Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging

• Published in: Chemical science (Cambridge) 2019-09, Vol.1 (34), p.7946-7951
• Main Authors: Chen, Hao, Wang, Jing, Feng, Xin, Zhu, Mark, Hoffmann, Simon, Hsu, Alex, Qian, Kun, Huang, Daijuan, Zhao, Feng, Liu, Wei, Zhang, Huimao, Cheng, Zhen
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Anticancer properties; Apoptosis; Biocompatibility; Cancer; Chemistry; Derivatives; Fluorescence; Imaging; In vivo methods and tests; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Mitochondria; Necrosis; Selectivity; Toxicity; Tumors
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c9sc01410a

Fluorescent mitochondria-accumulating delocalized lipophilic cations (DLCs) for cancer therapy have drawn significant attention in the field of cancer theranostics. One of the most promising fluorescent DLCs, F16, can selectively trigger the apoptosis and necrosis of cancer cells, making it an attractive targeted theranostic drug candidate. However, it suffers from low clinical translation potential, largely due to its inefficient anti-cancer activity (IC 50 in the μM range) and poorly understood structure-activity relationship (SAR). In this report, eleven indole-ring substituted F16 derivatives (F16s) were synthesized. Among these derivatives, 5BMF was identified as a highly effective theranostic agent, with in vitro studies showing a low IC 50 of ∼50 nM (to H2228 cells) and high cancer to normal cell selectivity index of 225. In vivo studies revealed that tumors treated with 5BMF were significantly suppressed (almost no growth over the treatment period) compared to the PBS treated control group, and also no obvious toxicity to mice was found. In addition, the tumor imaging capability of 5BMF was demonstrated by in vivo fluorescence imaging. Finally, we report for the first time a proposed SAR for F16 DLCs. Our work lays down a solid foundation for translating 5BMF into a novel and highly promising DLC for cancer theranostics. 5BMF is a new fluorescent mitochondria-accumulating delocalized lipophilic cations [DLC] that boasts significantly increased anti-cancer effects and low toxicity in comparison to previous DLCs, addressing current hurdles in DLC clinical translation.