NIR-II-triggered photothermal therapy with Au@PDA/PEG-PI for targeted downregulation of PSMA in prostate cancer

Although positron emission tomography (PET) imaging products targeting prostate-specific membrane antigen (PSMA) have been approved for marketing, clinical challenges remain in the study of its use as a therapeutic target, such as the complex synthesis process and side effects after treatment. Here, we developed a strategy for targeted photothermal therapy (PTT) using PSMA as the target. The results of molecular docking demonstrated that the synthesized PEG modified urea-based PSMA inhibitor (small molecular PSMA inhibitor, PI) PI-PEG has a high affinity energy (binding energy = - 8.3 kcal mol^-1) for the PSMA target. Therefore, modification of PI-PEG onto the surface of gold@polydopamine (Au@PDA) with NIR-II absorption could enable targeted PTT against PSMA. This work revealed that the prepared Au@PDA/PEG-PI were not only highly selective for PSMA, but also could efficiently ablate PSMA expression by targeted PTT at the maximum permissible exposure (MPE) of the NIR-II laser. Moreover, Au@PDA/PEG-PI also have potential for photoacoustic (PA) imaging and computed tomography (CT) imaging. As the first strategy to downregulate the expression of PSMA and successfully inhibit prostate cancer by targeted PTT, this study case provides a new idea for the clinical translation of PSMA as an integrated target for tumor diagnosis and anti-tumor treatment. STATEMENT OF SIGNIFICANCE: (1) Au@PDA/PEG-PI NPs were the novel PTT agent to target PSMA and successfully down-regulate PSMA expression. (2) Molecular docking results demonstrated that PI-PEG inhibitors have a high affinity energy for PSMA (binding energy = - 8.3 kcal mol^-1). (3) Au@PDA/PEG-PI NPs can be targeted for efficient PTT at the MPE of the NIR-II laser. (4) Au@PDA/PEG-PI NPs also have the potential for PA and CT imaging.