Enhancing Photodynamic Therapy Efficacy of Upconversion-Based Nanoparticles Conjugated with a Long-Lived Triplet Excited State Iridium(III)-Naphthalimide Complex: Toward Highly Enhanced Hypoxia-Inducible Factor-1.

Metal-based photosensitizers are of great interest in photodynamic therapy (PDT) due to their tunable photophysicochemical characteristics and structure flexibility. Herein, an iridium-based photosensitizer ( 1 ) with a long-lived intraligand ( 3 IL) excited state has been designed and synthesized, which shows significantly enhanced singlet oxygen ( 1 O 2 ) generation efficiency (∼45 folds) relative to that of the model iridium(III) complex ( 2 ) under 460 nm irradiation. In order to achieve deep tissue penetration, complex 1 was further covalently bonded to the upconversion nanoparticles (UCNPs). Besides, 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (YC-1), an effective HIF-1α inhibitor, was physically adsorbed into the hydrophobic layer at the surface of UCNPs. Once upon near-infrared (NIR) irradiation, iridium complex 1 -mediated toxic 1 O 2 was generated for PDT, whose efficient conversion of oxygen to 1 O 2 during the PDT would exacerbate the hypoxic condition of tumor tissue and lead to the upregulation of HIF-1α for the following HIF-1 targeting tumor therapy. This study highlights the potential for applying a nanoplatform composed of a long-lived iridium-based photosensitizer and an HIF-1α inhibitor in tumor therapy, which converts PDT-induced tumor hypoxia to a therapy advantage, thus opening up ideas to overcome the hypoxia in PDT therapy.