Synthesis of a novel zinc phthalocyanine with peripherally coordinated Ru(II) complexes; sono-photochemical, photochemical and photophysical studies

Highlights

• Synthesis and characterization of a novel multicomponent system, ZnPc-[Ru(bpy)₂(phen)]₄, as a sono-photosensitizer.

• Determination of aggregation and photophysico-chemical properties of soluble symmetrical zinc phthalocyanine with peripherally coordinated Ru(II) complexes.

• Comparison of singlet oxygen efficiency obtained by sono-photochemical method (Φ_Δ= 0.72 in DMSO, 0.66 in DMF) and photochemical method (Φ_Δ = 0.45 in DMSO, 0.43 in DMF).

• The highest singlet oxygen quantum yield (0.72) was obtained for complex 8 in DMSO with SPDT method.

Abstract

Sono-photodynamic therapy (SPDT), which is used in the treatment of cancer cells and is advantageous in therapeutic results, has been studied rarely academically as it is a new method. That's why a novel multicomponent system, ZnPc-[Ru(bpy)₂(phen)]₄, as a photosensitizer (Ps) was synthesized by the condensation reaction of the symmetrical zinc phthalocyanine substituted with four 4-(4-formylphenoxy) groups at peripheral positions and ruthenium (II) bis(bipyridine)-phenanthroline complexes including amine group. The compounds were characterized by elemental analysis, FT-IR, ¹H NMR, UV–Vis and MALDI-TOF MS spectral data and analyzed for photophysico-chemical properties. Singlet oxygen quantum yields of the photosensitizer were calculated using photochemical and sono-photochemical methods. When singlet oxygen yields were compared, higher efficiencies were achieved in singlet oxygen production by the sono-photochemical method (Φ_Δ= 0.72 in DMSO, 0.66 in DMF) compared to the photochemical method (Φ_Δ = 0.45 in DMSO, 0.43 in DMF). This work will lead to the synthesis of new sensitizers with high potential for use in SPDT.

Introduction

Cancer, which is one of the main health problems encountered in life-threatening issues today, is a disease of cells, forming the basic building blocks of the body. This disease causes local damage as a result of uncontrolled proliferation and growth of cells in any organ or tissue of the body. In addition, these cells spread to other parts of the body via the bloodstream or lymphatic vessels and form metastases. The standard therapeutic approaches used to control and treat the processes of this disease are chemotherapy, radiotherapy and surgery [1]. However, since there is no selectivity for those other than surgery, the drugs used have the same effect in both cells, regardless of whether they are healthy or cancer cells. As a result of damage to healthy cells, these treatment methods have very serious side effects that affect the quality of life of the patient and in some cases prevent the completion of the treatment. In addition, the existence of some limitations such as systemic toxicity, drug resistance and possible long-term side effects necessitate the use and development of different methods in combination of the treatment of cancer. The researches of alternative approaches for cancer treatment have led to the development of therapeutic methods [2,3]. Photodynamic therapy (PDT), which is one of the therapeutic methods, has become a method that has been studied intensively in recent years due to the fact that it has fewer side effects compared to other methods, although it is a different method for cancer treatment [3], [4], [5], [6]. PDT basically requires the presence of three nontoxic components. These are oxygen, photosensitizer (Ps), and light that initiates the production of highly reactive singlet oxygen. The resulting singlet oxygen and other reactive oxygen species (ROS) cause cells to die [7], [8], [9]. Since the penetration effect of light in deeper tissues is a limiting factor in the application of PDT, which is known to be good in superficial lesions [10,11], a sonodynamic therapy (SDT) method was developed based on PDT. The ultrasound used in SDT penetrates deeper and acoustic cavitation is observed, especially as a result of its non-thermal effect [2,12,13]. As in the PDT method, ROS, which is formed by the breakdown of water molecules in the environment as a result of the cavitation, destroys the target cells. In the SDT method, sono-sensitizers are activated by ultrasound rather than light [13,14]. But sonosensitizers used in the SDT method have not been accepted in clinical studies because they require high concentrations in practice [15,16]. Because of these inadequacies, the Sono-Photodynamic Therapy (SPDT) method, which is based on the combination of SDT and PDT applications, has been developed and this method is based on activating the sensitizer together with light and ultrasound [2,[17], [18], [19]]. Ultrasound, sensitizer type and light parameters used in the performance of SPDT applications are of great importance. The sensitizers to be used should be pure, soluble in water or in such as biocompatible DMSO and DMF and also should have stable chemical composition, good sono-photo sensitivity, nontoxic structure and should be able to easily get away from undamaged tissues [20], [21], [22], [23].

Their excellent electronic transitions due to their aromatic 18 π-electron systems, have made phthalocyanines (Pcs) extremely interesting, and for this reason they are widely used as sensitizers in PDT applications. Because phthalocyanines are suitable photosensitizers for photodynamic cancer treatment due to their high-wavelength absorption, high singlet oxygen production capacity and long half-life [24], [25], [26], [27]. These photosensitizers have the advantage of being more selective to tumor cells and being able to move and clean in a short time. In the literature, phthalocyanines used as photosensitizers were tested in a number of cancer cell lines, such as HeLa (epitheloid cervical carcinoma), HepG2 (human hepatocellular carcinoma) and gastric cancer cells by cytotoxicity with successful results [28], [29], [30].

Phthalocyanines used as photosensitizers have high thermal, chemical, light and ultrasound stability. Since the photochemical stability of the photosensitizers is very important in therapeutic studies, these stable macro molecules are vital for the effectiveness of photocatalytic applications such as photodynamic therapy [31], [32]. Because singlet oxygen cannot reach deep tissues in PDT, the localization of a photosensitizer in the cell, its absorption coefficient and quantum efficiency determine the cytotoxic activity of that photosensitizer [33], [34], [35]. An ideal photosensitizer should have high triplet state quantum yield and long triplet state residence time, high singlet oxygen production, be nontoxic if not stimulated by light of the appropriate wavelength, and should absorb long wavelength light (usually in the red or infrared region). In addition, an ideal Ps should be rapidly dispersed in metabolism and not accumulate in healthy cells after they enter the body and perform their duties. There are approved photosensitizers in the literature and practice, and scientific studies have been continued for the development of new photosensitizers [36,37]. Based on this, complexes containing Ru(II) are considered remarkable due to the suitability of their photophysical properties [38,39]. Also ruthenium phthalocyanine complexes, which provide a high triplet yield because of their intense absorption in the red region of the visible light that can be photoactive, are used as photosensitizers in PDT [[40], [41], [42]].

As a result, the success of therapeutic applications depends on singlet oxygen efficiency. Thus, this paper aimed to calculate the singlet oxygen yields by performing both photochemical and sono-photochemical methods and reveal the difference in singlet oxygen production. In this study, a novel symmetrical multicomponent ZnPc complex including Ru(II) bis(bipyridine) (phenanthroline) complexes at the peripheral positions was synthesized, characterized and the properties of aggregation, fluorescence and photodegredation of the synthesized complex were investigated. Afterwards, the singlet oxygen quantum yields were calculated by both of photochemical and sono-photochemical methods in DMSO and DMF for the purpose of presenting the difference in production of singlet oxygen.