Tang Hailing, Chen Xiaojing, Rui Mengjie, Sun Wenqiang, Chen Jian, Peng Jinliang, Xu Yuhong
School of Pharmacy, Shanghai Jiao Tong University , Shanghai 200240, People's Republic of China.
Mol Pharm. 2014 Oct 6;11(10):3242-50. doi: 10.1021/mp5001718. Epub 2014 Sep 12.
Targeting ligands displayed on liposome surface had been used to mediate specific interactions and drug delivery to target cells. However, they also affect liposome distribution in vivo, as well as the tissue extravasation processes after IV injection. In this study, we incorporated an EGFR targeting peptide GE11 on liposome surfaces in addition to PEG at different densities and evaluated their targeting properties and antitumor effects. We found that the densities of surface ligand and PEG were critical to target cell binding in vitro as well as pharmacokinetic profiles in vivo. The inclusion of GE11-PEG-DSPE and PEG-DSPE at 2% and 4% mol ratios in the liposome formulation mediated a rapid accumulation of liposomes within 1 h after IV injection in the tumor tissues surrounding neovascular structures. This is in addition to the EPR effect that was most prominently described for surface PEG modified liposomes. Therefore, despite the fact that the distribution of liposomes into interior tumor tissues was still limited by diffusion, GE11 targeted doxorubicin loaded liposomes showed significantly better antitumor activity in tumor bearing mice as a result of the fast active-targeting efficiency. We anticipate these understandings can benefit further optimization of targeted drug delivery systems for improving efficacy in vivo.
脂质体表面展示的靶向配体已被用于介导特异性相互作用以及将药物递送至靶细胞。然而，它们也会影响脂质体在体内的分布以及静脉注射后的组织外渗过程。在本研究中，我们除了以不同密度掺入聚乙二醇（PEG）外，还在脂质体表面掺入了表皮生长因子受体（EGFR）靶向肽GE11，并评估了它们的靶向特性和抗肿瘤效果。我们发现表面配体和PEG的密度对于体外靶细胞结合以及体内药代动力学特征至关重要。在脂质体制剂中以2%和4%的摩尔比包含GE11-PEG-DSPE和PEG-DSPE，介导了静脉注射后1小时内脂质体在新生血管结构周围的肿瘤组织中快速积累。这除了表面PEG修饰的脂质体最显著描述的增强渗透和滞留（EPR）效应之外。因此，尽管脂质体向肿瘤内部组织的分布仍然受扩散限制，但由于快速的主动靶向效率，GE11靶向的载阿霉素脂质体在荷瘤小鼠中显示出显著更好的抗肿瘤活性。我们预期这些认识能够有益于进一步优化靶向给药系统以提高体内疗效。
