The Synthesis And Preliminary Exploration Of Antitumor Activity Of MPEG-BSA-5-Fu

Objective: To extend the half-life and reduce the peak concentration of 5-FU, we prepared the mPEG-BSA-5-FU compounds, and explore its pharmacodynamic properties in vitro and invest its initial pharmacokinetics in vivo.Methods: Prepare 5-FUAC active ester with NHS-activated method, and coupled with albumin in borate buffer of pH9.0; prepare mPEG active aster with NHS-activated method, and coupled with BSA-5-FU prepared in pH 8.0 boric acid buffer solution, at last the compounds of mPEG-BSA-5-FU were got. Establish animal model of solid tumor of mouse with hepatoma cell line(H22), review the pharmacodynamics of the compounds of mPEG-BSA-5-FU comparison to 5-Fu,5-FU-BSANAP. Give 3 mg 5-FU and mPEG-BSA-5-FU (equivalent to the amount of 3 mg 5-FU prodrug) to each mouse with intraperitoneal injection. Measured the plasma drug concentration at different time points with HPLC, draw their time-concentration curve, calculate their pharmacokinetic parameters with 3p97 software provided by the Chinese Pharmacological Society.Results: as a result the coupled rate was 32.89μg/mg of BSA-5-FU, the modification degree was 43.37% of mPEG-BSA-5-FU. Under the same dose, the inhibition rate of mPEG-BSA-5-FU was 40.3%, significantly higher than 5-FU group (33.63%) and 5-FU-BSANAP group (20.54%) with statistical significance P<0.05. The minimum detection limit is 0.05 mg/L in HPLC analysis. The peak time is about 5.6 min. Its recovery rate,days coefficient,days coefficient were respective 103.7%,5.64%,6.35%. The peak plasma drug concentration of 5-FU crude drug is at 5.8 min, then quickly reduce. The peak plasma drug concentration of mPEG-BSA-5-FU is at 99.5 min, and maintain a high concentration for an extend period of time (1¹2 h). The T1/2(332.85 min) of mPEG-BSA-5-FU is significantly higher than the T1/2(9.88 min) of original drug 5-FU group, which reached a significant effect of long-circulating. The C_max(4.6mg/L) of mPEG-BSA-5-FU was significantly lower than the C_max(57.8 mg/L) of 5-FU group, and the AUC(2721 mg*min/L) is significantly higher than the AUC(1237 mg*min/L) of 5-FU group.Conclusion: the processes of coupling and modification were simple, but the result was not stable, the goal of the proceeds was a complex product, and there was difference in batches. Pharmacodynamic results showed that the anti-tumor rate of mPEG-BSA-5-FU was significantly higher than that of 5-FU group and 5-FU-BSANAP group. Pharmacokinetic results showed that the T_1/2 of mPEG-BSA-5-FU was significant prolonged; the peak time prolonged; the C_max had a substantially lowered; the AUC increased, which was possible to overcome the problems of 5-FU in high plasma concentration in short time, short activity, big side effects and so on.