In our pervious study, a dual-functional peptide R7 was developed to form a complex with paclitaxel (PTX) for enhancement of PTX translocation. However, because of the unstable noncovalent bond between R7 and PTX, PTX redistributed after the introduction of heparin, leading to R7-PTX complex dissociation, further causing less PTX penetration than expected. Thus, a novel positive CPP carrier of P9 was developed to improve CPP-PTX affinity via a double-proline (Pro, P) hairpin tail and enhance PTX translocation through the reduction of translocation energy barrier, confirmed by the MM-PBSA analysis and umbrella sampling simulation. Cellular uptake study reveals that P9 can quickly translocate into the HeLa cells within 1 min and exhibits no noticeable cytotoxicity. Compared to R7, P9 is able to help PTX translocation, leading to a remarkable increase in the intracellular concentration of PTX, eventually resulting in a significant loss in tumor cell viability. In vivo experiments demonstrate that a vein injection of P9-PTX complex dramatically inhibits tumor growth. Our study provides a novel perspective for designing CPP-facilitated drug carrier to enhance antitumor efficiency.

中文翻译：

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具有疏水性发夹尾巴的双功能CPP促进细胞内紫杉醇的递送

在我们先前的研究中，开发了一种双功能肽R7与紫杉醇（PTX）形成复合物，以增强PTX转运。但是，由于R7和PTX之间不稳定的非共价键，在引入肝素后PTX重新分布，导致R7-PTX复合物解离，进一步导致PTX的渗透少于预期。因此，开发了一种新型的P9阳性CPP载体，以通过双脯氨酸（Pro，P）发夹尾部改善CPP-PTX亲和力，并通过减少易位能垒来增强PTX易位，这已通过MM-PBSA分析和保护伞得到证实抽样模拟。细胞摄取研究表明，P9可以在1分钟内快速转移到HeLa细胞中，并且没有明显的细胞毒性。与R7相比，P9可以帮助PTX移位，体内实验表明，静脉注射P9-PTX复合物可显着抑制肿瘤生长。我们的研究为设计CPP促进药物载体提高抗肿瘤效率提供了新的视角。