Yuba Eiji, Fukaya Yoshiki, Yanagihara Shin, Kasho Nozomi, Harada Atsushi
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.
Pharmaceutics. 2020 Aug 11;12(8):754. doi: 10.3390/pharmaceutics12080754.
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.
特异性递送至抗原呈递细胞（APC）以及精确控制抗原在细胞内的命运对于诱导直接且特异性攻击癌细胞的细胞免疫至关重要。我们之前使用羧化凝胶多糖修饰的脂质体实现了抗原的胞质递送和APC的激活，这在体内诱导了细胞免疫。APC在其表面表达甘露糖受体以特异性识别病原体并促进抗原的交叉呈递。在本研究中，将甘露糖残基作为靶向APC的部分额外引入羧化凝胶多糖中，以进一步改进基于多糖的抗原载体。通过在pH敏感的凝胶多糖中引入氨基的甘露糖与羧基之间的缩合反应合成了甘露糖修饰的凝胶多糖衍生物。引入甘露糖残基的羧化凝胶多糖修饰的脂质体比用传统羧化凝胶多糖修饰的脂质体表现出更高的pH敏感性。在存在伴刀豆球蛋白A的情况下，向脂质体中引入甘露糖残基会诱导聚集，表明甘露糖残基呈现在脂质体表面。引入甘露糖残基的羧化凝胶多糖修饰的脂质体对APC表现出高度且选择性的细胞结合。此外，引入甘露糖残基的羧化凝胶多糖修饰的脂质体促进了抗原的交叉呈递，并对荷瘤小鼠诱导了强烈的抗肿瘤作用。因此，这些脂质体作为用于诱导抗原特异性细胞免疫的APC特异性抗原递送系统具有广阔前景。
