肽-半乳糖苷-阿霉素脂质体在肝细胞癌靶向治疗中作用

Effect of Peptide-galactoside-ADM Liposome on Target Therapy of Human Hepatocellular Carcinoma

目的:获得一种对肝细胞癌具有特异靶向的药物传递系统载体—聚乙二醇修饰的MMP-2底物肽-半乳糖苷-阿霉素脂质体(PEG-PD-Gal-ADM-liposomes),为临床肝癌的靶向治疗提供实验依据。方法:将二棕榈磷脂酰基乙醇胺(DOPE)与聚乙二醇化的MMP-2底物肽连接(Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln),即获得可被MMP-2切割的聚乙二醇-底物肽-DOPE,再与半乳糖苷脂质体(Gal-liposomes)、阿霉素(ADM)耦合,最终获得聚乙二醇修饰的MMP-2底物肽-半乳糖苷-阿霉素脂质体(PEG-PD- Gal-ADM-liposomes),体外观察其对人肝癌细胞株HepG2的效应。结果:MTT法显示PEG-PD-Gal-ADM脂质体对人肝癌细胞株HepG2的毒性作用弱于半乳糖苷-阿霉素脂质体(PEG-Gal-ADM)的作用(P<0.05),对人结肠癌细胞株SW480的毒性作用二者之间无显著差异;用MMP-2(5μ/ml)预处理后,PEG-PD-Gal-ADM脂质体对人肝癌细胞株HepG2的毒性作用与Gal-ADM脂质体的作用相近,无显著差异(P>0.05);加入过量的半乳糖封闭半乳糖受体后,二者的毒性作用均有下降,无显著性差异(P>0.05)。结论:PEG-PD-Gal-ADM脂质体是一种新型的HCC特异靶向治疗药物传递载体,可能是将来HCC靶向治疗的重要手段。

Objective： To obtain an HCC-selective target drug delivery system, PEGylated MMP-2 substrate peptide conjugated with galactosylated adriamycin liposomes, and provide the experimental basis for HCC-selective target therapy. Methods： The amino group of dioleoyl-phosphatidylethanolamine （ DOPE ） was conjugated with PEGylated MMP-2 substrate peptide（ Gly-Pro-Leu- Gly-Ile-Ala-Gly-Gln ）, then was incorporated with galactosylated adriamycin liposomes. Cytotoxicity assay on HepG2 in vitro was performed by MTT. Results： Cytotoxicity assay with MTT showed that the cytotoxicity ofPEG-PD-Gal-ADM liposome groups on HepG2was less than that of Gal-ADM liposome groups, and there was no remarkable cytotoxicity difference on SW480 between PEG-pD-Gal-ADM liposome groups and of Gal-ADM liposome groups. After the pretreatment by Hmmp-2 （ 5 μg/ml）, the cytotoxicity of PEG-PD-Gal-ADM liposome groups on HepG2 were silimar to that of Gal-ADM liposome groups, and in the presence of an excess of galactose, cytotoxicity of PEG-PD-Gal-ADM Liposome groups and Gal-ADM liposome groups were reduced, but not remarkably. Conclusion： PEG-PD-Gal-ADM liposomes was a novel HCC-selective target drug delivery vector, it may have further important applications in HCC-selective target strategy.