Heavy-atom engineered hypoxia-responsive probes for precisive photoacoustic imaging and cancer therapy

Photoacoustic agents combing photodynamic therapy (PDT) and photothermal therapy (PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared (NIR)-absorption and maximizing non-radiative energy transfer are essential for effective photoacoustic imaging (PAI) and therapy applications. In addition, such molecules with high specificity and affinity to cancer cells are urgently needed, which would further decrease the side effect during treatments. In this study, we applied a heavy-atom engineering strategy and introduced p-aminophenol, -thio, and -seleno moieties into NIR heptamethine cyanine (Cy7) skeleton (Cy7-X-NH2, X = O, S, Se) to significantly increase photothermal conversion efficiency for PTT and promote intersystem crossing for PDT. Additionally, we designed a series of nitroreductase (NTR)-activated photoacoustic probes (Cy7-X-NO2, X = O, S, Se), and target hypoxic tumors with NTR overexpression. Our prostate cancer targeting probe, Cy7-Se-NO2-KUE, exhibited specific tumor photoacoustic signals and effective tumor killing through outstanding synergistic PTT/PDT in vivo. These findings highlighted a versatile strategy for cancer photoacoustic diagnosis and enhanced phototherapy.