has been widely used in the treatment of various stages of breast cancer. The major challenge on breast cancer treatment is the failure of chemotherapy, which is likely due to the presence of the cancer stem cells (CSCs). There are evidences shown that “CSC-enriched side populations” which are a subpopulation of cancer cells, however, they have ability to self- renew and to differentiate into the heterogeneous lineages of cancer cells that comprise the tumor. Currently available chemotherapies can target fast growing tumor bulk, but CSCs could remain un-attacked, causing a cancer resistance, recurrence and distal metastasis later on due to stronger capability in DNA damage repair. Salinomycin is a polyether antibiotic isolated from Streptomyces Albus, has recently been shown to possess anti-tumor properties by selectively inhibiting cancer stem cells population. Studies have shown that salinomycin selectively targets and decreases CSCs in breast cancer cells as well as others. Further studies have demonstrated the use of salinomcin in combinatorial therapy with conventional chemotherapeutics. However, due to hydrophobicity of salinomycin, effective in vivo delivery remains a huge challenge. In Gupta et al. study, free salinomycin was administered by intraperitoneal injection in vivo with the aid of ethanol due to its poor aqueous solubility. To overcome this issue, there is a need to develop a nanoparticle delivery system for hydrophobic drug such as salinomycin in anti-cancer therapy.  Besides, nanoparticle delivery system has shown significantly higher efficacy in delivering therapeutics compared to free drugs by prolonging drug circulation time, stabilizing release of drugs, reducing systemic toxicity, increasing drug penetration by EPR effect and allowing higher accumulation of drugs at the target sites. In present study, to further confirm the CSCs targeting effect of salinomycin in combinatorial therapy with doxorubicin, a novel drug delivery system, crosslinked multilamellar liposomal vesicles (cMLVs) are utilized to encapsulate salinomycin (hydrophobic) and doxorubicin ( hydrophilic),enabling these drugs to be delivered simultaneously to the site of interest in a single carrier for investigating the in-depth characterization of dual- inhibitory effects on both CSCs and breast cancer cells by in vitro and in vivo breast cancer models.

Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughputscreening. Cell 2009;138:645e59.

Joo K, Xiao L, Liu S, Liu Y, Lee C, Conti P, et al. Crosslinked multilamellar liposomes for controlled delivery of anticancer drugs. Biomaterials. 2013;34:3098-109.

Liu Y, Fang J, Kim Y, et al. Codelivery of Doxorubicin and Paclitaxel by cross-linked multilamellar liposome enables synergistic antitumor activity. Mol Pharm. 2014;11(5):1651-61.