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Pharmacokinetic and pharmacodynamic properties of cationic liposomal delivery of the immunomodulatory agent R848 to the mouse peritoneal cavity for the treatment of advanced peritoneal cancer

University of British Columbia

Peritoneal cancer, defined as malignancies on the lining of the abdominal viscera, often originates from metastatic lesions in the ovaries, stomach and colon. The diffuse spreading of this cancer in the abdominal cavity makes it difficult to treat and causes relatively high recurrence rates. Currently, peritoneal cancer is treated by cytoreductive surgery and locoregional chemotherapeutic regimes. This procedure is associated with high morbidity and mortality, while not being sufficiently effective in diminishing recurrence rates. We hypothesized that peritoneal cancer treatment could benefit from an immunotherapeutic approach to reduce recurrence via generation of an anti-tumour immune response and modulation of the tumour microenvironment. To address this, we developed a liposome-based delivery system for the immune boosting agent Resiquimod (R848). We found that the liposomes incorporated with a positively charged lipid 1,2-stearoyl-3-trimethylammonium-propane (DSTAP) delivered by intraperitoneal (IP) injection increased peritoneal retention of R848 while minimizing its systemic absorption. Specifically, we observed that the peritoneal area under the curve concentration of R848 was 14 times greater when in the DSTAP-liposomes relative to the free drug formulation. Within 1 h post IP injection, ~60% of monocytes and macrophages, ~10% dendritic cells and ~8% natural killer (NK) cells in the peritoneal fluid were found to contain the liposomes. DSTAP-R848 significantly upregulated the production of TNF-α (2-fold), IL-6 (4-fold) and IFN-α (10-fold) mRNA relative to PBS control, leading to significantly reduced tumour progression in an IP metastasis model of CT-26 colorectal cancer in mice. Free R848 was ineffective in inducing the immune promoting cytokines nor antitumour efficacy. We demonstrated that DSTAP-R848 increased the trafficking of innate immune cells, specifically NK cells, in the peritoneal cavity.

Text

2021-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75908

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/