Design of an NO photoinduced releaser xerogel based on the controlled nitric oxide donor trans-[Ru(NO)Cl(cyclam)](PF6)2 (cyclam = 1,4,8,11-tetraazacyclotetradecane)

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Abstract

The immobilization and properties of the nitric oxide donor trans-[Ru(NO)Cl(cyclam)](PF6)2, Rusingle bondNO, entrapped in a silica matrix by the sol–gel process is reported herein. The entrapped nitrosyl complex was characterized by spectroscopic (UV–vis, infrared (IR), X-ray photoelectron, and 13C and 29Si MAS NMR) and electrochemical techniques. The entrapped species exhibit one characteristic absorption band in the UV–vis region of the electronic spectrum at 354 nm and one IR νNO stretching band at 1865 cm−1, as does the Rusingle bondNO species in aqueous solution. Our results show that trans-[Ru(NO)Cl(cyclam)](PF6)2 can be entrapped in a SiO2 matrix with preservation of the molecular structure. However, in a SiO2/SiNH2 matrix, the complex undergoes a nucleophilic attack by the amine group at the nitrosonium. Irradiation of the complex, entrapped in the SiO2 matrix, with light of 334 nm, resulted in NO release. The material was regenerated to its initial nitrosyl form by reaction with nitric oxide.

Graphical abstract

Trans-[Ru(NO)Cl(cyclam)]2+ is entrapped in a SiO2 xerogel without loss of integrity, delivers NO under irradiation with light and it can be regenerated. Amino functionalized xerogel reacts with the coordinated NO.

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Introduction

In mammalian species, nitric oxide (NO) plays key roles in almost every function [1], where high or low NO concentrations can be either beneficial or harmful and could accompany numerous pathological states [1]. For this reason, there has been a growing interest in NO donors and scavengers aiming at therapeutic applications [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. Ruthenium nitrosyl complexes have shown to be very promising NO donors [5], [6], [9], [10], [12], [14], [17], [18], [19], [20], [21], [22], [23], [24], [25], and some of them have shown biological activity [6], [22], [24], [25], [26], [27]. In these quite stable complexes, the coordinated NO has a nitrosonium character, and it can be released photochemically or via one-electron reduction [3], [12], [17], [18], [19], [20], [22], [26], [28].

Our laboratories have directed efforts toward the synthesis of ruthenium complexes as NO donors and scavengers [6], [14], [23], [24], [26]. The trans-[Ru(NO)Cl(cyclam)](PF6)2 complex releases NO photochemically or upon reduction [14], [29], [30], and it is less toxic than nitroprusside, a well-known vasodilator [6], [9], [14]. Furthermore, it is as effective at reducing blood pressure as nitroprusside, but with a longer effect [6]. The blood pressure effects were interpreted in terms of the reactivities of the complexes involved in NO release. The longer blood pressure reduction effect of trans-[Ru(NO)Cl(cyclam)]2+ was interpreted as a result of the much lower rate of NO release from trans-[Ru(NO)Cl(cyclam)]2+ than from similar tetraammine nitrosyl ruthenium complexes [6], [9], [14]. Aiming at extending the range of potential applications, there is an interest in designing carriers or supporters for such complexes. Conceivably, the immobilization of these complexes could result in materials that may be used in association with optical fibbers to provide the opportunity for controlled NO release at specific target sites using laser photoexcitation [31], [32].

In this regard, novel strategies using NO donors other than metal nitrosyl complexes have also been investigated. Nitric oxide-releasing diazeniumdiolates are successfully being immobilized in polymers, silica-gel, and metal surfaces, aiming at biological applications [33]. Recently, the preparation, characterization, and preliminary biomedical application of various nitric oxide (NO)-releasing fumed silica particles with amine groups has been reported [34]. These amine groups were then converted into the corresponding N-diazeniumdiolate groups via reaction with NO(g) at high pressure in the presence of methoxide bases. The N-diazeniumdiolate moieties attached to the silica surface underwent a primarily proton-driven dissociation to NO under physiological conditions, and they also underwent slow thermal dissociation to NO. These resulting NO-releasing fumed silica particles could be embedded into polymer films to create thromboresistant coatings, via NO release at fluxes that mimic healthy endothelial cells (EC), making them a very interesting system. The NO-addition efficiency for this direct reaction, however, was found to be 12% in an acetonitrile suspension of Sil-2N [6] particles. This NO-loading capacity is lower than the one observed for various free amines, which lead to a typical yield of 30–90% [35]. The immobilization of diazeniumdiolates in sol–gel to yield NO releasing materials has also been reported [36]. More recently, a ruthenium salen nitrosyl complex has been copolymerized with ethyleneglycol dimethylacrylate to form a material which is photolabile for NO release [37]. Toma et al. have also recently reported ruthenium hexaacetate clusters incorporated in polyvinyl alcohol films that are sensitive to daylight [38].

The use of ruthenium nitrosyl immobilized species as NO donors has some advantages in relation to other species, since ruthenium complexes can deliver and recover NO at milder conditions than those associated with the diazeniumdiolate system. Moreover, it should be noted that the NO delivery from ruthenium amine (or ammine) nitrosyl complexes can be tuned photochemically, through their different UV–vis spectra or by their different reduction potentials [3], [12], [14], [17], [20], [21], [24], [26], [39], [40], and thus, the choice of complex can be made based on the target and conditions. These NO donors attached to solid state matrices can be achieved by two different approaches: (a) grafting or physical adsorption of the complex on a matrix already prepared; (b) occlusion, where the complex is mixed with precursors of the matrix which is formed around the complex. The matrix must be inert toward the complex and the NO released, and it should also be chemically stable. Furthermore, in order to keep the photochemical NO release, the matrix should not absorb in the same wavelength range of the complex. Although an organic matrix [37] can be envisaged, a xerogel matrix has the advantage of exhibiting higher chemical and physical inertia, as well as displaying lower or zero absorbance in the near UV and visible region. Sanchez et al. have already reviewed the advantages and challenges of using hybrid xerogels for optical applications, and they clearly showed the feasibility of their use in such applications [41]. The first attempt to immobilize a ruthenium complex with potential ability to act as NO donor was achieved by Franco et al. They used the chemisorption of trans-[Ru(NH3)4(SO2)(H2O)]2+ on 3-(l-imidazolyl)propyl organomodified silica gel to prepare a ruthenium complex modified silica gel [single bondSi(CH2)3imN-Ru(NH3)4SO2] [42]. This method has the advantage of leading to a chemical bond between the ruthenium complex and the silica gel, possibly leading to a more stable material from the recycling point of view. However, the ruthenium loading in these materials is low even for relatively small complexes like the ruthenium ammine compounds because they are not able to diffuse inside the inner silica pores. Therefore, other methodologies should be used for the preparation of heavily loaded ruthenium nitrosyl silicas.

As suggested before, the immobilization by sol–gel entrapment/occlusion in silica matrices can be a better choice [43], [44], [45], [46]. The mild characteristics offered by the sol–gel process allow the introduction of inorganic complexes inside an inorganic network [47]. The sol–gel methodology has so far been used in the context of inorganic catalysts, as part of the matrix [48], as supports for dispersed metal particles [49], and for copolymerization with suitable silicon-containing ligands [50]. The introduction of a host molecule is obtained by adding its solution to the polymerizing mixture. When the polymerization is complete, the dopant molecules are entangled in the inorganic polymeric network. The nature of the entrapment is still not fully understood, and it is really remarkable to see how many applications of the entrapment have been developed, without a full understanding of the process at the molecular level [51]. The entrapment of ruthenium nitrosyls can conceivably lead to changes in kinetic properties, such as rate of release of NO, which would probably lower than in solution. Similarly, Avnir and Frenkel-Mullerad [52] recently studied the unusual stabilization of alkaline and acid phosphatases occluded in xerogels. Remarkably, the enzymes kept their activity even at pH as low as 0.9. The explanation proposed for such a high stability took into consideration the porous microenvironment in xerogels at a molecular level. The restricted space inside these pores seems to challenge the classical meaning of thermodynamic parameters like pH, and a nanoscopic view of the interactions inside the pores among the surface groups, i.e., silanols, adsorbed water and entrapped species, seems to be more appropriate. Therefore, the study of chemical reaction on largely restricted media (LRM) needs a different approach from that used in bulk solution chemistry.

In this context and considering that ruthenium nitrosyl complexes allow the possibility of tuning the NO donor properties [6], [14], [23], [24], [26], [30], we have extended our investigations to their immobilization for possible therapeutic applications. In this regard, initial studies on the immobilization of the ruthenium nitrosyl complex, [Ru(salen)(OH2)(NO)]+ (salen=N,N-bis-(salicylidene)ethylenediaminato), impregnated into a silica sol–gel have indicated that it releases NO under irradiation with light and it can also be regenerated [53].

In this paper, we describe the immobilization and characterization of the controlled NO donor trans-[Ru(NO)Cl(cyclam)](PF6)2 entrapped in xerogels containing tetraethylorthosilicate (TEOS), and 3-aminopropyltriethoxysilane (3-APTS), by the sol–gel process. The reaction of 3-aminopropyltriethoxysilane with the coordinated nitrosonium of the complex, the photochemical release of NO from the SiO2 material, and the regeneration of the ruthenium nitrosyl complex entrapped in the matrix are also described.

Section snippets

Chemicals and reagents

Ruthenium trichloride (RuCl3nH2O) (Strem) was the starting material for the synthesis of the ruthenium complexes. Acetone, acrylonitrile, chloroform, and ethanol were purified according to procedures published in the literature [54]. Doubly distilled water was used throughout. Tetraethylorthosilicate (TEOS) and 3-aminopropyltriethoxysilane (3-APTS) (Aldrich) were used without further purification. All other materials were reagent grade and were used without further purification.

Complex syntheses

Trans

Characterization of the material

The material containing trans-[Ru(NO)Cl(cyclam)](PF6)2 entrapped in the SiO2 matrix exhibits a homogeneous color and smooth surface as judged by optical microscopy. The homogeneous distribution of the Ru–NO complex was verified by scanning electronic spectroscopy (SEM) using the EDS detector to generate an elemental mapping of Si, and Cl X-ray emission. Unfortunately, it was not possible to collect enough signal to study the distribution of trans-[Ru(NO)Cl(cyclam)]2+, so we had to use the Cl κα

Summary

Our results show that the controlled NO donor trans-[Ru(NO)Cl(cyclam)](PF6)2 can be entrapped in a SiO2 matrix with preservation of its molecular structure and properties. In a SiO2/SiNH2 matrix, the complex undergoes a nucleophilic attack by the amine group at the nitrosonium, thus indicating that the use of amine functionalized silicas for metal nitrosyl complexes should be avoided. Like the complex in solution, irradiation of the complex entrapped in a SiO2 matrix with light of 334 nm

Acknowledgements

The authors thank the Brazilian agencies FAPESP, CNPq, and CAPES for financial support, Prof. Thiery Gacoin for helpful suggestions and Dr. Cynthia Maria de Campos Prado Manso, for the English revision of the manuscript.

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