Enhanced Antitumor Effects of 5-Fluorouracil and a Vagal Nerve Blocker Loaded in a Thermosensitive Hydrogel for Localized Drug Delivery in Gastric Cancer

Background/Objectives: Neural infiltration closely correlates with the progression and poor prognosis of gastrointestinal tumors. The vagus nerve regulates tumor cell proliferation and invasion through acetylcholine (ACh). Combining targeted neurotherapy with chemotherapy has recently emerged as a promising anticancer strategy. Methods: In this study, we designed a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) that co-delivers 5-fluorouracil (5-FU) and atropine (a vagal nerve blocker) for local gastric cancer chemotherapy. A key feature of this 5-FU + atropine/PLEL hydrogel system is its sol–gel phase transition in response to physiological temperature, enabling sustained drug release in vivo. Results: After intraperitoneal injection, this dual-drug-loaded hydrogel significantly reduced tumor growth in gastric cancer models, outperforming single-drug-loaded hydrogels and free 5-FU plus atropine combinations. This delivery system also reduced side effects. Conclusions: Therefore, this innovative dual-drug-loaded hydrogel shows strong potential for intratumoral gastric cancer chemotherapy and offers a clinically valuable option for postoperative management.