title: Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance.
abstract: Combination chemotherapy in clinical practice has been generally accepted as a feasible strategy for overcoming multidrug resistance (MDR). Here, we designed and successfully prepared a co-delivery system named S-D1@L-D2 NPs, where denoted some smaller nanoparticles (NPs) carrying a drug doxorubicin (DOX) were loaded into a larger NP containing another drug (vincristine [VCR]) via water-in-oil-in-water double-emulsion solvent diffusion-evaporation method. Chitosan-alginate nanoparticles carrying DOX (CS-ALG-DOX NPs) with a smaller diameter of about 20 nm formed S-D1 NPs; vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles carrying VCR (TPGS-PLGA-VCR NPs) with a larger diameter of about 200 nm constituted L-D2 NPs. Some CS-ALG-DOX NPs loaded into TPGS-PLGA-VCR NPs formed CS-ALG-DOX@TPGS-PLGA-VCR NPs. Under the acidic environment of cytosol and endosome or lysosome in MDR cell, CS-ALG-DOX@TPGS-PLGA-VCR NPs released VCR and CS-ALG-DOX NPs. VCR could arrest cell cycles at metaphase by inhibiting microtubule polymerization in the cytoplasm. After CS-ALG-DOX NPs escaped from endosome, they entered the nucleus through the nuclear pore and released DOX in the intra-nuclear alkaline environment, which interacted with DNA to stop the replication of MDR cells. These results indicated that S-D1@L-D2 NPs was a co-delivery system of intracellular precision release loaded drugs with pH-sensitive characteristics. S-D1@L-D2 NPs could obviously enhance the in vitro cytotoxicity and the in vivo anticancer efficiency of co-delivery drugs, while reducing their adverse effects. Overall, S-D1@L-D2 NPs can be considered an innovative platform for the co-delivery drugs of clinical combination chemotherapy for the treatment of MDR tumor.
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: DanDan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: Yan Yan
authors.initials: YY
authors.lastname: Kong
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: Jia Hui
authors.initials: JH
authors.lastname: Sun
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: Shao Jie
authors.initials: SJ
authors.lastname: Huo
authors.affiliation: School of Pharmacy, Jiangsu Food and Pharmaceutical Science College, Huai'an.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: Yi Ling
authors.initials: YL
authors.lastname: Gui
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: Xu
authors.initials: X
authors.lastname: Mu
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing.
authors.forename: Shu Qin
authors.initials: SQ
authors.lastname: Yu
authors.affiliation: Ministry of Education Key Laboratory of Environmental Medicine and Engineering, School of Public Health, Southeast University, Nanjing, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000464:Alginates / Q000737:chemistry; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004655:Emulsions / Q000737:chemistry; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology; D014810:Vitamin E / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000464:Alginates; D004337:Drug Carriers; D004655:Emulsions; D006603:Hexuronic Acids; D014810:Vitamin E; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D014750:Vincristine; D004317:Doxorubicin; D020723:Glucuronic Acid; D048271:Chitosan; C014225:tocophersolan
keywords: co-delivery; combination chemotherapy; intracellular precision release; multidrug resistance; nuclear drug delivery; pH-sensitive nano-particle