Oxygen-independent polycarbonate iridium(III) photosensitizer for photoactivated chemotherapy via photoredox catalysis boosted by NADH

Iridium (Ir(III)) complex are appealing candidates for photocatalytic chemistry and photodynamic therapy for their superior photoredox properties. However, their clinical applications are hampered by the high dark toxicity, poor water solubility and faint absorption in near-infrared (NIR) region. To overcome these limitations, herein, a biodegradable aliphatic polycarbonate-Ir(III) complex (PC-Ir) was synthesized by binding bis(cyclometalated) (pna)₄Ir₂²⁺ fragments (pna, 6-phenylnicotinaldehyde) to terpyridine ligands in the pendant of polycarbonate. The obtained PC-Ir exhibits two-photon absorption capability and presents strong ROS generation capacity via type I and type II mechanism with coenzyme nicotinamide adenine dinucleotide (NADH) as electron donors upon irradiation with 660 nm laser. Furthermore, PC-Ir could directly activate phenylboronic acid caged Doxorubicin prodrug (Dox-PBA) under normoxia and hypoxia conditions to release potent Dox. In vitro and in vivo data confirmed the highly efficient photodynamic therapy of PC-Ir NPs and synergetic photoactivated chemotherapy against 4T1 breast cancer. Overall, this work presents a promising strategy to construct Ir(III)-based polymeric photosensitizer with two-photon excitation and less oxygen dependent mechanism, which can also serve as a carrier for combination anticancer therapy.