Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan.
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe 657-8501, Japan.
Biomacromolecules. 2021 Jun 14;22(6):2524-2531. doi: 10.1021/acs.biomac.1c00267. Epub 2021 May 7.
Self-assembly of synthetic molecules has been drawing broad attention as a novel emerging approach in drug discovery. Here, we report selective cell death induced by a novel peptide amphiphile that self-assembles to form entangled nanofibers (hydrogel) based on intracellular pH (pH). We found that a palmitoylated hexapeptide (C-VVAEEE) formed a hydrogel below pH 7. The formation of the nanofibrous self-assembly was responsive to a small pH change around pH 7. The cytotoxicity of C-VVAEEE was correlated with pH of cells. Microscope observation demonstrated the self-assembly of C-VVAEEE inside HEK293 cells. experiments revealed that the transcutaneous administration of C-VVAEEE showed remarkable anti-tumor activity. This study proposes that distinct microenvironment inside living cells can be used as a trigger for the intracellular self-assembly of a peptide amphiphile, which provide a new clue to drug discovery.
自组装合成分子作为一种新兴的药物发现方法引起了广泛关注。在这里，我们报告了一种新型肽两亲物诱导的选择性细胞死亡，该肽两亲物自组装形成基于细胞内 pH 值 (pH) 的缠结纳米纤维 (水凝胶)。我们发现，一种棕榈酰化六肽 (C-VVAEEE) 在 pH 值低于 7 时形成水凝胶。纳米纤维自组装的形成对 pH 值左右的微小 pH 值变化有响应。C-VVAEEE 的细胞毒性与细胞的 pH 值相关。显微镜观察表明 C-VVAEEE 在 HEK293 细胞内的自组装。实验表明，C-VVAEEE 的经皮给药显示出显著的抗肿瘤活性。这项研究提出，活细胞内的不同微环境可以作为肽两亲物细胞内自组装的触发因素，为药物发现提供了新的线索。
