A prebiotic inulin derivative-containing liposome for oral berberine delivery improves the orthotopic colorectal cancer chemotherapy

Abstract

Berberine hydrochloride (BH), a classic drug for treating acute enteritis, has been found to possess multiple immunoregulatory functions. However, its impact on the chemotherapy of colorectal cancer (CRC) has not been revealed. In addition, a suitable oral delivery system for BH is required to reduce and slow its clearance in the intestines and to improve its bioavailability. In the present work, a BH-loaded hybrid liposome containing a prebiotic inulin derivative, named BLPN, was designed and constructed. BLPN was stable in media simulating the gastrointestinal environment. It showed a bidirectional modulatory effect on immune cells, depending on the BH concentration. After oral administration, BLPN prolonged the retention time of BH in the intestines and blood circulation. In an MC38 orthotopic CRC mouse model, BLPN substantially increased the BH accumulation inside tumors. A chemotherapeutic agent, irinotecan hydrochloride-loaded liposome (ILPS), was also prepared. The combination of BLPN with ILPS activated both innate and adaptive anti-tumor immune cells and promoted the secretion of proinflammatory cytokines, which enhanced the extravasation of ILPS from the blood vessels within the tumor. The combination with BLPN significantly improved the CRC tumor-suppressive effect of ILPS and extended the survival time of tumor-bearing mice. This study provides a potential strategy for improving CRC chemotherapy by combining it with a prebiotic oral delivery system for BH.