Initial Anti-Carcinoma Effect Of 5-FU Loaded Folate-targeted Caprolactone Polymer On Tumor Growth

Objective:The aim of current study was to investigate the in vitro and in vivo anti-carcinoma effect of 5-FU loaded folate-targeted caprolactone polymer (5-FU-P(CL-co-MCL)-FA) on SGC-7901 human gastric carcinoma and its toxicity in nude mice.Methods:In in vitro study, SGC-7901 human gastric cancer cells were recovered and cultured to the number concentrations. With different concentrations of P(CL-co-MCL), P(CL-co-MCL)-FA,5-Fu,5-FU-P(CL-co-MCL),5-FU-P(CL-co-MCL)-FA, drugs were treated on SGC-7901 cells for 24h and 48h. Along with control group, all treated groups were analyzed by inverted microscopy. The cytotoxicity was performed by MTT method. The cell optical density(OD), inhibition rate (IR) and half maximal inhibitory concentration(IC50) at 48h were detected respectively by using the MTT assay. In in vivo study, the SGC-7901 bearing nude mice were randomly allocated into 6 treatment groups including 5-FU-P(CL-co-MCL)-FA,5-FU-P(CL-co-MCL),5-FU, P(CL-co-MCL), P(CL-co-MCL)-FA and normal saline group. They were exposed by intravenous injection respectively (containing 5-FU 30 mg/kg) every other day. The tumor volume and weight of nude mice were measured every other day. The inhibition rate of tumor growth (IR) was calculated based on the results. The tumor was weighed at the end of the experiment and the tumor inhibition rate (TIR) was calculated. The mice were sacrificed at day 12, blood samples were collected for biochemistry parameters detection such as blood routine, galanine aminotransferase(ALT), aspartate aminotransferase (AST) and creatinine (Cr). At last, the pathological changes of tumor, liver and kidney were observed under light microscopy. The fluorescent signals of the tumor-bearing mice were detected by using the whole body optical imaging system.Results:Inverted microscopy and cell optical density results showed that two non-lactone polymer detected respectively did not sensitive to the carcinoma cells (IR<20%). The half maximal inhibitory concentration in SGC-7901 gastric carcinoma cells of 5-FU-P(CL-co-MCL)-FA,5-FU-P(CL-co-MCL and 5-Fu was 5.60ug/mL, 7.53μg/mL,9.83μg/mL.5-FU-P(CL-co-MCL)-FA exhibited more effective cytotoxicity and exhibited time-effect and dose-effect relationship as well. When the concentration was 20μg/mL, the inhibition rate (IR) of gastric carcinoma cell in 5-FU-P(CL-co-MCL)-FA group,5-FU-P(CL-co-MCL) group and 5-FU group was 75.0%,68.3% and 56.3%,40μg/mL was 85.7%,76.6% and 69.3%. At the end of the experiment, the general situation in nude mice observed with the saline group,5-Fu group and 5-FU-P(CL-co-MCL) group caused weight loss. The inhibition rate of tumor growth (IR) of the 5-FU group,5-FU-P(CL-co-MCL) group and 5-FU-P(CL-co-MCL)-FA group was significantly higher than NS group (43.66%, 49.41%,75.50%; p=0.000). Tumor inhibition rate (TIR) of 5-FU group, 5-FU-P(CL-co-MCL) group and 5-FU-P(CL-co-MCL)-FA group was significantly higher than NS group (44.40%,p=0.001;47.57%,p=0.000;72.93%,p=0.000). 5-FU-P(CL-co-MCL)-FA group possessed a stronger anti-carcinoma effect than 5-FU group(p=0.004) and 5-FU-P(CL-co-MCL) (p=0.0017) group. There was no difference in the IR and TIR between P(CL-co-MCL) group,P(CL-co-MCL)-FA group and NS group(p>0.05). The histopathologic results showed there was no significant difference on tumor necrosis between each group. Blood routine and serum parameters of nude mice suggested 5-FU could cause WBC level descend and aminotransferase (ALT) level increase, while 5-FU-P(CL-co-MCL)-FA didn’t. Histopathologic photo showed there was no significant change in liver cell and renal histology in all groups. In vivo fluorescence imaging of drug-loaded fluorescent material was in the visible tumor at the deposition.Conclusions:Comparing with 5-FU,5-FU-P(CL-co-MCL)-FA possessed more efficient cytotoxicity on SGC-7901 carcinoma cells and exhibited time-effect and dose-effect relationship as well. In vivo experiment demonstrated that 5-FU-P(CL-co-MCL)-FA could inhibit the growth of SGC-7901 gastric carcinoma more effectively than other drugs and resulted in less toxicity in nude mice than 5-FU. It is a safe, effective and new anti-carcinoma preparation, with favourable prospect in clinical application.