Sequentially Dual-Targeted Molecular Theranostic Probe for Radionuclide and Anti-Hypoxic Activatable Photodynamic Therapy of Cancer

Abstract

Type I photodynamic therapy (PDT), which utilizes type I photoreactions and is less O₂-dependent, is expected to exert ideal synergistic therapy performance when combined with targeted radionuclide therapy (TRT). However, this combination has been less explored. To achieve it, this study presents a sequentially dual-targeted molecular theranostic probe for combining TRT and antihypoxic activatable PDT against prostate cancer. The probe achieves prostate-specific membrane antigen (PSMA)-mediated lock-and-key targeting ability and monoamine oxidase A (MAO-A) hydrolysis with activated fluoro-photoacoustic signals and O₂^•– generation. The PSMA motif not only enhances the targeting specificity but also increases the intracellular accumulation capacity of probe and promotes more MAO-A activation. In this regard, an enhanced inhibition of tumor growth is obtained for combined activatable antihypoxic PDT and TRT in comparison to any single regimen, including the commercial ¹⁷⁷Lu-PSMA-617, thereby demonstrating the effective antitumor effect. This study provides a potential solution for a combination of TRT and PDT for effective tumor therapy.