Abstract
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.
Highlights
Recent success of immune checkpoint inhibitors such as CTLA-4 antibody or PD-1 antibody has increased attention to cancer immunotherapy [1]
The canceling of immunosuppression by tumor microenvironments leads to the activation of cancer-specific immune responses, especially cytotoxic T lymphocytes (CTLs), which play a crucial role in eliminating tumor cells, resulting in tumor regression
Carboxylated dextran derivatives (CHex-Dex) with different contents of CHex groups were synthesized by reacting hydroxyl groups of dextran with various amounts of 1,2
Summary
Recent success of immune checkpoint inhibitors such as CTLA-4 antibody or PD-1 antibody has increased attention to cancer immunotherapy [1]. We previously developedantigen antigencarriers carriersto toachieve achievethe thecontrol controlof ofantigen antigenfate fatewithin withindendritic dendritic cells and to induce cross-presentation using liposomes modified with pH-responsive cells and to induce cross-presentation using liposomes modified with pH-responsive fusogenic fusogenic polymers polymers [13,14,15,16] For this this purpose, purpose, carboxyl carboxyl group-introduced group-introduced poly(glycidol)s poly(glycidol)s or or polysaccharides polysaccharides have been designed as pH-sensitive polymers [13,14,15,16]. The effect of side chain pH-responsive membrane fusion ability compared with MGlu-Dex. Here, the effect of side chain structure structure of ofdextran dextran derivatives derivatives on on their their pH-responsive pH-responsive interaction interaction with with lipid lipid membrane, membrane, uptake uptake by by dendritic cells and intracellular delivery performance was examined.
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