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Abstract

Metastases in the peritoneum arise primarily from colorectal, ovarian, and gastric cancers, with colorectal and ovarian origins being the most prevalent. Peritoneal metastasis is marked by a high recurrence rate and mortality following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), mainly due to the incomplete eradication of cancer cells. Immunotherapy has gained traction rapidly in the past decades as a promising cancer treatment strategy, reactivating the immune system within the tumor microenvironment to attack cancer cells, which can lead to complete eradication when combined with chemotherapy. However, the efficacy of immunomodulatory agents is often hindered by solubility challenges. To address this issue, this dissertation focuses on developing novel immune boosting liposomal systems to enhance the delivery and efficacy of immunomodulatory agents for treating peritoneal metastasis. Oxaliplatin (OXA), an immunogenic cell death inducer used in HIPEC, was selected to promote the release of tumor antigens. Our formulations demonstrate that they can augment the existing therapy by leveraging the immune response against cancer. The first part of this dissertation focuses on developing a liposomal nanocarrier with a cationic lipid, allowing for localization of a toll-like receptor agonist, resiquimod (R848), within the peritoneal cavity. I evaluated the pharmacokinetic profile, immune cell uptake, tumor growth inhibition, and immune-modulating ability of this formulation. The second part of this thesis investigates utilizing a multivalent cationic lipopeptide to further improve the peritoneal retention of R848. A novel multivalent cationic lipopeptide-modified liposomal formulation was developed and characterized. I also performed a comparative analysis with the initial formulation regarding pharmacokinetics and in vivo immune activation. The third part of this dissertation explores anti-tumor efficacy, tumor immune infiltration, and specific long-term immunity against the cancer. In addition to assessing their efficacies in a murine tumor model, I studied the immune microenvironment reprogramming and the roles of various immune cell populations in cancer treatment using an immune depletion assay. This thesis demonstrates that cationic liposomal formulations, combined with current chemotherapy, hold promise for improving existing therapies for peritoneal metastasis. These advancements could significantly enhance treatment outcomes by addressing the challenges of R848 and optimizing the immune response against cancer.