State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, P. R. China.
Department of Ultrasound, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, P. R. China.
ACS Chem Biol. 2022 Aug 19;17(8):2355-2365. doi: 10.1021/acschembio.2c00475. Epub 2022 Jul 19.
Mitochondria as one of the key subcellular organelles have been well recognized as a promising druggable target and are closely associated with energy supply and various cellular functions. Realizing high accumulation and prolonged retention of radiosensitizers in the cellular mitochondria of tumors is an effective way to improve radiotherapeutic efficacy. Herein, we develop mitochondria-targeting and protein sulfenic acid (PSA)-reactive gold nanoparticles (dAuNP-TPP) that are fabricated by incorporating triphenylphosphine and 1,3-cyclohexanedione onto the surface of AuNPs (∼20 nm) to improve CT imaging and radiotherapeutic efficacy of tumors. Taking advantage of the specific mitochondrial targeting and PSA-mediated on-site covalent immobilization, this nanosystem shows significantly enhanced accumulation and retention in mitochondria with approximately 5.22-fold higher enrichment than nonimmobilizable AuNP-TPP. More notably, the covalent immobilization of dAuNP-TPP in cellular mitochondria could induce a dramatic reduction of ATP, leading to serious mitochondrial disruption, combined with the radiosensitization effect, in consequence achieving efficient radiotherapy of breast tumors in vivo. This subcellular organelle-targeted and immobilizable strategy may offer a valuable and universal tool for efficient tumor treatment.
线粒体作为细胞内的关键细胞器之一，已被广泛认为是一种有前途的可药物靶向目标，与能量供应和各种细胞功能密切相关。实现放射性增敏剂在肿瘤细胞线粒体中的高积累和长时间保留是提高放射治疗效果的有效方法。在此，我们开发了一种线粒体靶向和蛋白质亚磺酸（PSA）反应性金纳米颗粒（dAuNP-TPP），它是通过在 AuNPs（约 20nm）表面掺入三苯基膦和 1,3-环己二酮来制备的，以提高肿瘤的 CT 成像和放射治疗效果。利用特异性的线粒体靶向和 PSA 介导的现场共价固定化，该纳米系统在细胞线粒体中表现出显著增强的积累和保留，其富集度约为不可固定的 AuNP-TPP 的 5.22 倍。更值得注意的是，dAuNP-TPP 在细胞线粒体中的共价固定化可导致 ATP 的急剧减少，从而导致严重的线粒体破坏，再加上放射增敏作用，从而实现了体内乳腺癌的高效放射治疗。这种亚细胞细胞器靶向和固定化策略可能为高效肿瘤治疗提供了一种有价值的通用工具。
