State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Engineering (IMRE), A*STAR (Agency for Science, Technology and Research), Institute of Materials Research and Engineering, 138634 Singapore.
ACS Nano. 2024 Oct 29;18(43):29667-29677. doi: 10.1021/acsnano.4c08567. Epub 2024 Oct 15.
Subcellular biomineralization systems with cellular intervention functions have shown great potential in cancer theranostic applications. However, the lack of subcellular specificity, high ion concentrations, and long incubation time required for biomineralization still limit its therapeutic efficacy. Herein, we report a mitochondria-targeted polymer-gold complex (TPPM-Au) to realize mitochondrial biometallization, which involves analogous mechanisms during biomineralization, for cancer treatment . The TPP-containing TPPM-Au delivered more Au selectively into the mitochondria of cancer cells than normal cells, rapidly mineralizing to gold nanoparticles (GNPs) and consuming a large amount of the antioxidant glutathione (GSH). The formed GNPs can further continue consuming GSH with the atomic economy by forming Au-S with GSH, which further results in the accumulation of reactive oxygen species (ROS), thereby impairing mitochondrial function and inducing cell apoptosis. More importantly, TPPM-Au is capable of having superior tumor-penetrating, excellent photothermal and photoacoustic properties, endowing it with the ability to inhibit tumor growth through spatiotemporally monitorable mitochondria-targeted biometallization and photothermal therapy. The mitochondria-targeted gold biometallization theranostic platform provides insight into the application of subcellularly targeted biometallization or biomineralization in cancer therapy.
具有细胞干预功能的亚细胞生物矿化系统在癌症治疗应用中显示出巨大的潜力。然而，生物矿化所需的亚细胞特异性、高离子浓度和长孵育时间仍然限制了其治疗效果。在此，我们报告了一种线粒体靶向聚合物-金复合物（TPPM-Au），以实现线粒体生物矿化，这涉及生物矿化过程中的类似机制，用于癌症治疗。含 TPP 的 TPPM-Au 比正常细胞更选择性地将更多的 Au 递送至癌细胞的线粒体中，迅速矿化为金纳米颗粒（GNPs）并消耗大量抗氧化剂谷胱甘肽（GSH）。形成的 GNPs 可以通过与 GSH 形成 Au-S 进一步以原子经济性继续消耗 GSH，这进一步导致活性氧（ROS）的积累，从而损害线粒体功能并诱导细胞凋亡。更重要的是，TPPM-Au 具有优异的肿瘤穿透性、优异的光热和光声特性，能够通过时空可监测的线粒体靶向生物矿化和光热疗法抑制肿瘤生长。该线粒体靶向金生物矿化治疗平台为亚细胞靶向生物矿化或生物矿化在癌症治疗中的应用提供了新的思路。
