Liposomal Resiquimod for Enhanced Immunotherapy of Peritoneal Metastases of Colorectal Cancer

Abstract

Colorectal cancer with peritoneal metastases is currently treated by cytoreductive surgery and locoregional chemotherapeutics. This standard treatment is associated with high morbidity, mortality, and recurrence rate. To augment the existing therapy, we developed a liposome-based delivery system containing 1,2-stearoyl-3-trimethylammonium-propane chloride (DSTAP), a cationic lipid, to localize a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity (PerC) for enhancing the immune response against cancer that had spread to the PerC. The liposomes delivered by intraperitoneal injection increased peritoneal retention of R848 by 14-fold while retarding its systemic absorption, leading to a 5-fold decreased peak plasma concentration compared to free R848 in mice. Within the PerC, the DSTAP-liposomes were found in ~40% of the dendritic cells by flow cytometry. DSTAP-R848 significantly upregulated interferon α (IFN-α) in the peritoneal fluid by 2-fold compared to free R848, without increasing the systemic level. Combined with oxaliplatin, a cytotoxic agent inducing immunogenic cell death, DSTAP-R848 effectively inhibited the progression of CT26 murine colorectal tumor in the PerC, while the combination with free R848 only showed a mild effect. Moreover, the combination of oxaliplatin and DSTAP-R848 significantly increased infiltration of CD8+ T cells in the PerC compared to oxaliplatin combined with free R848, indicating enhanced immune response against the tumor. The results suggest that DSTAP-R848 exhibits potential in augmenting existing therapies for treating colorectal cancer with peritoneal metastases via immune activation.

Keywords

• liposomes
• drug delivery
• resiquimod
• peritoneal metastasis of cancer
• immunotherapy
• toll-like receptor agonist