Phosphorescent Iridium Hydrazinonicotinic Acid (HYNIC) Complexes That Bind to Prostate Specific Membrane Antigen: Potential Photodynamic Therapy of Prostate Cancer.

Phosphorescent metal complexes have the potential to be used for photodynamic detection of tumor margins in surgery and photodynamic therapy (PDT). In this work, iridium(III) complexes are prepared with two cyclometalating ligands, either phenylpyridine (ppy) or phenylisoquinoline (piq), and one 6-hydrazinonicotinic acid (HYNIC) ancillary ligand to give [Ir(ppy)2(HYNIC)]+ and [Ir(piq)2(HYNIC)]+. The extended conjugation in [Ir(piq)2(HYNIC)]+ results in a significant redshift in the absorption and emission properties. Both [Ir(ppy)2(HYNIC)]+ and [Ir(piq)2(HYNIC)]+ generate singlet oxygen upon irradiation with light in the presence of oxygen. Irradiation of [Ir(piq)2(HYNIC)]+ (λexc = 420 nm) results in the production of hydroxyl and superoxide radicals. The carboxylic acid functional group in HYNIC has been used to attach a lysine-ureido-glutamatic acid pharmacophore that selectively binds to prostate specific membrane antigen (PSMA) to give HYNIC-PSMA. PSMA is an enzyme that is overexpressed in prostate cancer. HYNIC-PSMA was used to prepare [Ir(ppy)2(HYNIC-PSMA)]+ and [Ir(piq)2(HYNIC-PSMA)]+. Both complexes bind to cells that overexpress the PSMA enzyme. [Ir(piq)2(HYNIC-PSMA)]+ is nontoxic to cells in the dark, but irradiation with visible light results in a dose-dependent cytotoxicity. These complexes have the potential to be of use to identify tumor margins, to guide robot-assisted surgical resection of tumors, as well as for molecularly targeted PDT.