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.
Two iridium(iii) complexes with ligands containing morpholine groups were used to track mitochondrial pH fluctuation during cell apoptosis as their emissive intensities linearly increased with increase in pH values.
Photodynamic therapy (PDT) is a promising noninvasive cancer treatment. PDT in the clinic faces several hurdles due to the unique tumor environment, a feature of which is high levels of...
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