title: A novel brain targeted 5-fU derivative with potential antitumor efficiency and decreased acute toxicity: synthesis, in vitro and in vivo evaluation.
abstract: The broad-spectrum antitumor agent 5-fluorouracil (5-FU), has been used to treat various solid malignant tumors. However, its short life-time in vivo and poor ability to cross the blood-brain barrier has limited its application to brain tumor therapy. In order to develop a 5-FU derivative that localizes efficiently to the brain while retaining potent antitumor activity, we conjugated 5-FU with N,N-dimethylethylenediamine via an amide bond. The stability of the resulting 5-FU derivative (D-FU) was tested in vitro in phosphate buffer, rat plasma and brain homogenate. The pharmacokinetic and biodistribution studies in brains of the rats showed a higher C(max) (the maximal concentration) and an increased AUC(0-t) (the area under the concentration-time curve) which was 6-fold that of 5-FU. In addition, compared to 5-FU, D-FU exhibited lower toxicity in an acute toxicity assay and similar antitumor activity in the C6 cell line. In conclusion, D-FU has the potential to be developed into an efficient brain delivery drug.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Wenqi
authors.initials: W
authors.lastname: Wu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002021:Buffers; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D002021:Buffers; D007202:Indicators and Reagents; D005472:Fluorouracil