title: Multidrug Delivery Systems Based on Human Serum Albumin for Combination Therapy with Three Anticancer Agents.
abstract: When administering several anticancer drugs within a single carrier, it is important to regulate their spatial distribution so as to avoid possible mutual interference and to thus enhance the drugs' selectivity and efficiency. To achieve this, we proposed to develop human serum albumin (HSA)-based multidrug delivery systems for combination anticancer therapy. We used three anticancer agents (an organic drug [5-fluorouracil, or 5FU], a metallic agent [2-benzoylpyridine thiosemicarbazide copper II, or BpT], and a gene agent [AS1411]) to treat liver cancer and confirm our hypothesis. The structure of the HSA-palmitic acid (PA)-5FU-BpT complex revealed that 5FU and BpT, respectively, bind to the IB and IIA subdomains of HSA. Our MALDI-TOF-MS spectral data show that one AS1411 molecule is conjugated to Cys-34 of the HSA-5FU-BpT complex via a linker. Compared with unregulated three-drug combination therapy, the HSA-5FU-BpT-AS1411 complex enhances cytotoxicity in Bel-7402 cells approximately 7-fold in vitro; however, in normal cells it does not raise cytotoxicity levels. Importantly, our in vivo results demonstrate that the HSA-5FU-BpT-AS1411 complex is superior to the unregulated three-drug combination in enhancing targeting ability, inhibiting liver tumor growth, and causing fewer side effects.
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Jinxu
authors.initials: J
authors.lastname: Qi
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gou
authors.affiliation: Ben May Department for Cancer Research, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Philbert
authors.initials: P
authors.lastname: Lee
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Shifang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Guangxi Universities Key Laboratory of Stem Cell and Pharmaceutical Biotechnology, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Zuping
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Ben May Department for Cancer Research, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi 541004, China.|Guangxi Universities Key Laboratory of Stem Cell and Pharmaceutical Biotechnology, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi 541004, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D008807:Mice, Inbred BALB C; D012709:Serum Albumin / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000970:Antineoplastic Agents; D012709:Serum Albumin; D005472:Fluorouracil
keywords: anticancer drug; combination therapy; drug delivery systems; human serum albumin; protein structure