Terada Takeshi, Mizobata Miki, Kawakami Shigeru, Yamashita Fumiyoshi, Hashida Mitsuru
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
J Control Release. 2007 Jun 22;119(3):262-70. doi: 10.1016/j.jconrel.2007.01.018. Epub 2007 Feb 9.
We have previously shown that the peptide, KRTGQYKLC (bFGF), is recognized by fibroblast growth factor (FGF) receptor (FGFR) via binding to basic FGF (bFGF), and is capable of being used for drug delivery to tumors highly expressing FGFR and bFGF. However, although the binding and uptake of the liposomes (bFGFp-liposomes) modified by the peptide increased in the presence of bFGF, the modification induced non-specific uptake. To overcome this problem, here, we prepared bFGFp-liposomes including mPEG-DSPE. The 5 and 10% mPEG(5000)/ and 10% mPEG(3000)/bFGFp-liposomes reduced most of the interaction with erythrocytes and the uptake by macrophages, suggesting the sustained blood circulation of bFGFp grafted PEGylated liposomes. Furthermore, 10% mPEG(3000)/bFGFp-liposomes produced a significant increase in uptake in NIH3T3, A549, and B16BL6 cells with the expression of FGFR following pre-incubation with bFGF, but no increase in CHO-K1 cells lacking FGFR expression. Taken together, these results lead us to believe that bFGFp grafted PEGylated liposomes possess the functions of both PEGylated stealth liposomes and the tumor-targeting liposomes. This strategy could be applied to the development of novel tumor-selective drug delivery systems.
我们之前已经表明，肽KRTGQYKLC（bFGF）通过与碱性成纤维细胞生长因子（bFGF）结合，被成纤维细胞生长因子（FGF）受体（FGFR）识别，并且能够用于向高表达FGFR和bFGF的肿瘤进行药物递送。然而，尽管在bFGF存在的情况下，经该肽修饰的脂质体（bFGFp-脂质体）的结合和摄取增加，但这种修饰诱导了非特异性摄取。为了克服这个问题，在此我们制备了包含mPEG-DSPE的bFGFp-脂质体。5%和10%的mPEG(5000)/以及10%的mPEG(3000)/bFGFp-脂质体减少了与红细胞的大部分相互作用以及巨噬细胞的摄取，这表明接枝聚乙二醇化脂质体的bFGFp能够实现持续血液循环。此外，10%的mPEG(3000)/bFGFp-脂质体在与bFGF预孵育后，在表达FGFR的NIH3T3、A549和B16BL6细胞中的摄取显著增加，但在缺乏FGFR表达的CHO-K1细胞中没有增加。综上所述，这些结果使我们相信接枝聚乙二醇化脂质体的bFGFp兼具聚乙二醇化隐形脂质体和肿瘤靶向脂质体的功能。这种策略可应用于新型肿瘤选择性药物递送系统的开发。
