Department of Applied Chemistry Graduate School of Engineering , Osaka Prefecture University , 1-1 Gakuen-cho , Naka-ku, Sakai , Osaka 599-8531 , Japan.
Bioconjug Chem. 2019 May 15;30(5):1518-1529. doi: 10.1021/acs.bioconjchem.9b00221. Epub 2019 Apr 11.
Induction of cancer-specific cytotoxic T lymphocytes is crucially important to complement therapeutic effects of immune checkpoint inhibitors and to achieve efficient cancer immunotherapy. To induce cancer-specific cytotoxic T lymphocytes, cancer antigen carriers must have multiple functions to deliver cancer antigens to antigen presenting cells, release antigens into cytosol, and promote the maturation of these cells. We earlier achieved cytosolic delivery of antigens and induction of antigen-specific cytotoxic T lymphocytes using carboxylated polyglycidol or polysaccharide derivative-modified liposomes that can induce membrane fusion with endosomes in response to weakly acidic pH. Furthermore, pH-sensitivity and adjuvant properties of these polymers were enhanced strongly by introduction of hydrophobic carboxylated units to dextran. Against our expectations, these polymer-modified liposomes only slightly induce cancer immunity, probably because of the high hydrophobicity of spacer units. This study used a polysaccharide with charged groups (chondroitin sulfate) instead of dextran as a backbone to reduce hydrophobicity. Chondroitin sulfate derivative-modified liposomes showed almost equal pH-sensitivity to that of dextran derivative-modified liposomes and achieved selective delivery to dendritic cells, whereas dextran derivative-modified liposomes were highly taken up by both dendritic cells and fibroblasts. Chondroitin sulfate derivative-modified liposomes delivered model antigenic proteins into cytosol of dendritic cells and promoted cytokine production from the cells, leading to tumor regression on tumor-bearing mice after subcutaneous administration. Results demonstrate that charged groups having polysaccharide as a backbone can be used in an effective strategy to balance strong hydrophobicity of spacer units with their utilization for immunity-inducing systems.
诱导肿瘤特异性细胞毒性 T 淋巴细胞对于补充免疫检查点抑制剂的治疗效果和实现有效的癌症免疫治疗至关重要。为了诱导肿瘤特异性细胞毒性 T 淋巴细胞，肿瘤抗原载体必须具有多种功能，将肿瘤抗原递送至抗原呈递细胞，将抗原释放到细胞质中，并促进这些细胞的成熟。我们之前使用羧基聚甘醇或多糖衍生物修饰的脂质体实现了细胞质内抗原的传递和抗原特异性细胞毒性 T 淋巴细胞的诱导，这些脂质体可以在弱酸性 pH 下响应内体融合诱导膜融合。此外，通过向葡聚糖中引入疏水性羧基单元，这些聚合物的 pH 敏感性和佐剂特性得到了极大增强。出乎意料的是，这些聚合物修饰的脂质体仅能轻微诱导癌症免疫，可能是由于间隔基的高度疏水性所致。本研究使用带电荷基团的多糖（硫酸软骨素）代替葡聚糖作为骨架，以降低疏水性。硫酸软骨素衍生物修饰的脂质体显示出与葡聚糖衍生物修饰的脂质体几乎相等的 pH 敏感性，并能选择性递送至树突状细胞，而葡聚糖衍生物修饰的脂质体则被树突状细胞和成纤维细胞高度摄取。硫酸软骨素衍生物修饰的脂质体将模型抗原蛋白递送至树突状细胞的细胞质中，并促进细胞因子的产生，导致荷瘤小鼠皮下给药后肿瘤消退。结果表明，具有多糖作为骨架的带电基团可用于一种有效的策略，在间隔基的强疏水性与其用于免疫诱导系统的利用之间取得平衡。
