Abstract: The blood-brain barrier represents a significant challenge in delivering anticancer drugs for glioblastoma treatment. The study investigates the potential of a series of octahedral photoactivatable cyclometalated iridium complexes ( Ir1 – Ir10 ) with the general formula [Ir(ttpy)(C ∧ N)Cl]PF 6 as photoactivated therapy candidates for the treatment of this aggressive tumor. These complexes, which include the terdentate ligand 4′-(p-tolyl)-2,2′:6′,2″-terpyridine (ttpy), and a C ∧ N ligand based on the deprotonated 2-arylbenzimidazole backbone, were tested on human glioblastoma using 2D cell cultures and 3D spheroidal models, including a fusion system comprising cerebral organoids from nonmalignant human-induced pluripotent stem cells and spheroids derived from malignant brain cells. The iridium complexes catalyze NADH photooxidation and photogenerate 1 O 2 and/or • OH under blue light irradiation. Blood-brain barrier penetration was assessed using various in vitro models. The complex Ir4 , containing deprotonated methyl 1-butyl-2-phenylbenzimidazolecarboxylate, shows promise for targeted therapy of resistant brain tumors when photoactivated with blue light. Ir4 induces rapid and sustained ROS-mediated cytotoxicity and selectively accumulates in tumor tissue. This suggests its potential for fluorescently guided-PDT cooperative resection of glioblastoma. Notably, Ir4 significantly reduces glioblastoma growth even under dark conditions compared to conventional Temozolomide treatment without affecting healthy brain tissue.
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