Estrogen receptor β-targeted hypoxia-responsive near-infrared fluorescence probes for prostate cancer study.

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.