Study of Cytotoxic and Photodynamic Activities of Dyads Composed of a Zinc Phthalocyanine Appended to an Organotin.

Isabelle Toubia,Magali Gary-Bobo,Marine Pays,Céline Frochot,Marwan Kobeissi,Stéphane Diring,Elodie Mattana,Fabrice Odobel,Philippe Arnoux,Christophe Nguyen

doi:10.3390/ph14050413

Abstract

The combination of photodynamic therapy and chemotherapy is a promising strategy to enhance cancer therapeutic efficacy and reduce drug resistance. In this study two zinc(II) phthalocyanine-tin(IV) conjugates linked by a triethylene glycol chain were synthesized and characterized. In these complexes, the zinc(II) phthalocyanine was used as a potential photosensitizer for PDT and the tin complex was selected as cytostatic moiety. The two dyads composed of zinc(II) phthalocyanine and tin complexes exhibited high cytotoxicity, in absence of light stimulation, against MCF-7 human breast cancer cells with low LC50 values in the range of 0.016–0.453 µM. In addition, these complexes showed superior cytotoxicity than their mixture of equimolar component, accompanied with a higher activity towards cancer cells compared to human healthy fibroblasts. However, under irradiation of the zinc phthalocyanine unit (at 650 nm) no photodynamic activity could be detected, due to the most likely quenching of zinc(II) phthalocyanine singlet excited state by the nearby tin complex according to a photoinduced electron transfer process. This study demonstrates the potential of heterometallic anticancer chemotherapeutics composed of a zinc phthalocyanine and tin complex, and it highlights that the development of such conjugates requires that the sensitizer preserves its photophysical properties and in particular its singlet oxygen sensitization ability in the conjugate in order to combine the PDT activity with the cytotoxicity of the anticancer drug.

Highlights

There has been considerable interest in combining photodynamic therapy (PDT) with a chemotherapeutic anticancer agent [1,2,3,4,5,6]
We have investigated the combination of tin complexes with a zinc phthalocyanine photosensitizer in order to take advantage of the intrinsic cytotoxicity of tin complex in the dark added to the potentially high phototoxicity of zinc phthalocyanine upon light excitation
Cytotoxicity studies of the ZnPc-SnPh2 and ZnPc-Sn2 Ph6 dyads on cancer cells (MCF-7) and on healthy fibroblasts show that they exhibit high cytotoxicity

Summary

Introduction

There has been considerable interest in combining photodynamic therapy (PDT) with a chemotherapeutic anticancer agent [1,2,3,4,5,6]. The combination of different therapeutic approaches that acts on distinct disease pathways has shown several advantages, such as enhanced therapeutic efficacy, reduced side effects, and drug resistance problems. There are generally three approaches to combine PDT and chemotherapy, including consecutive administration of a photosensitizer and an anticancer drug, the use of their covalent and noncovalent conjugates, and co-encapsulation of these agents in a polymeric nanocarrier [7,8]. Pharmaceuticals 2021, 14, 413 obtained showing an enhanced anticancer efficacy at lower drug doses [18] due to the dark chemostatic effect of the drug amplified by the PDT effect generated upon light excitation of the photosensitizer. The cytotoxic activity of these compounds results from the inhibition of macromolecular synthesis, the alteration of energy-producing metabolism in the mitochondria, and the reduction of DNA synthesis. Phthalocyanines are promising second-generation photosensitizers for PDT, owing to their suitable photo-physical and photo-chemical properties, such as the strong absorption in the tissue-penetrating red visible region and high efficiency in generating singlet oxygen [19,20,21,22,23]

Methods

Results

Conclusion