Sequentially\nDual-Targeted Molecular Theranostic Probe\nfor Radionuclide and Anti-Hypoxic Activatable Photodynamic Therapy\nof Cancer

Type I photodynamic therapy (PDT),\nwhich utilizes type\nI photoreactions\nand is less O<sub>2</sub>-dependent, is expected to exert ideal synergistic\ntherapy performance when combined with targeted radionuclide therapy\n(TRT). However, this combination has been less explored. To achieve\nit, this study presents a sequentially dual-targeted molecular theranostic\nprobe for combining TRT and antihypoxic activatable PDT against prostate\ncancer. The probe achieves prostate-specific membrane antigen (PSMA)-mediated\nlock-and-key targeting ability and monoamine oxidase A (MAO-A) hydrolysis\nwith activated fluoro-photoacoustic signals and O<sub>2</sub><sup>•–</sup> generation. The PSMA motif not only enhances\nthe targeting specificity but also increases the intracellular accumulation\ncapacity of probe and promotes more MAO-A activation. In this regard,\nan enhanced inhibition of tumor growth is obtained for combined activatable\nantihypoxic PDT and TRT in comparison to any single regimen, including\nthe commercial <sup>177</sup>Lu-PSMA-617, thereby demonstrating the\neffective antitumor effect. This study provides a potential solution\nfor a combination of TRT and PDT for effective tumor therapy.