Song Chung Kil, Jung Suk Hyun, Kim Dae-Duk, Jeong Kyu-Sung, Shin Byung Cheol, Seong Hasoo
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul, South Korea.
Int J Pharm. 2009 Oct 1;380(1-2):161-9. doi: 10.1016/j.ijpharm.2009.07.014. Epub 2009 Jul 25.
Sterically stabilized liposomes (SSL) were known to be accumulated passively in cancer due to the effect of enhanced permeability and retention (EPR). However, drug delivery via SSL to cancer seemed to show an insufficient improvement of chemotherapeutic efficacy. Herein, carbohydrate-binding proteins (lectins) of cell surface, which express on the plasmic membrane of many malignant cells, can be a good model of surface-modified liposomes. In this study, we investigated the in vitro characteristics of liposomes of which the surface was modified with a disaccharide molecule, sucrose or maltose. The disaccharide-modified lipids such as sucrose-modified lipid and maltose-modified lipid, in which the disaccharide was conjugated to the one end of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)-2000 (DSPE-PEG2000), was synthesized. The disaccharide-modified liposomes were prepared by thin film-hydration method and then doxorubicin (DOX), an anticancer drug, was loaded to the prepared liposomes by the remote loading method with ammonium ion gradient. Flow cytometry and confocal microscopy analyses showed that the disaccharide-modified liposomes enhanced the intracellular uptake of liposomes into various cancer cell lines via lectin-mediated endocytosis. The disaccharide-modified liposomes in which DOX was loaded inside of liposomes exhibited higher cytotoxicity against various cancer cells than DOX-loaded SSL did. These results suggest that disaccharide-modified liposomes may be promising cancer targeting carriers which can enhance intracellular uptake and cytotoxicity of the drug-loaded liposomes via lectin-mediated endocytosis.
由于增强的渗透和滞留（EPR）效应，空间稳定脂质体（SSL）已知会被动地在癌症中积累。然而，通过SSL向癌症递送药物似乎对化疗疗效的改善不足。在此，许多恶性细胞质膜上表达的细胞表面碳水化合物结合蛋白（凝集素）可以作为表面修饰脂质体的良好模型。在本研究中，我们研究了表面用二糖分子（蔗糖或麦芽糖）修饰的脂质体的体外特性。合成了二糖修饰的脂质，如蔗糖修饰的脂质和麦芽糖修饰的脂质，其中二糖与1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-（聚乙二醇）-2000（DSPE-PEG2000）的一端偶联。通过薄膜水化法制备二糖修饰的脂质体，然后通过铵离子梯度远程加载法将抗癌药物阿霉素（DOX）加载到制备的脂质体中。流式细胞术和共聚焦显微镜分析表明，二糖修饰的脂质体通过凝集素介导的内吞作用增强了脂质体对各种癌细胞系的细胞内摄取。负载DOX的二糖修饰脂质体对各种癌细胞的细胞毒性高于负载DOX的SSL。这些结果表明，二糖修饰的脂质体可能是有前景的癌症靶向载体，其可以通过凝集素介导的内吞作用增强载药脂质体的细胞内摄取和细胞毒性。
