State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, China.
Eur J Pharm Biopharm. 2010 Mar;74(3):467-73. doi: 10.1016/j.ejpb.2010.01.002. Epub 2010 Jan 11.
Arg-Gly-Asp (RGD) modified doxorubicin-loaded liposomes could improve anticancer effect, and vascular disrupting agents (VDAs) could induce a rapid and selective shutdown of the blood vessels of tumors. We propose that RGD-modified liposomes for co-encapsulation and sequential release of vascular disrupting agent combretastatin A-4 (CA-4) and cytotoxic agent doxorubicin (Dox) could enhance tumor inhibition responses. In this study, we encapsulated Dox and CA-4 in RGD-modified liposomes. The release rate of Dox was proved to be much slower than that of CA-4 in vitro. Flow cytometry and laser confocal scanning microscopy clearly showed that RGD-modification promoted intracellular uptake of liposomal drugs by B16/B16F10 melanoma tumor cells and human umbilical vein endothelial cells (HUVECs). Cytotoxicity assay showed that the IC(50) of RGD-modified liposomes was lower than that of the corresponding unmodified liposomes. Therapeutic benefits were examined on B16F10 melanoma tumors subcutaneously growing in C57BL/6 mice. In vivo study demonstrated that RGD-modified liposomes exhibited the most pronounced tumor regression effect when both CA-4 and Dox were co-encapsulated. These results suggest that the targeted drug delivery system for co-encapsulation of vascular disrupting agents and anticancer agents may be a promising strategy for cancer treatment.
精氨酸-甘氨酸-天冬氨酸（RGD）修饰的阿霉素载脂质体可以提高抗癌效果，而血管破坏剂（VDAs）可以诱导肿瘤血管迅速而选择性地关闭。我们提出，RGD 修饰的脂质体可以共同包封和顺序释放血管破坏剂康普瑞汀 A-4（CA-4）和细胞毒性药物阿霉素（Dox），从而增强肿瘤抑制反应。在这项研究中，我们将 Dox 和 CA-4 封装在 RGD 修饰的脂质体中。体外实验证明，Dox 的释放速度明显慢于 CA-4。流式细胞术和激光共聚焦扫描显微镜清楚地表明，RGD 修饰促进了 B16/B16F10 黑色素瘤肿瘤细胞和人脐静脉内皮细胞（HUVEC）对脂质体药物的细胞内摄取。细胞毒性试验表明，RGD 修饰的脂质体的 IC（50）低于相应的未修饰的脂质体。我们在皮下生长于 C57BL/6 小鼠的 B16F10 黑色素瘤肿瘤上进行了治疗益处的检查。体内研究表明，当共同包封 CA-4 和 Dox 时，RGD 修饰的脂质体表现出最显著的肿瘤消退效果。这些结果表明，共包封血管破坏剂和抗癌剂的靶向药物递送系统可能是癌症治疗的一种有前途的策略。
