細胞内標的化スマートナノＤＤＳを用いた効率的かつ安全ながんワクチンの開発

我们合成了具有ph敏感释放谱的葡萄糖修饰和表柔比星共轭聚合物胶束。表柔比星胶束尺寸小，粒径分布均匀。分别用0%、25%、50%和100%葡萄糖修饰表柔比星胶束。葡萄糖分子对胶束的表面修饰显著影响了胶束的内吞作用和在细胞质中的命运。具体来说，在GLUT-1过表达的单层细胞培养条件下，葡萄糖偶联胶束在胞吐和内吞作用的同时伴有胞吐机制。此外，在三维多细胞球状肿瘤条件下，葡萄糖胶束的胞吐机制有助于驱动葡萄糖胶束在胞吞作用后深入肿瘤球体。我们观察到，葡萄糖表柔比星胶束比对照胶束（即0%葡萄糖修饰胶束）具有更高的穿透性。我们证实了不同葡萄糖修饰量的表柔比星胶束具有长血循环特性，这是其具有治疗作用的前提之一。我们在原位乳腺癌模型中进行了肿瘤积累和抗肿瘤活性研究。由于MDA-MB-231细胞过表达GLUT1，因此选择该肿瘤模型作为中试研究。我们发现游离表柔比星和表柔比星胶束组之间存在显著差异。但未观察到胶束组之间的差异。目前正在进行胶质母细胞瘤模型的抗肿瘤活性研究。

We synthesized glucose decorated and epirubicin conjugated polymeric micelles that have pH-sensitive release profile. Epirubicin micelles had small size and uniform size distribution. We prepared epirubicin micelle decorated with different amount of glucose ( 0%, 25%, 50%, and 100%). The surface decoration of micelles by glucose molecule significantly affected their endocytosis, and fate in the cytoplasm. Specifically, glucose conjugated micelles are accompanied by exocytosis mechanism in parallel to endocytosis under monolayer cell culture condition with GLUT-1 overexpressed cell. Furthermore, under 3D multicellular tumor spheroid condition, this exocytosis mechanism of glucose micelles helps to drive the glucose micelles to penetrate deeper into tumor spheroid following transcytosis. And we observed, glucose epirubicin micelles having higher penetration than control micelles (that is 0% glucose decorated micelle). We confirmed that the epirubicin micelles with different amount of glucose decoration have long blood circulation property, which is one of the prerequisites for its therapeutic activities. We performed tumor accumulation and antitumor activity in an orthotopic breast cancer model. This tumor model had been selected as a pilot-study due to the fact that MDA-MB-231 cells overexpress GLUT1. We found significant difference between free epirubicin and epirubicin micelle groups. But no difference between the micelle groups was observed. Antitumor activity study against Glioblastoma models is currently undergoing.