(M1030-09-48) Polysaccharide Emulsion Gels for Reducing Postoperative Adhesions and Delivering 5-Fluorouracil

Purpose: Postoperative tissue adhesion is a common complication, and complete prevention is challenging despite advances in anti-adhesion agents. In colorectal cancer, both adhesion prevention and postoperative chemotherapy are essential. Loading drugs into an anti-adhesion agent can enhance drug effects locally and minimize side effects. This study introduces an anti-adhesion agent serving as a drug delivery system, using an emulsion forming a gel matrix with polysaccharides, xanthan gum, and pectin. It showed sustained drug release over 12 hours in vitro and enhanced pharmacokinetics in vivo, although concerns about systemic release and toxicity were noted. Therefore, the xanthan gum/pectin emulsion gel demonstrates outstanding anti-adhesion properties and has potential for development as a drug delivery system.

Methods: 5-FU-loaded anti-adhesion emulsion gels were prepared by mixing water and oil phases with an overhead stirrer (CK Science, Republic of Korea). Xanthan gum, pectin, and PEG 4000 were used in the water phase as hydrophilic polysaccharide polymers and a swelling agent. 5-FU was included as the anticancer drug, with poloxamer 407, polysorbate 80, and PEG 400 aiding emulsion formation. The mixture was stirred at 500 rpm for 30 minutes before adding soybean oil and stirring at 1000 rpm for 1 hour to form the gels.

Results: In vivo: therapeutic efficacy evaluation (Figure 1). To evaluate emulsion gels, formulations were tested on laparotomy models in 8-week-old SD rats with abraded peritoneum. Seven groups were performed: no treatment control, Guardix® sol, and five emulsion formulations (F1-4, Emulsion). Adhesions were assessed after 10 days, with scores for severity and extent given by three independent, blinded manner. In the control group, 7 out of 8 rats had severe adhesions (extent score 2.08, severity score 2.17). The Guardix® sol group had weaker adhesions (extent 1.29, severity 1.58), but this was not statistically significant. F1-treated rats had reduced adhesion scores (extent 1.08, severity 1.38). F2 and F3 (xanthan gum and pectin) showed strong anti-adhesion effects (F2: extent 0.29, severity 0.17; F3: 0.17 for both). F4 (pectin only) also had significantly lower adhesion scores (extent 0.83, severity 0.71). Emulsions without polysaccharides had better scores than the control (extent 0.79, severity 1.25). Adding polysaccharides to the emulsion gel enhanced anti-adhesion effects. F1 had the best retention in vitro but lacked therapeutic efficacy. F4, despite poor retention, showed low adhesion scores, suggesting pectin’s anti-inflammatory properties. F2 and F3 significantly outperformed the control, demonstrating strong anti-adhesion effects. In vivo: PK assessment (Figure 2), Table 1) To determine the pharmacokinetic (PK) profiles of 5-FU in emulsion gels, SD rats underwent laparotomy and received gels containing 1.5 mg 5-FU. A 5-FU intraperitoneal (IP) injection was the control. Emulsion gels F1, F2, and F3 had extended Tmax and higher AUC values, indicating sustained release. Tmax for F1 and F2 increased by 4.03 and 2.52 times, respectively (P < 0.05), with AUC values 2.32 (P < 0.01) and 2.13 times higher than the control. Gel matrix strength followed F1 > F2 > F3 > F4, affecting Tmax. F4, with the weakest matrix, released 5-FU rapidly like the IP injection. Gels released 5-FU within one day, showing limitations in sustained release due to increased surface area during surgery.

Conclusion: In this study, a polysaccharide-based emulsion gel was developed as an anti-adhesion agent and drug delivery system. Polysaccharides enhanced tissue adhesive force and stabilized the matrix, demonstrating strong biocompatibility and anti-adhesion properties. Emulsion gels F2 and F3, containing xanthan gum and pectin, effectively prevented postoperative adhesions in animal models compared to untreated and commercial Guardix® sol. The 5-FU-loaded emulsion gel with xanthan gum showed sustained drug release but also rapid initial release within the first 12 hours, indicating room for improvement in sustained delivery. Future research aims to enhance sustained release capabilities using a carrier system for better drug delivery in colorectal cancer surgery.

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Acknowledgements: This work was supported by the Mid-Career Researcher Program (No. NRF-2021R1A2C2008834), the Basic Research Infrastructure Support Program (University-Centered Labs-2018R1A6A1A03023718), and the Bio & Medical Technology Development Program (NRF-2022M3A9G8016257) through the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT).

Fig. 1. In vivo therapeutic efficacy of emulsion gel anti-adhesion agents. (A) Photographic images indicating adhesion in each treatment group. The blue dotted circle indicates adhesion at the abrasion site, while the black circle denotes adhesion at the incision suture site. (B) Number of animals in each group that developed adhesions at the abrasion site following adhesion induction. (C) Number of animals in each group that developed adhesions at the resection suture site due to laparotomy. (D) Number of animals in each group that exhibited adhesions at any of the evaluated sites. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2. Pharmacokinetic profile of 5-FU loaded emulsion gels and 5-FU intra- peritoneal injection in Sprague Dawley rats (mean ± standard deviation, N = 3). The dose was equivalent to 1.5 mg of 5-FU. 5-FU, 5-fluorouracil.

Table 1.
Pharmacokinetic parameters of 5-FU loaded emulsion gels and 5-FU IP injection
in Sprague Dawley rats (mean ± standard deviation, N = 3).