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敏感性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。制备了不同葡萄糖含量(0%、25%、50%、100%)修饰的表阿霉素胶束。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去向。具体地说，在GLUT-1过表达的单层细胞培养条件下，葡萄糖结合胶束伴随着胞吐作用和内吞作用机制。此外，在三维多细胞肿瘤球体条件下，葡萄糖胶束的这种胞吐机制有助于推动葡萄糖胶束在穿胞后更深地渗透到肿瘤球体中。并且我们观察到，葡萄糖表柔比星胶束比对照胶束(即0%葡萄糖修饰胶束)具有更高的渗透率。我们证实了不同葡萄糖修饰量的表阿霉素胶束具有长时间的血液循环特性，这是其治疗活性的前提之一。我们在一个原位乳腺癌模型中进行了肿瘤聚集和抗肿瘤活性的研究。由于MDA-MB-231细胞过表达GLUT1，该肿瘤模型已被选为先导性研究。我们发现游离表阿霉素组和表阿霉素组之间有显著差异。但胶束组之间没有观察到差异。针对胶质母细胞瘤模型的抗肿瘤活性研究目前正在进行中。

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.