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]-PF6 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 1O2 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.

Czech Academy of Sciences Institute of Biophysics Kralovopolska 135 CZ 61200 Brno Czech Republic

Departamento de Química Inorgánica Universidad de Murcia and Institute for Bio Health Research of Murcia Murcia E 30100 Spain

Department of Biophysics Faculty of Science Palacky University Slechtitelu 27 779 00 Olomouc Czech Republic

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