Tumor targeting of a cell penetrating peptide by fusing with a pH-sensitive histidine-glutamate co-oligopeptide.
Tumor targeting of a cell penetrating peptide by fusing with a pH-sensitive histidine-glutamate co-oligopeptide.
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DOI：
10.1016/j.biomaterials.2014.01.047
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发表时间：
2014-04
期刊：
影响因子：
14
通讯作者：
Zaro, Jennica L.
中科院分区：
文献类型：
--
作者：
Fei, Likun;Yap, Li-Peng;Conti, Peter S.;Shen, Wei-Chiang;Zaro, Jennica L.
细胞穿透肽(CPPs)已被公认为是蛋白质/多肽治疗药物细胞内递送的潜在载体。然而，它们缺乏选择性，阻碍了它们在体内的应用。为了提高它们的特异性，将一个对pH高度敏感的组氨酸-谷氨酸(HE)共寡肽与一个CPP即模型两亲肽(MAP)融合，并以谷胱甘肽S转移酶(GST)为载体蛋白进行融合表达。与其他两种含有HE或MAP的融合蛋白相比，只有融合多肽(HE-MAP)能够在pH 6.5或更低的条件下有效地将货物GST蛋白传递到细胞，而在pH 7.0或更高的条件下保持低水平的传递。利用人类乳腺癌的异种移植小鼠模型，荧光成像显示，只有HE-MAP可以有效地将GST靶向肿瘤部位，同时减少MAP在其他器官中的非特异性关联。本报告提供的数据显示了融合多肽HE-MAP针对酸性肿瘤微环境的诊断和/或治疗潜力。这种对pH敏感的多肽的简洁设计为克服CPP缺乏选择性提供了一种简单的方法，这可能会导致CPP和大分子疗法的更多应用。
Cell penetrating peptides (CPPs) have been well established as potential carriers for intracellular delivery of protein/peptide therapeutics. However, their lack of selectivity impedes their application in vivo. In order to increase their specificity, a highly pH-sensitive histidine-glutamate (HE) co-oligopeptide was fused with a CPP, i.e. model amphipathic peptide (MAP), and was expressed as fusion protein with glutathione S-transferase (GST) acting as a cargo protein. Compared with two other fusion proteins containing either HE or MAP, only the fused peptide (HE-MAP) could effectively deliver the cargo GST protein to cells at pH 6.5 or below, while maintaining low delivery to cells at pH 7.0 and above. Using a xenograft mouse model of human breast cancer, fluorescent imaging showed that only HE-MAP could effectively target GST to the tumor site, while reducing non-specific association of MAP in other organs. The data presented in this report demonstrates the diagnostic and/or therapeutic potential of the fused peptide, HE-MAP, for targeting the acidic tumor microenvironment. The concise design for this pH-sensitive peptide offers a simple way to overcome CPP’s lack of selectivity, which could lead to increased application of CPPs and macromolecular therapeutics.
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影响因子：
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