Issue 1, 2022

Photodynamic therapy with mitochondria-targeted biscyclometallated Ir(iii) complexes. Multi-action mechanism and strong influence of the cyclometallating ligand

Abstract

Photodynamic therapy is an alternative to classical chemotherapy due to its potential to reduce side effects by a controlled activation of a photosensitizer through local irradiation with light. The photosensitizer then interacts with oxygen and generates reactive oxygen species. Iridium biscyclometallated complexes are very promising photosensitizers due to their exceptional photophysical properties and their ability to target mitochondria. Four Ir(III) biscyclometallated complexes of formula [Ir(C^N)2(N^N′)]Cl, where N^N′ is a ligand containing a benzimidazolyl fragment, have been synthesized and characterized. The C^N ligands were 2-phenylpyridinate (ppy) and 2-(2,4-difluorophenyl)pyridinate (dfppy). The complexes exhibited high photostability. The electrochemical and photophysical properties were modulated by both the cyclometallating and the ancillary ligands. The dfppy derivatives yielded the highest emission energy values, quantum yields of phosphorescence and excited state lifetimes. All complexes generated 1O2 in aerated solutions upon irradiation. Biological studies revealed that these complexes have a moderate cytotoxicity in the dark against different human cancer cell lines: prostate (PC-3), colon (CACO-2) and melanoma (SK-MEL-28), and against non-malignant fibroblasts (CCD-18Co). However, derivatives with ppy ligands ([1a]Cl, [2a]Cl) yielded a relevant photodynamic activity upon light irradiation (450 nm, 24.1 J cm−2), with phototoxicity indexes (EC50,dark/EC50,light) of 20.8 and 17.3, respectively, achieved in PC-3 cells. Mechanistic studies showed that these complexes are taken up by the cells through endocytosis and preferentially accumulate in mitochondria. Upon photoactivation, the complexes induced mitochondrial membrane depolarization and DNA damage, thus triggering cell death, mainly by apoptosis. Complex [1a]Cl is also able to oxidize NADH. This mitochondria-targeted photodynamic mechanism greatly inhibited the reproductive capacity of cancer cells and provides a valuable alternative to traditional chemotherapy for the controlled treatment of cancer.

Graphical abstract: Photodynamic therapy with mitochondria-targeted biscyclometallated Ir(iii) complexes. Multi-action mechanism and strong influence of the cyclometallating ligand

Supplementary files

Article information

Article type
Paper
Submitted
10 ספט 2021
Accepted
11 אוק 2021
First published
14 אוק 2021

Dalton Trans., 2022,51, 111-128

Photodynamic therapy with mitochondria-targeted biscyclometallated Ir(III) complexes. Multi-action mechanism and strong influence of the cyclometallating ligand

E. Zafon, I. Echevarría, S. Barrabés, B. R. Manzano, F. A. Jalón, A. M. Rodríguez, A. Massaguer and G. Espino, Dalton Trans., 2022, 51, 111 DOI: 10.1039/D1DT03080A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements