title: MicroRNA-200c delivered by solid lipid nanoparticles enhances the effect of paclitaxel on breast cancer stem cell.
abstract: BACKGROUND
  One of the major obstacles in the treatment of breast cancer is breast cancer stem cells (BCSC) which are resistant to standard chemotherapeutic drugs. It has been proven that microRNA-200c (miR-200c) can restore sensitivity to microtubule-targeting chemotherapeutic drugs by reducing the expression of class III β-tubulin. In this study, combination therapy with miR-200c and paclitaxel (PTX) mediated by lipid nanoparticles was investigated as an alternative strategy against BCSC.
  
  
  METHODS
  A cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane was strategically selected to formulate solid lipid nanoparticles (SLN) for miR-200c delivery. Nanostructured lipid carriers (NLC) with 20 wt% oleic acid were prepared for PTX delivery. Mammospheres, which gained the characteristics of BCSC, were used as a cell model to evaluate the efficiency of combination therapy.
  
  
  RESULTS
  The cationic SLN could condense anionic miRNA to form SLN/miRNA complexes via charge interactions and could protect miRNA from degradation by ribonuclease. SLN/miR-200c complexes achieved 11.6-fold expression of miR-200c after incubation for 24 hours, compared with that of Lipofectamine™ 2000/miR-200c complexes (*P<0.05). Intracellular drug release assay proved that miRNA can be released from SLN/miRNA complexes efficiently in 12 hours after cellular uptake. After BCSC were transfected with SLN/miR-200c, the expression of class III β-tubulin was effectively downregulated and the cellular cytotoxicity of PTX-loaded NLC (NLC/PTX) against BCSC was enhanced significantly (**P<0.01).
  
  
  CONCLUSIONS
  The results indicated that the cationic SLN could serve as a promising carrier for miRNA delivery. In addition, the combination therapy of miR-200c and PTX revealed a novel therapeutic strategy for the treatment of BCSC.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Tingting
authors.initials: T
authors.lastname: Meng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Bolin
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, School of Medicine Science, Jiaxing University, Jiaxing.
authors.forename: Xuan
authors.initials: X
authors.lastname: Huang
authors.affiliation: The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Hu
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D065546:Drug Liberation; D004357:Drug Synergism; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry; D061986:MCF-7 Cells / Q000187:drug effects; D035683:MicroRNAs / Q000008:administration & dosage*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D005229:Fatty Acids, Monounsaturated; D008055:Lipids; C086724:Lipofectamine; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D000644:Quaternary Ammonium Compounds; C498585:TUBB3 protein, human; D014404:Tubulin; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane; D017239:Paclitaxel
keywords: breast cancer stem cells; combination therapy; microRNA-200c; nanostructured lipid carriers; paclitaxel; solid lipid nanoparticles