Inulin and hyaluronic acid-based oral liposome for enhanced photo-chemotherapy against orthotopic colon cancer and its reversal effects on tumor hypoxia and intestinal microbiota.

Colon cancer has a complex microenvironment and course, and conventional chemotherapy is hindered by low permeability and immunosuppression at the cancer site, leading to poor efficacy. Integrating intestinal environment regulation and molecularly targeted drugs are more attractive strategies. This study aimed to developed an oral colonic targeted delivery system (5-Flu/MET@MSNs/Ce6@HIL) using hyaluronic acid (HA) and inulin (IN) as key components. IN is a polymer with colon-specific targeting capabilities, while HA targets CD44 on the surface of colon cancer cells. We used IN and HA-modified liposomes to co-encapsulate three therapeutic agents, chemotherapy drug 5-Fluorouracil (5-Flu), photosensitizer chlorin e6 (Ce6), and hypoxia reliever metformin (MET). 5-Flu and Ce6 effectively induced cell apoptosis, whereas MET downregulated Hypoxia-Inducible Factor 1-α (HIF-1α) and alleviate the hypoxic microenvironment. In orthotopic colon-tumor-bearing-mice, the final product of 5-Flu@MET@MSNs/Ce6@HIL effectively hindered growth of tumors, which was inhibited by 3.31, 14.31, and 7.88 times when compared to 5-Flu, MET, or Ce6 single-loaded formulations, respectively. Furthermore, after oral administration, the multifunctional liposomes showed good in vivo safety and compliance. In conclusion, this study proposes a novel orthotopic colon-targeted cancer treatment strategy with accurate tumor targeting capabilities, which has certain potential and development value in future clinical applications.