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Screening and characterization of a novel high-efficiency tumor-homing cell-penetrating peptide from the buffalo cathelicidin family.
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2019-07-15 , DOI: 10.1002/psc.3201
Yuan-Yuan Xu 1 , Xue-Wei Cao 1 , Long-Yun Fu 2 , Tao-Zhu Zhang 2 , Fu-Jun Wang 2, 3 , Jian Zhao 1
Affiliation  

Targeted delivery of antitumor drugs is especially important for tumor therapy. Cell‐penetrating peptides (CPPs) have been shown to be very effective drug carriers for tumor therapy. However, most CPPs lack tumor cell specificity. Here, we identified a highly efficient CPP, CAT, from the newly identified buffalo‐derived cathelicidin family, which exhibits a preferential binding capacity for multiple tumor cell lines and delivers carried drug molecules into cells. CAT showed an approximately threefold to sixfold higher translocation efficiency than some reported cell‐penetrating antimicrobial peptides, including the well‐known classical CPP TAT. Moreover, the delivery efficiency of CAT was greater in a variety of tested tumor cells than in normal cells, especially for the human hepatoma cell line SMMC‐7721, for which delivery was 7 times more efficient than the normal human embryonic lung cell line MRC‐5, according to fluorescent labeling experiment results. CAT was conjugated to the Momordica charantia‐derived type‐I ribosome‐inactivating protein MAP 30, and the cytotoxicity of the MAP 30‐CAT fusion protein in the tumor cell line SMMC‐7721 was significantly enhanced compared with that of the unconjugated MAP 30. The IC50 value of MAP 30‐CAT was approximately 83 times lower than the IC50 value of the original MAP 30. Interestingly, the IC50 value of MAP 30 alone for MRC‐5 was approximately twofold higher than the value for SMMC‐7721, showing a small difference. However, when MAP 30 was conjugated to CAT, the difference in IC50 values between the two cell lines was significantly increased by 38‐fold. The results of the flow cytometric detection of apoptosis revealed that the increase in cytotoxicity after CAT conjugation was mainly caused by the increased induction of apoptosis by the fusion protein. These results suggest that CAT, as a novel tumor‐homing CPP, has great potential in drug delivery applications in vivo and will be beneficial to the development of tumor therapeutics.

中文翻译:

水牛cathelicidin家族的新型高效肿瘤归巢细胞穿透肽的筛选和表征。

抗肿瘤药物的靶向递送对于肿瘤治疗尤其重要。细胞穿透肽(CPPs)已被证明是用于肿瘤治疗的非常有效的药物载体。但是,大多数CPP缺乏肿瘤细胞特异性。在这里,我们从新发现的水牛源cathelicidin家族中鉴定了一种高效的CPP,CAT,它对多种肿瘤细胞系具有优先的结合能力,并将携带的药物分子传递到细胞中。与一些报道的穿透细胞的抗菌肽(包括著名的经典CPP TAT)相比,CAT的转运效率大约高三到六倍。此外,CAT在各种测试肿瘤细胞中的传递效率要比正常细胞更高,尤其是对于人类肝癌细胞系SMMC-7721,根据荧光标记实验结果,其交付效率是正常人胚胎肺细胞系MRC-5的7倍。CAT与苦瓜衍生的I型核糖体失活蛋白MAP 30结合,与未结合的MAP 30相比,肿瘤细胞SMMC-7721中MAP 30-CAT融合蛋白的细胞毒性显着增强。 MAP 30-CAT的IC50值比原始MAP 30的IC50值低约83倍。有趣的是,仅MRC-5的MAP 30的IC50值比SMMC-7721的IC50值高大约两倍。差异不大。但是,当MAP 30与CAT偶联时,两种细胞系之间IC50值的差异显着增加了38倍。流式细胞仪检测凋亡的结果表明,CAT缀合后细胞毒性的增加主要是由于融合蛋白诱导的凋亡增加。这些结果表明,CAT作为一种新型的肿瘤归巢CPP,在体内药物递送应用方面具有巨大潜力,并且将有利于肿瘤治疗剂的开发。
更新日期:2019-07-15
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