A Cyclometalated Ir^III Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

Abstract

A cyclometalated IrIII complex conjugated to a far‐red‐emitting coumarin, IrIII‐COUPY (3), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis. Herein, we show, using DU145 tumor cells, taken as the model of hormone‐refractory and aggressive prostate cancer cells resistant to conventional antineoplastic drugs, that the photoactivated conjugate 3 very efficiently eliminates both prostate bulk (differentiated) and prostate hardly treatable CSCs simultaneously and with a similar efficiency. Notably, the very low toxicity of IrIII‐COUPY conjugate in the prostate DU145 cells in the dark and its pronounced selectivity for tumor cells compared with noncancerous cells could result in low side effects and reduced damage of healthy cells during the photoactivated therapy by this agent. Moreover, the experiments performed with the 3D spheroids formed from DU145 CSCs showed that conjugate 3 can penetrate the inner layers of tumor spheres, which might markedly increase its therapeutic effect. Also interestingly, this conjugate induces apoptotic cell death in prostate cancer DU145 cells associated with calcium signaling flux in these cells and autophagy. To the best of our knowledge, this is the first study demonstrating that a photoactivatable metal‐based compound is an efficient agent capable of killing even hardly treatable CSCs.

Polyurethane–polyurea hybrid nanocapsules as efficient delivery systems of anticancer Ir(iii) metallodrugs

“…The C^N ligands in both complexes have in common the benzimidazole core which has been shown to be a widely used pharmacophore 26 and has exhibited good biological performance in previous studies of some of the authors. 27 The Ir( iii )-loaded nanocapsules were efficiently internalized in living HeLa cells compared to free complexes, and their photophysical properties resembled those of the compounds dissolved in an organic solvent owing to the hydrophobic and protective environment provided by the nanocapsules around the compounds. Besides studying the antiproliferative activity of the Ir( iii )-loaded NCs in 2D monolayer cancer cells and in 3D tumorsphere cancer models, the mode of cell death was investigated in detail.…”

Fluorescently Labeled Ceramides and 1-Deoxyceramides: Synthesis, Characterization, and Cellular Distribution Studies

“…The attachment of the fluorophore moiety did not alter the biological properties of Octreotide and, thus, the resulting conjugates could be used for visualizing living HeLa cells overexpressing the SSTR2 receptor. In addition, some COUPY dyes can be used as efficient photosensitizers for photodynamic therapy, either alone or when conjugated with cyclometalated Ir­(III) complexes. − …”

COUPY Coumarins as Novel Mitochondria-Targeted Photodynamic Therapy Anticancer Agents

“…In addition, conjugation of COUPY dyes to cyclometalated Ir(III) complexes allowed us to develop a new class of PSs for PDT whose mechanism of action is based on the generation of superoxide anion radicals. 27 , 28 Remarkably, the COUPY derivative alone was also found to be highly phototoxic under visible-light irradiation. In such a context, COUPY coumarins hold great potential for the development of novel theranostic agents because they combine imaging and therapy in a single compound.…”

“…Mitochondria selectivity can be attributed to the lipophilic positively charged N-alkyl pyridinium/pyrimidinium moieties in the coumarin scaffold, which exploit the negative potential across the outer and inner mitochondrial membrane. In addition, conjugation of COUPY dyes to cyclometalated Ir­(III) complexes allowed us to develop a new class of PSs for PDT whose mechanism of action is based on the generation of superoxide anion radicals. , Remarkably, the COUPY derivative alone was also found to be highly phototoxic under visible-light irradiation. In such a context, COUPY coumarins hold great potential for the development of novel theranostic agents because they combine imaging and therapy in a single compound.…”