Photodecaging of a Mitochondria-Localized Iridium(III) Endoperoxide Complex for Two-Photon Photoactivated Therapy under Hypoxia
Résumé
Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors which are hampering the production of the therapeutically necessary singlet oxygen (1 O2). To overcome this limitation, we report on a novel mitochondria-localized iridium(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in the NIR, synergistically releases a highly cytotoxic iridium(III) complex (2-IrAn), singlet oxygen and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)toxic in hypoxic tumor cells and multicellular tumor spheroids in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated with a biotin functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors.
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