title: Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells.
abstract: The development of drug resistance in cancer cells is one of the major obstacles to achieving effective chemotherapy. We hypothesized that the combination of a doxorubicin (Dox) prodrug and microRNA (miR)21 inhibitor might show synergistic antitumor effects on drug-resistant breast cancer cells. In this study, we aimed to develop new high-density lipoprotein-mimicking nanoparticles (HMNs) for coencapsulation and codelivery of this potential combination. Dox was coupled with a nuclear localization signal (NLS) peptide to construct a prodrug (NLS-Dox), thereby electrostatically condensing miR21 inhibitor (anti-miR21) to form cationic complexes. The HMNs were formulated by shielding these complexes with anionic lipids and Apo AI proteins. We have characterized that the coloaded HMNs had uniformly dispersed distribution, favorable negatively charged surface, and high coencapsulation efficiency. The HMN formulation effectively codelivered NLS-Dox and anti-miR21 into Dox-resistant breast cancer MCF7/ADR cells and wild-type MCF7 cells via a high-density-lipoprotein receptor-mediated pathway, which facilitated the escape of Pgp drug efflux. The coloaded HMNs consisting of NLS-Dox/anti-miR21 demonstrated greater cytotoxicity with enhanced intracellular accumulation in resistant MCF7/ADR cells compared with free Dox solution. The reversal of drug resistance by coloaded HMNs might be attributed to the suppression of miR21 expression and the related antiapoptosis network. Furthermore, the codelivery of anti-miR21 and NLS-Dox by HMNs showed synergistic antiproliferative effects in MCF7/ADR-bearing nude mice, and was more effective in tumor inhibition than other drug formulations. These data suggested that codelivery of anti-miR21 and chemotherapeutic agents by HMNs might be a promising strategy for antitumor therapy, and could restore the drug sensitivity of cancer cells, alter intracellular drug distribution, and ultimately enhance chemotherapeutic effects.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People's Republic of China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Rui
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People's Republic of China.
authors.forename: Tong
authors.initials: T
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People's Republic of China.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People's Republic of China.
authors.forename: Chunlai
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, People's Republic of China.
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism; D061986:MCF-7 Cells / Q000187:drug effects; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D019913:Nuclear Localization Signals / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000494:pharmacology; D018110:Receptors, Lipoprotein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D008075:Lipoproteins, HDL; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D019913:Nuclear Localization Signals; D011355:Prodrugs; D018110:Receptors, Lipoprotein; C031616:high density lipoprotein receptors; D004317:Doxorubicin
keywords: breast cancer therapy; doxorubicin prodrug; drug resistance; lipoprotein-mimicking nanoparticles; microRNA21 inhibitor; nuclear localization signal peptide