Unlocking lysosomal acidity to activate membranolytic module for accurately cancer theranostics

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-08-28 DOI:10.1016/j.bioorg.2024.107764

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Abstract

Chemotherapy drug efflux, toxic side effects, and low efficacy against drug-resistant cells have plagued safe and efficient cancer theranostics. However, the materials or methods that resolve these defects all-in-one are scarce. Here, a new cancer theranostics strategy is proposed by utilizing changes in lysosomal acidity in cancer cells to activate the membranolytic model to overcome these obstacles together. Therefore, a simple fluorescent anthracene derivative Lyso-Mito is developed, which has a perfect pK_a (4.62) value that falls between the pH of lysosomes in cancer and normal cells. Lyso-Mito itself can precisely target and convert the pH perturbation of lysosomes in cancer cells to fluorescent response and membranolytic module activity to accomplish the low drug efflux, weak toxic side effects, and low drug-resistant cancer diagnosis and treatment without linking other functional units or any additional assistance. Hereby, a new cancer theranostics strategy of integrating organelle microenvironment and the membranolytic model is realized.

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解锁溶酶体酸性，激活膜溶解模块，实现准确的癌症疗法

化疗药物外流、毒副作用以及对耐药细胞的低疗效一直困扰着安全高效的癌症治疗技术。然而，能一举解决这些缺陷的材料或方法却十分稀缺。本文提出了一种新的癌症治疗策略，即利用癌细胞溶酶体酸度的变化来激活膜溶解模型，从而一并克服这些障碍。因此，我们开发了一种简单的荧光蒽衍生物 Lyso-Mito，它具有完美的 pKa 值（4.62），介于癌细胞和正常细胞溶酶体的 pH 值之间。Lyso-Mito 本身可以精确靶向癌细胞溶酶体的 pH 值扰动，并将其转化为荧光反应和膜溶解模块活性，从而实现低药物外流、弱毒副作用和低耐药性的癌症诊断和治疗，而无需连接其他功能单元或任何额外辅助。由此，一种整合细胞器微环境和膜溶解模型的新型癌症治疗策略得以实现。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.