title: pH-sensitive micelles for the intracellular co-delivery of curcumin and Pluronic L61 unimers for synergistic reversal effect of multidrug resistance.
abstract: Pluronic L61 unimers, which are biomacromolecular modulators, and curcumin, a small-molecule modulator, were co-formulated into pH-sensitive micelles to reveal the full synergistic potential of combination drug treatments to reverse multidrug resistance (MDR). Compared to monotherapy, combined therapy significantly improved the cytotoxicity, cellular uptake and apoptotic effects of doxorubicin (DOX) against MCF-7/ADR cells. In mechanistic studies, both L61 and curcumin enhanced the cytotoxic effect by acting on mitochondrial signalling pathways. The compounds selectively accumulated in the mitochondria and disabled the mitochondria by dissipating the mitochondrial membrane potential, decreasing the ATP levels, and releasing cytochrome c, which initiated a cascade of caspase-9 and caspase-3 reactions. Furthermore, both curcumin and L61 down-regulated the expression and function of P-gp in response to drug efflux from the MCF-7/ADR cells. In the MCF-7/ADR tumour-bearing mouse model, intravenous administration of the combined therapy directly targeted the tumour, as revealed by the accumulation of DiR in the tumour site, which led to a significant inhibition of tumour growth without measurable side effects. In conclusion, co-formulation consisting of L61 and curcumin in pH-sensitive micelles induced significant synergistic effects on the reversal of MDR. Therefore, the intracellular co-delivery of various MDR modulators has great potential to reverse MDR in tumours.
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.|School of Pharmacy, China Pharmaceutical University, Longmian Avenue 639, Jiangning District, Nanjing, 211198, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning Province, 110016, P.R. China.
authors.forename: Mingxi
authors.initials: M
authors.lastname: Qiao
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.
authors.forename: Zehui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Yang
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.
authors.forename: Lingying
authors.initials: L
authors.lastname: Dong
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.
authors.forename: Fucheng
authors.initials: F
authors.lastname: Xie
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.
authors.forename: Chunpeng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Dongling Road 120, Shenyang, Liaoning Province, 110866, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Kang
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage; D004339:Drug Compounding; D016503:Drug Delivery Systems; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008823:Micelles; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020442:Poloxamer / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D008823:Micelles; C480965:pluronic L61; D020442:Poloxamer; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D003474:Curcumin