Mumcuoglu Didem, Sardan Ekiz Melis, Gunay Gokhan, Tekinay Turgay, Tekinay Ayse B, Guler Mustafa O
Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University , Ankara 06800, Turkey.
ACS Appl Mater Interfaces. 2016 May 11;8(18):11280-7. doi: 10.1021/acsami.6b01526. Epub 2016 Apr 27.
Oligonucleotides are promising drug candidates due to the exceptionally high specificity they exhibit toward their target DNA and RNA sequences. However, their poor pharmacokinetic and pharmacodynamic properties, in conjunction with problems associated with their internalization by cells, necessitates their delivery through specialized carrier systems for efficient therapy. Here, we investigate the effects of carrier morphology on the cellular internalization mechanisms of oligonucleotides by using self-assembled fibrous or spherical peptide nanostructures. Size and geometry were both found to be important parameters for the oligonucleotide internalization process; direct penetration was determined to be the major mechanism for the internalization of nanosphere carriers, whereas nanofibers were internalized by clathrin- and dynamin-dependent endocytosis pathways. We further showed that glucose conjugation to carrier nanosystems improved cellular internalization in cancer cells due to the enhanced glucose metabolism associated with oncogenesis, and the internalization of the glucose-conjugated peptide/oligonucleotide complexes was found to be dependent on glucose transporters present on the surface of the cell membrane.
由于寡核苷酸对其靶DNA和RNA序列表现出极高的特异性，它们是很有前景的候选药物。然而，它们较差的药代动力学和药效学性质，以及与细胞内化相关的问题，使得需要通过专门的载体系统进行递送以实现有效治疗。在此，我们通过使用自组装的纤维状或球状肽纳米结构来研究载体形态对寡核苷酸细胞内化机制的影响。尺寸和几何形状均被发现是寡核苷酸内化过程的重要参数；直接穿透被确定为纳米球载体内化的主要机制，而纳米纤维则通过网格蛋白和发动蛋白依赖性内吞途径内化。我们进一步表明，由于与肿瘤发生相关的葡萄糖代谢增强，载体纳米系统与葡萄糖的缀合改善了癌细胞中的细胞内化，并且发现葡萄糖缀合的肽/寡核苷酸复合物的内化依赖于细胞膜表面存在的葡萄糖转运蛋白。
