Abstract
Specific delivery to antigen presenting cells (APC) and precise control of the intracellular fate of antigens are crucial to induce cellular immunity that directly and specifically attacks cancer cells. We previously achieved cytoplasmic delivery of antigen and activation of APC using carboxylated curdlan-modified liposomes, which led to the induction of cellular immunity in vivo. APCs express mannose receptors on their surface to recognize pathogen specifically and promote cross-presentation of antigen. In this study, mannose-residue was additionally introduced to carboxylated curdlan as a targeting moiety to APC for further improvement of polysaccharide-based antigen carriers. Mannose-modified curdlan derivatives were synthesized by the condensation between amino group-introduced mannose and carboxy group in pH-sensitive curdlan. Mannose residue-introduced carboxylated curdlan-modified liposomes showed higher pH-sensitivity than that of liposomes modified with conventional carboxylated curdlan. The introduction of mannose-residue to the liposomes induced aggregation in the presence of Concanavalin A, indicating that mannose residues were presented onto liposome surface. Mannose residue-introduced carboxylated curdlan-modified liposomes exhibited high and selective cellular association to APC. Furthermore, mannose residue-introduced carboxylated curdlan-modified liposomes promoted cross-presentation of antigen and induced strong antitumor effects on tumor-bearing mice. Therefore, these liposomes are promising as APC-specific antigen delivery systems for the induction of antigen-specific cellular immunity.
Highlights
Cancer immunotherapy has been gained much attention as one of cancer treatment modalities since the success of immune checkpoint inhibitors in a clinic [1,2]
Obtained curdlan derivatives (MGlu-Curd-A-Man) were modified onto antigen-loaded liposomes. These liposomes are expected to promote antigen presenting cells (APC)-specific uptake via recognition by mannose receptors, activate APC via recognition by curdlan receptor (Dectin-1) and induce cytoplasmic delivery of antigen, which leads to cross-presentation and induction of antigen-specific cellular immunity (Figure 1)
To introduce mannose residue into MGlu-Curd-A, amino group-introduced mannose derivative was prepared via thiol-ene reaction of allyl-α-D-mannopyranoside and cysteamine hydrochloride in the presence of AIBN as a catalysis [35] (Supplementary Scheme S1)
Summary
Cancer immunotherapy has been gained much attention as one of cancer treatment modalities since the success of immune checkpoint inhibitors in a clinic [1,2]. These polymer-modified liposomes containing antigenic proteins or peptides could deliver antigens into cytosol of APC via fusion with endosomal membrane responding to weakly acidic pH in endosomes [25] These polymer-modified liposomes could achieve cross-presentation in dendritic cells and the induction of antigen-specific cellular immunity in vivo [25,27]. In addition to APC-specific delivery performance, mannose receptor-mediated antigen uptake by dendritic cells is known to promote cross-presentation via weakly acidic intracellular compartments, which is called as “vacuolar pathway” [13,14]. Obtained curdlan derivatives (MGlu-Curd-A-Man) were modified onto antigen-loaded liposomes These liposomes are expected to promote APC-specific uptake via recognition by mannose receptors, activate APC via recognition by curdlan receptor (Dectin-1) and induce cytoplasmic delivery of antigen, which leads to cross-presentation and induction of antigen-specific cellular immunity (Figure 1). The percent release of pyranine from the liposomes was measured as described above
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