Li Jing, Song Jiaqi, Shao Liang, Zhang Xianpeng, Wang Ziyi, Li Guanying, Wang Jiansheng, Zhang Jia
The Second Clinical Medical School, Shaanxi University of Chinese Medicine Xianyang Shaanxi China
The Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University Xi'an Shaanxi China
RSC Adv. 2024 May 15;14(23):15840-15847. doi: 10.1039/d4ra01328j.
Induced lysosomal membrane permeabilization (LMP) by peptide self-assembly has emerged as an effective platform for lysosome-targeted cancer therapy. In this study, we shift this strategical paradigm and present an innovative approach to LMP induction through amino acid-based self-assembly. Pyrene-capped tyrosine (Py-Tyr), as a proof-of-concept molecule, is designed with acidity-responsive self-assembly. Under acidic conditions (pH 4), Py-Tyr is protonated with reduced charge repulsion, and self-assembles into micrometer-scaled aggregates, which exceed the biological size of lysosomes. Cell experiments showed that Py-Tyr specifically accumulates in lysosomes and induces lysosome rupture, leading to the release of cathepsin B into the cytoplasm for subsequent apoptosis activation in cancer cells. This study capitalizes on the concept of amino acid assembly for efficient LMP induction, providing a simple and versatile platform for precise and effective therapeutic interventions in cancer therapy.
通过肽自组装诱导溶酶体膜通透性（LMP）已成为溶酶体靶向癌症治疗的有效平台。在本研究中，我们转变了这一战略范式，提出了一种通过基于氨基酸的自组装诱导LMP的创新方法。芘封端的酪氨酸（Py-Tyr）作为概念验证分子，设计为具有酸度响应性自组装。在酸性条件下（pH 4），Py-Tyr质子化，电荷排斥减少，并自组装成微米级聚集体，其尺寸超过溶酶体的生物学大小。细胞实验表明，Py-Tyr特异性积聚在溶酶体中并诱导溶酶体破裂，导致组织蛋白酶B释放到细胞质中，从而在癌细胞中激活后续的细胞凋亡。本研究利用氨基酸组装的概念进行高效的LMP诱导，为癌症治疗中的精确有效治疗干预提供了一个简单且通用的平台。
