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.

• Klíčová slova
• 3D spheroids, ROS-mediated cytotoxicity, blood-brain barrier penetration, human brain glioblastoma, iridium complexes, photodynamic therapy,
• Publikační typ
• časopisecké články MeSH

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate 1O2 and/or •OH in cell-free media.

• MeSH
• benzothiazoly MeSH
• fotosenzibilizující látky farmakologie   terapeutické užití   MeSH
• fototoxická dermatitida * farmakoterapie   MeSH
• iridium farmakologie   MeSH
• komplexní sloučeniny * farmakologie   MeSH
• lidé MeSH
• lyzozomy MeSH
• nádorové buněčné linie MeSH
• nádory * farmakoterapie   MeSH
• protinádorové látky * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzothiazoly MeSH
• fotosenzibilizující látky MeSH
• iridium MeSH
• komplexní sloučeniny * MeSH
• protinádorové látky * MeSH