SN38 PLGA nanoparticles provide sustained antitumor efficacy and ameliorate colitis severity in a murine colitis-associated cancer model.

Irinotecan is a cornerstone therapy for metastatic colorectal cancer (CRC); however, the poor solubility and instability of its active metabolite, SN38, limit its therapeutic efficacy. This study aimed to improve SN38 delivery using poly(lactic-co-glycolic acid) (PLGA) nanoparticles and to evaluate their efficacy and safety in vitro and in a murine colitis-associated CRC model. SN38-PLGA nanoparticles exhibited a mean diameter of 170.7 ± 0.95 nm with a polydispersity index of 0.18 ± 0.04. In vitro, SN38-PLGA exhibited selective cytotoxicity-potent against HCT116 CRC cells but less toxic to HEK293T cells-and provided sustained SN38 release over 48 h. In the azoxymethane/dextran sodium sulfate-induced colitis-associated CRC model, intraperitoneal administration of either free SN38 or SN38-PLGA five times per week, combined with bevacizumab, significantly reduced tumor numbers compared with saline controls (7.2 vs. 7.7 vs. 14.8, p < 0.001), with comparable efficacy between the two treatment groups (p = 0.987). Notably, reducing SN38-PLGA dosing frequency from five to three times weekly maintained comparable efficacy (7.7 vs 5.5, p = 0.455). Moreover, SN38-PLGA markedly alleviated colitis severity, as demonstrated by improved body weight, increased colon length, reduced disease activity and histological scores, and lower serum levels of TNF-α, IL-1β, and IL-6 compared with free SN38 or saline. Histological evaluation revealed no significant damage to major organs, indicating a favorable safety profile. In conclusion, PLGA encapsulation preserves antitumor efficacy while reducing the severity of colitis. SN38-PLGA represents a promising therapeutic platform for colorectal cancer, with the potential to reduce dosing frequency and gastrointestinal toxicity.