title: Precise Ratiometric Control of Dual Drugs through a Single Macromolecule for Combination Therapy.
abstract: A major challenge of combinatorial therapy is the unification of the pharmacokinetics and cellular uptake of various drug molecules with precise control of the dosage thereby maximizing the combined effects. To realize ratiometric delivery and synchronized release of different drugs from a single carrier, a novel approach was designed in this study to load dual drugs onto the macromolecular carrier with different molar ratio by covalently preconjugating dual drugs through peptide linkers to form drug conjugates. In contrast to loading individual types of drugs separately, these drug conjugates enable the loading of dual drugs onto the same carrier in a precisely controllable manner to reverse multidrug resistance (MDR) of human hepatoma (HepG2) cells. As a proof of concept, the synthesis and characterization of xyloglucan-mitomycin C/doxorubicin (XG-MMC/DOX) conjugates were demonstrated. This approach enabled MMC and DOX to be conjugated to the same polymeric carrier with precise control of drug dosage. The cytotoxicity and combinatorial effects were significantly improved compared to the cocktail mixtures of XG-MMC and XG-DOX as well as the individual conjugate of the mixture. Moreover, the results also showed that there was an optimum ratio of dual drugs showing the best cytotoxicity effect and greatest synergy among other tested polymeric conjugate formulations.
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Shiying
authors.initials: S
authors.lastname: Luo
authors.affiliation: §Prenatal Diagnosis Center, Lianyungang Maternal and Child Hospital, Lianyungang, 222002, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Yuannian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: Guo
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Jean Felix
authors.initials: JF
authors.lastname: Mukerabigwi
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Lei
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: ∥Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P. R. China.
authors.forename: Hongxuan
authors.initials: H
authors.lastname: He
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003131:Combined Modality Therapy / Q000379:methods; D004317:Doxorubicin / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005936:Glucans / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D046911:Macromolecular Substances / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016685:Mitomycin / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D014990:Xylans / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D005936:Glucans; D046911:Macromolecular Substances; D011108:Polymers; D014990:Xylans; C029353:xyloglucan; D016685:Mitomycin; D004317:Doxorubicin
keywords: combinational therapy; drug delivery; polymeric conjugates; ratiometric drug loading; reversion of multidrug resistance