Scientists synthesize a prebiotic carrier assists regorafenib in treating colorectal cancer

In a study published in Advanced Functional Materials, a research team from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences developed an oral molecular targeted drug delivery system based on an inulin derivative, which combines gut microbiota modulation with precise drug delivery, enhancing colorectal cancer (CRC) therapy.

Regorafenib (REG), a small-molecule multi-pathway protein kinase inhibitor, was approved by U.S. Food and Drug Administration in 2017 to treat metastatic CRC. Due to its poor water solubility and low oral absorption efficiency, high doses and frequent administration are required to maintain effective intratumoral drug concentrations, which can lead to dose-related toxicity. Therefore, it is important to develop a drug delivery system that improves the pharmacokinetic properties and tumor targeting of REG.

Gut microbiota has been shown to affect the development of CRC. Both regulating gut microbiota and improving intestinal environment can serve as complementary approaches to enhance CRC therapy.

Inulin, a kind of prebiotic material, promotes the proliferation of beneficial bacteria, regulates metabolism, maintains immune balance, and protects the intestinal barrier. It is resistant to gastric acid and digestive enzymes, while is only degraded by microorganisms in the colon. These properties make inulin a potential carrier material for colon-targeting oral drug delivery.

In this study, researchers synthesized an amphiphilic inulin-ursodeoxycholic acid conjugate that self-assembled in water and encapsulated REG to form the prebiotic nanoparticle, named UIRN.

In the in vitro stability study, UIRN remained stable in normal physiological conditions and upper gastrointestinal tract environments, and an increased rate of REG release from UIRN was achieved in medium containing gut microbiota.

After oral administration in healthy mice, UIRN delayed the adhesion-uptake-transport process of REG in the small intestine, increased REG distribution in the large intestine, prolonged drug circulation in blood, and increased intratumoral accumulation.

In the CT26 CRC mouse model, UIRN significantly improved the composition of gut microbiota, increasing the proportion of beneficial bacteria and decreasing that of pathogenic bacteria, and it also increased the content of intestinal beneficial metabolites short-chain fatty acids.

Additionally, UIRN increased the intratumoral number of CD8⁺ T cells, induced polarization of tumor-associated macrophages towards the M1-type, promoted the maturation of dendritic cells in the lymph nodes, and reduced the number of regulatory T cells, thus enhancing the anti-tumor immune response. The tumor inhibition rate reached 95.4% during UIRN administration, and combining UIRN with oxaliplatin or immune checkpoint antibodies further prolonged survival time.

UIRN also exhibited functions of microbial regulation and tumor suppression in the drug-induced colitis-associated colorectal cancer mouse model.

This study shows that this inulin derivative-based delivery system offers a promising strategy for CRC treatment.