Experimental Study Of Antitumor Activity Of Targeted Drug Dilivery System For Folate-dextran-pirarubicin

The folic acid also named vatamin B₁₁ can be reduced to tetrahydro-folic acid, which is the coenzyme of one carbon unit transferase, participating in the metabolism of one carbon unit and de nove synthesis of purine and thymine. The folic acid which is also named vatamin B₁₁ The folate receptor, which is abcent in most normal tissues and elevated in a number of malignancies.Folic acid enters the cells via folate-receptor-mediated endocytosis, conjugates of anti-tumor drugs to folic acids or folate analogues which as carriers can be delivered to folate receptor expressing tumor cells and generate targeted effects.Objective: The aim of this investigation was to testify the selective affinity of folate(F) to tumor cells, and to develop tumor targeted drug delivery system for folate- pirarubicin using dextran as the cartier. Antitumor activity of the tumor targeted drug delivery system was observed. And whether the tumor targeted drug targeted to the SGC-7901 cell plant highly expressing the folate acceptor to surface was investigated.Method:1 .Free amino groups of F and THP were conjugated to the poly- aldehyde groups of DEX through Schiff bases using oxidizing reaction of NaIO₄. To control the quality of F-DEX-THP, F and THP dialysis-ultraviolet light-photometry method was established to accurately detect the contents of of F and THP in the conjugate.2. Inhibition rate(4h) of THP, F-DEX-THP and inhibition rate(48h) of THP, F-DEX-THP,F-DEX-THP+F (1mmol/L),F-DEX-THP+F (10mmol/L) and IC50 of the all drugs on human gastric cancer cell line SGC-7901 were detected by MTT method through in vitro antitumor activity experiment.3. Animal tumor transplanted method was adopted as in vivo antitumor experiment, in which SGC-7901 gastric cancer cells were transplanted abdominal cavity of nude mouse to form ascites tumor. Ascitic volume change was observed after administration. The group of 0.9% NaC1 solution served as a control group.Result:1. 250nm and 363nm were respectively selected as detection wavelength, and standard curves A = 0.0313 C-0.0212, r2 = 0.9991 and A = 0.0397 C + 9 E-05, r2 = 0.9999 were formulated.The drug loading content of the conjugated was 3.1% according to the regression equations..2. F-DEX-THP appeared an obvious dosage and effect relatio on SGC-7901 cell in vitro, when the concentration and culture time increased, F-DEX-THP increased the ability of killing and suppressing the cells. On the action time of 4h and 48h, IC50 of F-DEX-THP were lower than that ofTHP (P＜0.001) ; On the action time of 48h, it was alsolower than F-DEX-THP+F (1 mmol/L) ( P＜0.05 ) ;and there was no obvious difference between F-DEX-THP + F (1 mmol/L) and F-DEX-THP + F (10 mmol/L) ( P＞0.05).3. Significant inhibition of the tumor growth was seen in the group of THP, F-DEX-THP and F-DEX-THP + F (lmmol/L) as compared with the group of 0.9% NaC1 (P＜0.001 ) .Tumor growth inhibitory rate of the group of F-DEX-THP higher than of the other groups (P＜0.001) .Conclusion:Free amino groups of F and THP were conjugated to the poly- aldehyde groups of DEX through Schiff bases using oxidizing reaction of NaIO₄. F-DEX-THP is targeted to cultured human gastric cancer SGC-7901 cell line whether in vitro or in vivo. As a new praeparatum for targeted tumor therapy, F-DEX-THP presents poor target activity, so we prepare to investigate pharmacokinetics effect in vivo and toxicology effect pro—clinical of F-DEX-THP in following experiment.