Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging
Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging
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用于高效癌症生长抑制和成像的线粒体靶向荧光分子
DOI：
10.1039/c9sc01410a
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发表时间：
2019-09-14
期刊：
影响因子：
8.4
通讯作者：
Cheng, Zhen
中科院分区：
文献类型：
--
作者：
Chen, Hao;Wang, Jing;Cheng, Zhen
用于癌症治疗的荧光聚集性离域亲脂性阳离子（DLC）在癌症治疗诊断学领域引起了极大的关注。F16是最有前途的荧光DLC之一，可以选择性地触发癌细胞的凋亡和坏死，使其成为有吸引力的靶向治疗诊断药物候选者。然而，它的临床翻译潜力低，主要是由于其抗癌活性低（IC 50在μ M范围内）和结构-活性关系（SAR）知之甚少。本文合成了11个吲哚环取代的F16衍生物（F16）。在这些衍生物中，5 BMF被鉴定为高效的治疗诊断剂，体外研究显示出类似于50 nM的低IC 50（对H2228细胞）和225的高癌症对正常细胞的选择性指数。体内研究表明，与PBS处理的对照组相比，用5 BMF处理的肿瘤被显著抑制（在处理期间几乎没有生长），并且也没有发现对小鼠的明显毒性。此外，通过体内荧光成像证实了5 BMF的肿瘤成像能力。最后，我们首次报告了F16 DLC的建议SAR。我们的工作为将5 BMF翻译成一种新颖且极具前景的癌症治疗诊断学DLC奠定了坚实的基础。
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 (IC50 in the mu M 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 IC50 of similar to 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.