Novel PLA-based shape-memory formulation: Design, preparation, and evaluation for gastro-retentive delivery of 5-fluorouracil to enhance oral bioavailability

Abstract

5-fluorouracil (5-FU) is one of the most effective chemotherapeutic drugs for various solid tumors. However, its low water solubility and limited absorption rates in the stomach are crucial limitations that prevent it from being effectively applied in clinical practice. To address these issues, we first encapsulated 5-FU in β-cyclodextrin (5-FU–β-CD) to enhance its solubility, and the resulting 5-FU–β-CD was then loaded into a PLA film to prepare a novel gastro-retentive drug delivery system (GRDDS) based on shape-memory properties. The excipients, such as tributyl citrate (TBC), hydroxyethyl cellulose (HEC), citric acid (CA), and sodium bicarbonate (NaHCO₃), were incorporated into the PLA matrix at an optimized ratio. This was done to enhance the performance of PLA as an ideal matrix material in GRDDS, including improvements in drug release, floating behavior, shape recovery, gastric retention, and in vivo anti-tumor activity. The results suggested that the solubility of the 5-FU–β-CD inclusion complex was significantly enhanced, which was 1.88-fold higher than that of pure 5-FU. The optimal shape-memory drug delivery formulation, 5-FU–β-CD–PLA/TBC (86/14), prepared in this study consists of PLA/TBC (86/14) incorporating 3 % HEC, 3 % NaHCO₃, 1 % CA, and 3 % 5-FU. Its gastric retention time was notably prolonged to approximately 8 h following oral administration in mice, whereas the residual amount of 5-FU–β-CD at this time point was much lower than the initial loading. The oral bioavailability of the 5-FU–β-CD–PLA/TBC (86/14) was 269 % higher than that of pure 5-FU. Additionally, the mean tumor size and weight in the mouse model of gastric carcinoma administered with 5-FU–β-CD–PLA/TBC (86/14) were 215.3 mm³ and 241.4 mg respectively, significantly smaller than those in the 5-FU group. This indicates that the novel PLA-based drug delivery system has significantly enhanced anti-tumor effects. Its excellent therapeutic effects were further confirmed through HE, Ki67, and TUNEL staining. Taken together, 5-FU–β-CD–PLA/TBC (86/14) can be retained in the stomach to improve relative bioavailability. This system represents a promising carrier not only for 5-FU but also for other poorly soluble drugs that require prolonged retention in the stomach.