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Published on: April 16, 2019
Photoactivatable Cyclometalated Ir(III) Compound Penetrates the Blood-Brain Barrier in 3D Spheroidal and Advanced 3D
Vojtech Novohradsky1, Alicia Marco2, Marie Svitelova1
1Czech Academy of Sciences, Institute of Biophysics, Kralovopolska 135, CZ-61200 Brno, Czech Republic.
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]-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.
Insights
Researchers developed novel iridium complexes for glioblastoma treatment. Complex Ir4 effectively targets brain tumors, reducing growth via photoactivated therapy and showing promise for improved patient outcomes.
Area of Science:
- Medicinal Chemistry
- Nanotechnology
- Oncology
Background:
- The blood-brain barrier (BBB) poses a major obstacle for effective glioblastoma (GBM) treatment.
- Developing targeted therapies that can penetrate the BBB is crucial for improving outcomes in aggressive brain tumors.
Purpose of the Study:
- To investigate novel octahedral photoactivatable cyclometalated iridium complexes as potential therapeutic agents for glioblastoma.
- To evaluate the efficacy of these complexes in crossing the BBB and their mechanism of action in cancer cells.
Main Methods:
- Synthesis and characterization of ten iridium complexes (Ir1-Ir10) featuring ttpy and C^N ligands.
- Assessment of complexes' ability to penetrate the BBB using in vitro models.
- Evaluation of cytotoxicity and reactive oxygen species (ROS) generation in 2D and 3D glioblastoma models, including organoid-spheroid co-cultures.
- Comparison with Temozolomide (TMZ) treatment.
Main Results:
- Complex Ir4 demonstrated significant BBB penetration and selective accumulation in tumor tissue.
- Photoactivation of Ir4 under blue light induced ROS (¹O₂ and/or •OH) generation, leading to rapid and sustained cytotoxicity.
- Ir4 significantly inhibited glioblastoma growth in vitro, outperforming Temozolomide and showing no toxicity to healthy brain tissue.
- Ir4 exhibited potential for fluorescently guided photodynamic therapy (PDT) and cooperative resection.
Conclusions:
- The iridium complex Ir4 shows significant promise as a photoactivatable therapeutic agent for glioblastoma, effectively overcoming BBB challenges.
- Ir4's ability to generate ROS and its selective tumor targeting offer a potential new strategy for treating resistant brain tumors.
- The findings suggest Ir4's utility in combination with surgical resection for improved glioblastoma management.
