Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Interdisciplinary Research Academy (IRA), Zhejiang Shuren University, Hangzhou, 310015, China.
Eur J Med Chem. 2022 Aug 5;238:114506. doi: 10.1016/j.ejmech.2022.114506. Epub 2022 Jun 2.
Aberrant expression of estrogen receptor β (ERβ) and tumor hypoxia have been observed in castration-resistant prostate cancer (CRPC); therefore, hypoxia-responsive labeling of ERβ will be beneficial for the early diagnosis and treatment of CRPC. Herein, we report the first ERβ-targeted hypoxia-responsive near-infrared fluorescent probes, which showed superior ERβ selectivity and favorable optical properties. These two probes exhibited excellent hypoxia responsiveness and specific mitochondrial ERβ imaging ability in CRPC cells. In addition, P1 displayed strong anti-interference ability and good tumor imaging capacity in vivo, contributing to effective diagnosis of CRPC. Mechanistic studies, including high resolution mass spectrometry (HRMS) and density functional theory (DFT) calculations, showed that the introduction of a nitro group quenched the probe fluorescence by inducing a PET effect, while in the hypoxic tumor microenvironment, reduction of the nitro group blocked the PET effect and turned on the probe fluorescence. These novel ERβ-targeted hypoxia-responsive near-infrared fluorescent probes may promote the study of prostate cancer.
在去势抵抗性前列腺癌（CRPC）中观察到雌激素受体β（ERβ）的异常表达和肿瘤缺氧；因此，对 ERβ 的缺氧反应性标记将有利于 CRPC 的早期诊断和治疗。在此，我们报告了首例 ERβ 靶向的缺氧反应性近红外荧光探针，其表现出优异的 ERβ 选择性和良好的光学性质。这两种探针在 CRPC 细胞中表现出优异的缺氧反应性和特异性线粒体 ERβ 成像能力。此外，P1 在体内表现出较强的抗干扰能力和良好的肿瘤成像能力，有助于 CRPC 的有效诊断。包括高分辨率质谱（HRMS）和密度泛函理论（DFT）计算在内的机制研究表明，硝基的引入通过诱导 PET 效应使探针荧光猝灭，而在缺氧的肿瘤微环境中，硝基的还原阻断了 PET 效应并开启了探针的荧光。这些新型的 ERβ 靶向的缺氧反应性近红外荧光探针可能会促进前列腺癌的研究。
