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.
Highlights
The peritoneum is a serous mesothelial lining that encloses the abdominal viscera and acts as a conduit for blood, nervous, and lymphatic structures, in addition to restricting the movement of the internal organs [1]
peritoneal carcinomatosis (PC) of colorectal cancer is currently treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) often composed of folinic acid, 5-fluorouracil, and oxaliplatin
To test our hypothesis that cationic liposomes would exhibit enhanced IP retention, we prepared three liposomal formulations displaying different surface charge characteristics corresponding to the incorporation of a neutral (DSPC), cationic (DSTAP), or anionic (DSPG) lipid and compared their retention in the peritoneal cavity (PerC) after IP delivery (Table S1)
Summary
The peritoneum is a serous mesothelial lining that encloses the abdominal viscera and acts as a conduit for blood, nervous, and lymphatic structures, in addition to restricting the movement of the internal organs [1]. PC of colorectal cancer is currently treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) often composed of folinic acid, 5-fluorouracil, and oxaliplatin. Despite this aggressive approach, the median survival of PC in colorectal cancer patients is only 12 months, and the long-term survival remains negligible, with a high recurrence rate between 20 and 50% [3,4,5,6,7]. The reason behind this poor prognosis is complex; the reorganization of the tumor and peritoneal cavity (PerC) microenvironment towards an immunosuppressive phenotype is gaining recognition as a contributing factor [8,9]
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