(T1430-09-49) Preparation and Evaluation of 5-Fluorouracil Loaded Oil In Water Emulgel for Anti-Adhesion and Cancer Chemotherapy

Purpose: This study focused on developing a drug delivery system that prevents adhesion of organs and tissues, a common complication after surgical procedures. Especially in the colon cancer, both prevention of adhesion after surgery and chemotherapy are necessary. We studied the preparation of a specific type of emulgel (e.g., oil-in-water) loaded with 5-fluorouracil (5-FU), a widely used anticancer drug. In this study, we focused on developing a drug that added Na-CMC for anti-adhesion efficacy and glycerol to increased anti-adhesion efficacy by raising viscosity. The anticancer and anti-adhesion effects of the prepared emulgel were confirmed through in vitro cell viability analysis and in vivo histopathological evaluation.

Methods: Preparation of anti-adhesion emulgel: The water phase contains the anticancer agent 5-FU and is prepared by dissolving it in distilled water (DW) with poloxamer 188. The oil phase includes Na-CMC, solutol HS 15, Span 80, Glycerol and soybean oil. An emulgel was prepared by stirring the prepared water and oil phases using an overhead stirrer (CK Science, Korea). To increase viscosity and increase anti-adhesion effect, two sets of formulations were prepared; Set 1 (F1, F2, F3) with decreasing amounts of deionized water in the water phase and Set 2 (F3, F4, F5) with increasing amounts of glycerol in the oil phase. Evaluation of anti-adhesion emulgel: The rheological properties, in vitro drug release of 5-FU, viability of colon and lung cancer cell lines (HCT 116, A459 cell lines), and in vivo pharmacokinetics and tissue histological effects were evaluated in the anti-adhesion emulgel.

Results: Rheological analysis and adhesion of emulsion. The viscosity of the prepared emulgel increased as the distilled water ratio decreased, and the glycerol content increased (Figure 1A). This behavior was consistent in the shear stress–shear rate diagram (Figure 1B). All formulations showed high adhesion at 100 and 300 gf conditions. Adhesion was reduced for EF5, which had the highest glycerol content. This suggests that the combination of high viscosity and moderate adhesion, as seen in EF5, can lead to improved anti-adhesion efficacy. In vitro drug release study. All formulations showed sustained release of 5-FU ranging from 30% to 40% over 48 hours. EF5, which had the highest viscosity, showed the highest sustained release behavior. This correlation between viscosity and drug release demonstrates its potential as an effective anti-adhesion agent. Survivability of cancer cells. Cancer cell survival rate was performed to evaluate the anticancer efficacy of emulgel (EF5), which has high viscosity and high mucosal adhesion. Anti-adhesion emulsels did not significantly reduce cell viability when compared to EF5 and 5-FU solutions (Figure 2A-B). This shows that 5-FU released from the emulgel exhibits anticancer effects in colon cancer (HCT 116) and lung cancer (A549). In vivo evaluation of the anti-adhesion effect in the abdominal cavity. In vivo evaluation confirmed the anti-adhesion efficacy of EF5. The control group showed severe adhesions, whereas no adhesions were observed in the EF5-treated group (Figure 3A). To further substantiate these findings, tissue histological analysis was performed (Figure 3B). Through this analysis, it was successfully confirmed that there was no adhesion between adjacent tissues in the EF5 administered group.

Conclusion: This study developed an anti-adhesion emulgel loaded with 5-FU to prevent postoperative adhesion and deliver chemotherapy. The emulgel exhibited excellent rheological properties, sustained drug release in vitro, and anticancer efficacy. It also showed a successful anti-adhesion effect in vivo. The formulated anti-adhesion agent's high viscosity promotes a prolonged residence time at the surgical site, contributing to both its anti-adhesion and anti-cancer effects. The findings suggest that this emulgel has the potential to serve as an effective drug delivery system for both adhesion prevention and chemotherapy in colon cancer patients.

References: 1. Dinh, L. Hong, J. Kim, D. Lee, G. Park, E, Baik, S, and Hwang, s (2022). A novel thermosensitive poloxamer-hyaluronic acid- kappa-carrageenan-based hydrogel anti-adhesive agent loaded with 5-fluorouracil: A preclinical study in Sprague-Dawley rats. International Journal of Pharmaceutics, Volume 621, 121771
2. Lee, J. Dinh, L. Kim, H. Lee, J. Lee, J. Sung, Y. Yeo, S. and Hwang, s (2024). Polysaccharide-based emulsion gels for the prevention of postoperative adhesions and as a drug delivery system using 5-fluorouracil. International Journal of Pharmaceutics, Volume 661, 124386

Acknowledgements: This work was supported by the Mid-Career Researcher Program (No. NRF-2021R1A2C2008834) and the Basic Research Infrastructure Support Program (University-Centered Labs-2018R1A6A1A03023718) through the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT).

Figure 1. Rheological analysis and adhesion force of the emulgel anti-adhesion agents. (A-B) Rotational assessments of various formulations.

Figure 2. Cell viability of anti-adhesion emulgels. (A) HCT 116 cell lines treated with 5-FU solution and EF5, (B) A459 cell lines treated with 5-FU solution and EF5. (n=3).

Figure 3. (A) In vivo evaluation of intraperitoneal anti-adhesion effect. (B) Histological analysis of intraperitoneal adhesion tissues.