The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising approach for anti-cancer immunotherapy by bridging innate and adaptive immunity. Recent evidence... Show moreThe cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising approach for anti-cancer immunotherapy by bridging innate and adaptive immunity. Recent evidence suggests that chemotherapy-induced DNA damage can directly induce dendritic cell (DC) maturation and recruitment, which synergizes with STING activation to enhance anti-tumor effects. As an immunogenic cell death (ICD) inducer, oxaliplatin generates massive double-stranded DNA (dsDNA) crosslinks, release of tumor-associated antigens and promoting the "eat me" signal. STING activation improves antigen immunogenicity, which can promote T cell activation and infiltration. In this study, we developed liposomes encapsulating oxaliplatin and combine this formulation with a STING agonist (ADU-S100) for treating colorectal cancer. The liposomes efficiently inhibited the proliferation of tumor cells while induced ICD in CT26 colorectal cancer cells, which enhanced dendritic cell maturation and phagocytosis in vitro. The liposome-based immunochemotherapy exhibited the strongest efficacy, resulting in complete remission upon tumor inoculation. Mechanistic studies showed this potent anti-cancer effect was related to the significant recruitment of infiltrating CD8 and CD4 T cells, reduction of suppressive Treg cells, and a shift in the phenotype of tumor-associated suppressive macrophages that promote cancer to immune stimulating macrophages. Thus, our study demonstrated the potential of combining oxaliplatin-loaded liposomes with a STING agonist to reduce tumor growth by regulating the immunosuppressive state in the tumor. Show less
Tumor heterogeneity favors tumor tissue to survive and resist drugs, leading to the failure of chemotherapeutic agents to induce a therapeutic response. In addition, the absorption mechanisms,... Show moreTumor heterogeneity favors tumor tissue to survive and resist drugs, leading to the failure of chemotherapeutic agents to induce a therapeutic response. In addition, the absorption mechanisms, metabolism and excretion of chemotherapeutic drugs, which are commonly used for cancer patients and the lack of specific targeting of these drugs can cause adverse effects on treated patients. Thus, the general objective of this thesis is to investigate the biological activity of targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) as a drug delivery system (DDS) for carvedilol (CVDL) or oxaliplatin (OXA), in vitro and in vivo, to treat colorectal cancer (CRC). DDSs were formulated to achieve this goal. In chapters 2, 3 and 4, our studies were discussed in detail on the formulations and characterizations of NPs as DDSs with ideal characteristics to increase the therapeutic range of drugs at the tumor site. As well as the biological evaluation of these DDS when its anti-inflammatory activity (Chapter 2) and its antitumor activity in vitro (Chapters 2, 3 and 4) and in vivo (Chapters 3 and 4). Taken together, all the DDSs studied in this thesis were able to improve the chemotherapeutic efficiency of the drugs studied in Chapters 2, 3 and 4. Show less
