Pharmacokinetic properties and antitumor efficacy of the 5-fluorouracil loaded PEG-hydrogel

Abstract

Background: We have studied the in vitro and in vivo utility of polyethylene glycol (PEG)-hydrogels for the development of an anticancer drug 5-fluorouracil (5-FU) delivery system.

Methods: A 5-FU-loaded PEG-hydrogel was implanted subcutaneously to evaluate the drug retention time and the anticancer effect. For the pharmacokinetic study, two groups of male rats were administered either an aqueous solution of 5-FU (control group)/or a 5-FU-loaded PEG-hydrogel (treated group) at a dose of 100 mg/kg. For the pharmacodynamic study, a human non-small-cell lung adenocarcinoma (NSCLC) cell line, A549 was inoculated to male nude mice with a cell density of 3 x 10(6). Once tumors start growing, the mice were injected with 5-FU/or 5-FU-loaded PEG-hydrogel once a week for 4 weeks. The growth of the tumors was monitored by measuring the tumor volume and calculating the tumor inhibition rate (IR) over the duration of the study.

Results: In the pharmacokinetic study, the 5-FU-loaded PEG-hydrogel gave a mean residence time (MRT) of 8.0 h and the elimination half-life of 0.9 h; these values were 14- and 6-fold, respectively, longer than those for the free solution of 5-FU (p < 0.05). In the pharmacodynamic study, A549 tumor growth was significantly inhibited in the 5-FU-loaded PEG-hydrogel group in comparison to the untreated group beginning on Day 14 (p < 0.05-0.01). Moreover, the 5-FU-loaded PEG-hydrogel group had a significantly enhanced tumor IR (p < 0.05) compared to the free 5-FU drug treatment group.

Conclusion: We suggest that 5-FU-loaded PEG-hydrogels could provide a useful tool for the development of an anticancer drug delivery system.

Figure 1

The chemical structures of the 6-arm PEG- AM and 6-arm PEG- SG. PEG-hydrogel network made by 6-arm PEG-AM and 6-arm PEG-SG. After displacement of the NHS (N-hydroxy succinimide) from 6-arm PEG-SG, amine residues on 6-arm PEG-AM are cross-linked with 6-arm PEG-SG.

Figure 2

In vitro release of 5-FU from PEG-hydrogel. The error bars represent the range from two experiments.

Figure 3

Serum concentration curves for 5-FU following subcutaneous injection of 100 mg/kg of the free 5-FU drug (open circle) and 5-FU-loaded PEG-hydrogel (closed circle) to SD rats (n = 3). Right panel shows serum concentration curves through 0 to 8 hour.

Figure 4

Comparison of relative tumor volumes among treatment groups. * Compared to the untreated control group (n = 6, * p < 0.05, ** p < 0.01). ^† Compared between 5-FU-treated control and 5-FU-loaded PEG-hydrogel groups (n = 6, † p < 0.05).