Lee Jeonghun, Oh Eun-Taex, Lee Hae-June, Lee Eunkyoung, Kim Ha Gyeong, Park Heon Joo, Kim Chulhee
Department of Polymer Science and Engineering, Program in Environmental and Polymer Engineering, Inha University, Incheon 22212, Korea.
Department of Biomedical Sciences, School of Medicine, Inha University, Incheon 22212, Korea.
ACS Omega. 2022 Aug 16;7(34):29684-29691. doi: 10.1021/acsomega.2c02127. eCollection 2022 Aug 30.
Although diverse cell penetrating motifs not only from naturally occurring proteins but also from synthetic peptides have been discovered and developed, the selectivity of cargo delivery connected to these motifs into the desired target cells is generally low. Here, we demonstrate the selective cytotoxicity tuning of an anticancer KLA peptide with a cell penetrating motif activatable by matrix metalloproteinase-2 (MMP2). The anionic masking sequence introduced at the end of the KLA peptide through an MMP2-cleavable linker is selectively cleaved by MMP2 and the cationic cell penetrating motif is activated. Upon treatment of the peptide to H1299 cells (high MMP2 level), it is selectively internalized into the cells by MMP2, which consequently induces membrane disruption and cell death. In contrast, the peptide shows negligible cytotoxicity toward A549 cancer cells with low MMP2 levels. Furthermore, the selective therapeutic efficacy of the peptide induced by MMP2 is also corroborated using in vivo study.
尽管不仅从天然存在的蛋白质而且从合成肽中发现并开发了多种细胞穿透基序，但与这些基序相连的货物递送至所需靶细胞的选择性通常较低。在此，我们展示了一种具有可被基质金属蛋白酶-2（MMP2）激活的细胞穿透基序的抗癌KLA肽的选择性细胞毒性调节。通过MMP2可切割的接头在KLA肽末端引入的阴离子掩蔽序列被MMP2选择性切割，阳离子细胞穿透基序被激活。将该肽处理H1299细胞（MMP2水平高）后，它被MMP2选择性内化到细胞中，从而导致膜破坏和细胞死亡。相比之下，该肽对MMP2水平低的A549癌细胞显示出可忽略不计的细胞毒性。此外，使用体内研究也证实了MMP2诱导的该肽的选择性治疗效果。
