Intracellular Protein Delivery System Using a Target-Specific Repebody and Translocation Domain of Bacterial Exotoxin
Intracellular Protein Delivery System Using a Target-Specific Repebody and Translocation Domain of Bacterial Exotoxin
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DOI：
10.1021/acschembio.7b00562
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发表时间：
2017-11-01
影响因子：
4
通讯作者：
Kim, Hak-Sung
中科院分区：
文献类型：
--
作者：
Kim, Hee-Yeon;Kang, Jung Ae;Kim, Hak-Sung
凭借基于蛋白质的疗法的高效性和大量的细胞内药物靶点，以细胞特异性方式进行的胞浆蛋白递送在精准医学领域引起了相当大的关注。在此，我们提出了一种基于靶标特异性重复体和铜绿假单胞菌外毒素A易位结构域的细胞内蛋白质递送系统。该递送平台是通过将EGFR特异性重复体作为靶向部分与易位结构域进行基因融合而构建的，而蛋白质货物则融合到递送平台的C末端。研究表明，该递送平台能够以特定目标的方式有效地将蛋白质货物转移到胞质溶胶中。当使用 gelonin 作为细胞毒性蛋白货物时，我们在异种移植小鼠模型中显示出显着的肿瘤消退和可忽略不计的毒性，从而证明了该递送平台的实用性和潜力。本平台可以在许多领域广泛应用于多种蛋白质的细胞选择性胞质递送。
With the high efficacy of protein-based therapeutics and plenty of intracellular drug targets, cytosolic protein delivery in a cell-specific manner has attracted considerable attention in the field of precision medicine. Herein, we present an intracellular protein delivery system based on a target-specific repebody and the translocation domain of Pseudomonas aeruginosa exotoxin A. The delivery platform was constructed by genetically fusing an EGFR-specific repebody as a targeting moiety to the translocation domain, while a protein cargo was fused to the C-terminal end of the delivery platform. The delivery platform was revealed to efficiently translocate a protein cargo to the cytosol in a target-specific manner. We demonstrate the utility and potential of the delivery platform by showing a remarkable tumor regression with negligible toxicity in a xenograft mice model when gelonin was used as the cytotoxic protein cargo. The present platform can find wide applications to the cell-selective cytosolic delivery of diverse proteins in many areas.