A novel brain targeted 5-FU derivative with potential antitumor efficiency and decreased acute toxicity: synthesis, in vitro and in vivo evaluation

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.