Immunomodulatory intraperitoneal chemotherapy with DACHPt-loaded biomaterial nanoparticles in colorectal...

Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a promising therapeutic option for the treatment of colorectal cancer-derived peritoneal carcinomatosis (CRC-PC) because of the possibility to spread high concentration of drugs throughout the entire peritoneal cavity while limiting the systemic side effects. However, PIPAC effectiveness is hampered by rapid drug clearance from the peritoneal cavity and poor drug specificity towards tumor nodules. This study employed diaminocyclohexane platinum-loaded hyaluronic acid-polyarginine nanoparticles (DACHPt NPs) for pressurized locoregional treatment of CRC-PC, aiming to compare the anticancer and immunomodulatory activities of free oxaliplatin and its active moiety, DACHPt, when delivered via nanoparticles. DACHPt NPs, produced via microfluidics presented a hydrodynamic volume of approximately 150 nm and marked DACHPt encapsulation efficiency (≈ 60 %). In vitro DACHPt NPs displayed a higher cytotoxic activity on murine colorectal carcinoma cell line (CT26) than oxaliplatin solution (IC₅₀: 4.79 µm vs 19.77 µm). Notably, DACHPt NPs demonstrated superior anticancer efficacy than oxaliplatin on a CT26-derived PC mouse model treated with PIPAC (mean survival: 29.5 days vs 22.5 days, respectively). This effect is associated to immunomodulatory properties of DACHPt NPs that induced a significant reduction of the granulocyte population within spleen, peritoneal fluid and tumor nodules and increased CD8 + T lymphocytes percentage in tumor nodules (CD8 + cells: 5.5 %) when compared to the saline group (CD8 + cells: 1.5 %). These findings suggest that DACHPt NPs not only possess superior anticancer effect than oxaliplatin solution, but also contribute to re-shape the immunosuppressive microenvironment toward a more antitumoral immune setting.