College of Pharmacy, Seoul National University, Seoul, South Korea.
Biomaterials. 2011 Jan;32(3):849-57. doi: 10.1016/j.biomaterials.2010.09.027.
Amphiphilic α-tocopherol oligochitosan conjugates were constructed by conjugating α-tocopherol succinate to water soluble oligochitosans with various molecular weights. In aqueous medium, the tocopherol oligochitosan conjugates self-assembled to single layered oligomersomes. The sizes of α-tocopherol-oligochitosan-based oligomersomes (TCOsomes) could be controlled by chain lengths of oligochitosans. The mean sizes of TCOsomes were 220 and 377 nm as the sizes of oligochitosans were 4000 and 12,500, respectively. For all TCOsomes formed in this study, polydispersity indexes were in the ranges of 0.111-0.256. Cryo-TEM images showed clear thickening in the unilamellar layer of TCOsomes upon complexation with siRNAs. Zeta potentials decreased as the ratios of siRNA/TCOsomes increased. TCOsomes self-assembled from tocopherol-oligochitosan 4K (TCOsome(4K)) significantly enhanced the cellular uptake of siRNAs (>98%), and reduced the expression of target proteins more effectively than did Lipofectamine 2000. In tumor xenografted mice, the intratumoral administration of siMcl-1 using TCOsomes substantially silenced the expression of Mcl-1 and prevented the growth of tumor. The hematoxylin-eosin staining showed the apoptosis of cells in the tissues of the mice treated with siMcl-1/TCOsome(4K) complexes, but not with siGL2/TCOsome(4K) complexes. The self-assembling and size-controllable oligomersomes might be suitable for effective in vivo delivery of siRNAs.
两亲性α-生育酚低聚壳聚糖缀合物通过将α-生育酚琥珀酸酯与各种分子量的水溶性低聚壳聚糖缀合而构建。在水介质中，生育酚低聚壳聚糖缀合物自组装成单层寡聚物囊泡。α-生育酚-低聚壳聚糖基寡聚物囊泡（TCOsomes）的大小可以通过低聚壳聚糖的链长来控制。当低聚壳聚糖的分子量分别为 4000 和 12500 时，TCOsomes 的平均粒径分别为 220nm 和 377nm。对于本研究中形成的所有 TCOsomes，多分散指数在 0.111-0.256 范围内。冷冻 TEM 图像显示，TCOsomes 与 siRNA 复合时，其单层厚度明显变厚。随着 siRNA/TCOsomes 比例的增加，Zeta 电位降低。TCOsomes 自组装的生育酚-低聚壳聚糖 4K（TCOsome(4K)）显著增强了 siRNAs 的细胞摄取（>98%），并比 Lipofectamine 2000 更有效地降低了靶蛋白的表达。在肿瘤异种移植小鼠中，TCOsomes 中 siMcl-1 的瘤内给药可显著沉默 Mcl-1 的表达并阻止肿瘤生长。苏木精-伊红染色显示，用 siMcl-1/TCOsome(4K) 复合物处理的小鼠组织中的细胞发生凋亡，但用 siGL2/TCOsome(4K) 复合物处理的则没有。自组装和尺寸可控的寡聚物囊泡可能适合于 siRNA 的有效体内递送。
