Enhanced transfection efficiency of a systemically delivered tumor-targeting immunolipoplex by inclusion of a pH-sensitive histidylated oligolysine peptide
Enhanced transfection efficiency of a systemically delivered tumor-targeting immunolipoplex by inclusion of a pH-sensitive histidylated oligolysine peptide
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DOI：
10.1093/nar/gnh049
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发表时间：
2004-03-01
影响因子：
14.9
通讯作者：
Chang, EH
中科院分区：
文献类型：
--
作者：
Yu, W;Pirollo, KF;Chang, EH
成功的癌症基因治疗依赖于无毒、高效、肿瘤细胞特异性的系统性基因递送系统的开发。我们的实验室已经开发了一种全身给药的配体-脂质体复合物，可以有效地和优先地将其治疗有效载荷递送到原发性和转移性肿瘤。为了进一步提高该靶向复合物的转染效率，将合成的pH敏感性组氨酰化寡聚赖氨酸K[K（H）KKK]（5）-K（H）KKC（HoKC）包括在该复合物中，该复合物被设计用于帮助DNA的内体逃逸和缩合。HoKC的存在增加了体外转染效率超过原来的复合物。此外，由于HoKC肽的存在，没有观察到细胞毒性的增加。在无胸腺裸鼠的DU 145人前列腺癌异种移植肿瘤模型中，包含HoKC肽不干扰静脉内施用的配体/脂质体/DNA复合物的肿瘤靶向特异性。最重要的是，转基因表达水平在肿瘤中显著升高，但在接受掺入HoKC的复合物的那些动物的正常组织中没有。通过这种修饰的基因递送载体的转染效率的体内增强可以导致抗肿瘤功效所需的给药次数的减少。
Successful cancer gene therapy depends on the development of non-toxic, efficient, tumor cell- specific systemic gene delivery systems. Our laboratory has developed a systemically administered, ligand-liposome complex that can effectively and preferentially deliver its therapeutic payload to both primary and metastatic tumors. To further improve the transfection efficiency of this targeting complex, a synthetic pH-sensitive histidylated oligolysine K[K(H)KKK](5)-K(H)KKC (HoKC), designed to aid in endosomal escape and condensation of DNA, was included in the complex. The presence of HoKC increased the in vitro transfection efficiency over that of the original complex. Moreover, no increase in cytotoxicity was observed due to the presence of the HoKC peptide. In a DU145 human prostate cancer xenograft tumor model in athymic nude mice, inclusion of the HoKC peptide did not interfere with the tumor targeting specificity of the i.v. administered ligand/liposome/DNA complex. Most importantly, the level of transgene expression was significantly elevated in the tumors, but not in the normal tissue in those animals receiving the complex incorporating HoKC. The in vivo enhancement of transfection efficiency by this modified gene delivery vehicle could lead to a reduction in the number of administrations required for antitumor efficacy.