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, hampering the production of therapeutically necessary singlet oxygen (1O2). To overcome this limitation, we report on a novel mitochondria-localized iridium­(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in 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 (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into 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.

The clinical application of photodynamic therapy is hindered by the high glutathione concentration, poor cancer-targeting properties, poor drug loading into delivery systems, and an inefficient activation of the cell death machinery in cancer cells. To overcome these limitations, herein, the formulation of a promising Ir III complex into a biodegradable coordination polymer (IrS NPs) is presented. The nanoparticles were found to remain stable under physiological conditions but deplete glutathione and disintegrate into the monomeric metal complexes in the tumor microenvironment, causing an enhanced therapeutic effect. The nanoparticles were found to selectively accumulate in the mitochondria where these trigger cell death by hybrid apoptosis and ferroptosis pathways through the photoinduced production of singlet oxygen and superoxide anion radicals. This study presents the first example of a coordination polymer that can efficiently cause cancer cell death by apoptosis and ferroptosis upon irradiation, providing an innovative approach for cancer therapy.

Design and development of photosensitizers that can efficiently convert energy of near-infrared (NIR) laser irradiation are of major importance for cancer photoassisted therapeutics. Herein, for the first time, it is demonstrated that Prussian blue (PB), a classic coordination compound, can act as a novel photosensitizer with efficient generation of singlet oxygen and excellent photothermal conversion via NIR photoirradiation-induced energy transfer. After modification with hyaluronic acid (HA), the as-prepared HA-modified PB nanocubes (HA@PB) are highly dispersible in aqueous and physiological solutions, as well as show excellent photothermal/photodynamic activities under NIR (808 nm) photoexcitation. On the basis of these features, HA@PB is used to study their in vitro and in vivo combined therapeutic effect. Owing to the CD44 ligand of HA, HA@PB have specific uptake by CD44-positive cells in vitro and can be precisely in vivo delivered to the tumor site. HA@PB as one of the synergistically photodynamic/photothermal combination nanoplatforms could achieve excellent therapeutic efficacy with targeted specificity under the guidance of dual-modality photoacoustic/infrared thermal imaging. Hence, this work is expected to pave the way for using PB-based nanomaterials as a promising multifunctional theranostic nanoplatform in biomedical fields.

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