To achieve efficient cancer immunotherapy, the induction of cytotoxic T lymphocyte-based cellular immunity is necessary. In order to induce cellular immunity, antigen carriers that can deliver antigen into cytosol of antigen presenting cells and can activate these cells are required. We previously developed 3-methyl glutarylated dextran (MGlu-Dex) for cytoplasmic delivery of antigen via membrane disruption ability at weakly acidic pH in endosome/lysosomes. MGlu-Dex-modified liposomes delivered model antigens into cytosol of dendritic cells and induced antigen-specific cellular immunity. However, their antitumor effects were not enough to complete the regression of the tumor. In this study, antigen delivery performance of dextran derivatives was improved by the introduction of more hydrophobic spacer groups next to carboxyl groups. 2-Carboxycyclohexane-1-carboxylated dextran (CHex-Dex) was newly synthesized as pH-responsive dextran derivative. CHex-Dex formed stronger hydrophobic domains at extremely weak acidic pH and destabilized lipid membrane more efficiently than MGlu-Dex. CHex-Dex-modified liposomes were taken up by dendritic cells 10 times higher than MGlu-Dex-modified liposomes and delivered model antigen into cytosol. Furthermore, CHex-Dex achieved 600 times higher IL-12 production from dendritic cells than MGlu-Dex. Therefore, CHex-Dex is promising as multifunctional polysaccharide having both cytoplasmic antigen delivery function and strong activation property of dendritic cells for induction of cellular immunity.

Recent success of immune checkpoint inhibitors has revealed that canceling of immunosuppression in tumor microenvironments is crucially important to achieve effective cancer immunotherapy using tumor-specific cytotoxic T lymphocytes (CTLs). Transforming growth factor (TGF)- signaling also contributes to immunosuppression in tumors via inactivation of CTL and activation of regulatory T cells. The combination of the CTL induction system and blocking system of TGF- signaling is attempted in this study using antigen-loaded pH-sensitive polysaccharide-modified liposome and liposome embedded SB505124: an inhibitor of TGF- type I receptor. 3-Methylglutarylated dextran (MGlu-Dex)-modified liposomes delivered the model antigenic protein, ovalbumin (OVA), into cytosol of dendritic cell line via pH-responsive membrane disruption. Subcutaneous administration of these liposomes induced the regression of OVA-expressing tumor in mice. Additional administration of SB505124-embedded liposomes improved antitumor effects and survival in mice. Results show that intravenous administration of SB505124-embedded liposomes promoted the infiltration of CTL to tumor tissues significantly compared with single administration of MGlu-Dex-modified liposomes, leading to strong immunotherapeutic effects. Results of the present study demonstrate that the combination of pH-sensitive polysaccharide-modified liposomes and SB-embedded liposomes is promising as an immunity-inducing system for cancer immunotherapy.

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