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，ERβ的缺氧反应标记将有利于CRPC的早期诊断和治疗。在此，我们报告了第一个以 ERβ 为靶点的缺氧响应近红外荧光探针，该探针显示出优异的 ERβ 选择性和良好的光学特性。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在体内表现出很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) 计算在内的机理研究表明，硝基的引入通过诱导 PET 效应来淬灭探针荧光，而在缺氧肿瘤微环境中，硝基的还原阻断PET效应并打开探针荧光。这些新型 ERβ 靶向缺氧响应近红外荧光探针可能会促进前列腺癌的研究。