Construction of in situ temperature-sensitive gel of Tegafur derivative TAK5399 and its evaluation against breast cancer.

Tegafur (FT) is widely used in the treatment of breast cancer. However, it has poor efficacy and significant toxic side effects. In this study, we first modified FT with aspirin to obtain a new FT derivative, named TAK5399. Then, TAK5399 in situ thermosensitive gel (TAK5399-TSG) was prepared using poloxamer F68 and F127 as carriers, and evaluated in vitro and in vivo. Among the five tested tumor cell lines, TAK5399 exhibited the highest sensitivity toward human breast cancer cells (MCF-7), with an inhibition rate 8.41 times higher than that of FT. Its potential anti-breast cancer mechanism may be related to inhibiting the PI3K/AKT signaling pathway to induce apoptosis and blocking the S phase of the cell cycle. The optimal formulation process for TAK5399-TSG is F127: 24.0%, F68: 6.5%, TAK5399 content of 1.25 mg/mL, and curing time of 24 hours. The maximum drug solubility, gelation temperature, and dissolution time were 1.25 mg/mL, 31 ± 0.21°C, and 6.5 ± 0.25 h, respectively. The Cmax of TAK5399-TSG administered via in situ injection was 15.5% and 23.8% of that of oral and in situ injection of TAK5399, respectively. In tumor-bearing mice, the tumor inhibition rates of oral TAK5399 and in situ injection of TAK5399-TSG were 1.28-fold and 1.82-fold higher than those of oral FT, respectively, with good biocompatibility. In conclusion, TAK5399-TSG is an in situ gel delivery system with potential for the treatment of breast cancer.