Sadzuka Yasuyuki, Sugiyama Ikumi, Tsuruda Tomoko, Sonobe Takashi
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Int J Pharm. 2006 Apr 7;312(1-2):83-9. doi: 10.1016/j.ijpharm.2005.12.043. Epub 2006 Feb 2.
Liposomes are recognized as one of the useful drug carriers, but have many problems to overcome before their clinical application. Liposomes, bonding peculiarly with serum protein (opsonization), are taken up by reticuloendothelial system (RES) cells in the liver and spleen. It is known that polyethyleneglycol (PEG) modification of the liposome surface induces the formation of a fixed aqueous layer around the liposomes due to the interaction between the PEG-polymer and water molecule, and thus prevents the attraction of opsonins. Namely, PEG-modified liposomes are able to escape trapping by the RES cells, and have a prolonged circulation time. In this study, the effects of different anchors with the same PEG molecular weight on the cell uptake and cytotoxicity of mixed PEG-modified liposomal doxorubicin (DOX) were examined. The fixed aqueous layer thickness (FALT) of liposomes covered with mixtures of PEG-molecules which differ in their chain length were increased, compared to that of the single PEG2000-modified liposome. Mixed PEG-modification of liposomes with different anchors (PEG2000-(1-monomethoxypolyethyleneglycol-2,3-distearoylglycerol (DSG): cholesterol (CHO)=1:1)-modified liposome) led to an increase in the FALT, compared to that of each single PEG-modification. The uptake of DOX into Ehrlich ascites carcinoma cells by the liposomes covered with PEG-CHO was higher than the other liposomes. Thus, liposomes covered with PEG-DSG and PEG-CHO have an enhanced cytotoxicity. In conclusion, it was confirmed that mix-modified liposomes using PEG-lipid with different anchors were superior.
脂质体被认为是一种有用的药物载体，但在临床应用前还有许多问题需要克服。脂质体与血清蛋白特异性结合（调理作用）后，会被肝脏和脾脏中的网状内皮系统（RES）细胞摄取。已知对脂质体表面进行聚乙二醇（PEG）修饰会由于PEG聚合物与水分子之间的相互作用而在脂质体周围诱导形成固定的水层，从而防止调理素的吸附。也就是说，PEG修饰的脂质体能够逃避RES细胞的捕获，并具有延长的循环时间。在本研究中，研究了相同PEG分子量下不同锚定基团对混合PEG修饰的脂质体阿霉素（DOX）细胞摄取和细胞毒性的影响。与单一PEG2000修饰的脂质体相比，覆盖有链长不同的PEG分子混合物的脂质体的固定水层厚度（FALT）增加。用不同锚定基团（PEG2000-(1-甲氧基聚乙二醇-2,3-二硬脂酰甘油（DSG）:胆固醇（CHO）=1:1）修饰的脂质体进行混合PEG修饰，与每种单一PEG修饰相比，导致FALT增加。用PEG-CHO覆盖的脂质体对DOX进入艾氏腹水癌细胞的摄取高于其他脂质体。因此，用PEG-DSG和PEG-CHO覆盖的脂质体具有增强的细胞毒性。总之，证实了使用具有不同锚定基团的PEG-脂质进行混合修饰的脂质体更具优势。
