Kim Hee-Yeon, Kang Jung Ae, Ryou Jeong-Hyun, Lee Gyeong Hee, Choi Dae Seong, Lee Dong Eun, Kim Hak-Sung
Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology (KAIST) , 291 Daehak-ro, Yuseong-gu, Daejeon, 305-701, Korea.
Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute , 29 Geumgu-gil, Jeongeup-si, Jeollabuk-do 580-185, Korea.
ACS Chem Biol. 2017 Nov 17;12(11):2891-2897. doi: 10.1021/acschembio.7b00562. Epub 2017 Oct 25.
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.
鉴于基于蛋白质的治疗方法具有高效性以及存在大量细胞内药物靶点，以细胞特异性方式进行胞质蛋白递送在精准医学领域引起了相当大的关注。在此，我们展示了一种基于靶向特异性重复体和铜绿假单胞菌外毒素A转位结构域的细胞内蛋白递送系统。通过将作为靶向部分的表皮生长因子受体（EGFR）特异性重复体与转位结构域进行基因融合来构建递送平台，同时将蛋白质货物融合到递送平台的C末端。结果表明，该递送平台能够以靶向特异性方式有效地将蛋白质货物转运至胞质溶胶。当使用相思子毒素作为细胞毒性蛋白质货物时，我们在异种移植小鼠模型中展示了显著的肿瘤消退且毒性可忽略不计，从而证明了该递送平台的实用性和潜力。本平台可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。
