Huang Sujie, Zhu Zhongwen, Jia Bo, Zhang Wei, Song Jingjing
School of Life Sciences, Lanzhou University, Lanzhou, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
J Pept Sci. 2021 Oct;27(10):e3354. doi: 10.1002/psc.3354. Epub 2021 Jun 7.
Camptothecin (CPT), a DNA-toxin drug, exerts anticancer activity by inhibiting topoisomerase I. Targeted delivery of CPT into the cancer cell nucleus is important for enhancing its therapeutic efficiency. In this study, a new type of acid-activated cell-penetrating peptide (CPP) with nuclear localization capacity was constructed by conjugating six histidine residues and a hydrophobic peptide sequence, PFVYLI, to the nuclear localization sequence (NLS). Our results indicated that HNLS-3 displayed significant pH-dependent cellular uptake efficiency, endosomal escape ability, and nuclear localization activity. More importantly, the HNLS-3-CPT conjugate showed obviously enhanced cytotoxicity and selectivity compared with CPT. Taken together, our findings provide an effective approach to develop efficient CPPs with both cancer- and nucleus-targeting properties.
喜树碱（CPT）是一种DNA毒素药物，通过抑制拓扑异构酶I发挥抗癌活性。将CPT靶向递送至癌细胞核对于提高其治疗效果至关重要。在本研究中，通过将六个组氨酸残基和一个疏水肽序列PFVYLI与核定位序列（NLS）偶联，构建了一种具有核定位能力的新型酸激活细胞穿透肽（CPP）。我们的结果表明，HNLS-3表现出显著的pH依赖性细胞摄取效率、内体逃逸能力和核定位活性。更重要的是，与CPT相比，HNLS-3-CPT偶联物显示出明显增强的细胞毒性和选择性。综上所述，我们的研究结果为开发具有癌症靶向和细胞核靶向特性的高效CPPs提供了一种有效方法。
