Photoactivatable Cyclometalated Ir(III) Compound Penetrates the Blood-Brain Barrier in 3D Spheroidal and Advanced 3D Organoid Models of Inherently Resistant and Aggressive Brain Tumors

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.