Li Tianshu, Amari Takuya, Semba Kentaro, Yamamoto Tadashi, Takeoka Shinji
Research Organization for Nano & Life Innovation, Waseda University (TWIns), Tokyo, Japan.
Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), Tokyo, Japan.
Nanomedicine. 2017 Apr;13(3):1219-1227. doi: 10.1016/j.nano.2016.11.018. Epub 2016 Dec 10.
1,5-Dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (GGLG) liposomes were previously developed to enhance drug delivery efficiency in tumor cells owing to its pH-responsive properties. Herein, we report the modification of GGLG liposomes by conjugating a Fab' fragment of an ErbB2 antibody to the terminus of PEG (polyethylene glycol)-lipid (Fab'-GGLG liposomes). The conjugation of Fab' fragments did not affect the antibody activity, drug (doxorubicin, DOX) encapsulation efficiency, stability during storage or pH-sensitivity. However, the binding affinity of Fab'-GGLG liposomes was enhanced to ErbB2-overexpressing HCC1954 cells specifically, and the cell association increased 10-fold in comparison to GGLG liposomes. Consequently, intracellular DOX delivery was enhanced, with an increased cytotoxicity in HCC1954 cells (i.e., IC of 1.17 and 3.08 μg/mL for Fab'-GGLG-DOX and GGLG-DOX liposomes, respectively). Further, a significantly enhanced tumor growth inhibition was obtained in an ErbB2-overexpressing breast cancer-bearing mouse model. Therefore, a potent anticancer drug delivery system was constructed by the immunological modification of pH-sensitive liposomes.
1,5 - 二十六烷基 - N,N - 二谷氨酰 - 赖氨酰 - L - 谷氨酸（GGLG）脂质体因其pH响应特性，先前已被开发用于提高肿瘤细胞中的药物递送效率。在此，我们报告了通过将ErbB2抗体的Fab'片段与聚乙二醇（PEG） - 脂质的末端偶联来修饰GGLG脂质体（Fab' - GGLG脂质体）。Fab'片段的偶联不影响抗体活性、药物（阿霉素，DOX）包封效率、储存期间的稳定性或pH敏感性。然而，Fab' - GGLG脂质体与过表达ErbB2的HCC1954细胞的结合亲和力特异性增强，与GGLG脂质体相比，细胞结合增加了10倍。因此，细胞内DOX递送增强，HCC1954细胞中的细胞毒性增加（即Fab' - GGLG - DOX和GGLG - DOX脂质体的IC分别为1.17和3.08μg/mL）。此外，在过表达ErbB2的荷乳腺癌小鼠模型中获得了显著增强的肿瘤生长抑制。因此，通过对pH敏感脂质体进行免疫修饰构建了一种有效的抗癌药物递送系统。
