title: Novel liver-specific cholic acid-cytarabine conjugates with potent antitumor activities: Synthesis and biological characterization.
abstract: OBJECTIVE
  Cytarabine is an efficient anticancer agent for acute myelogenous leukemia, but with short plasma half-life and rapid deamination to its inactive metabolite. The aim of this study was to design and synthesize novel cholic acid-cytarabine conjugates to improve its pharmacokinetic parameters.
  
  
  METHODS
  The in vitro stability of novel cholic acid-cytarabine conjugates was investigated in simulated gastric and intestinal fluid, mouse blood and liver homogenate using HPLC. The portacaval samples of the conjugates were examined in male Sprague-Dawley rats using LC/MS, and in vivo distribution was examined in male Kunming mice using LC/MS. Antitumor activities were tested in HL60 cells using MTT assay.
  
  
  RESULTS
  Cholic acid-cytarabine compounds with four different linkers were designed and synthesized. All the four cholic acid-cytarabine conjugates could release cytarabine when incubated with the simulated gastric and intestinal fluid, mouse blood and liver homogenate. The conjugates 6, 12, and 16 were present in the portacaval samples, whereas the conjugate 7 was not detected. The conjugates 6 and 16 showed high specificity in targeting the liver (liver target index 34.9 and 16.3, respectively) and good absorption in vivo, as compared with cytarabine. In cytarabine-sensitive HL60 cells, the conjugates 6, 12, and 16 retained potent antitumor activities.
  
  
  CONCLUSIONS
  Three novel cholic acid-cytarabine conjugates with good liver-targeting properties and absorption were obtained. Further optimization of the conjugates is needed in the future.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Dan-qi
authors.initials: DQ
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Jin-xue
authors.initials: JX
authors.lastname: He
authors.forename: Ze-hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Jing-kang
authors.initials: JK
authors.lastname: Shen
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019826:Cholic Acid / Q000737:chemistry*; D002853:Chromatography, Liquid; D003561:Cytarabine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems; D018922:HL-60 Cells; D006207:Half-Life; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D019826:Cholic Acid