Theoretical Investigation of Ru(II) Complexes as Photosensitizer for Photodynamic Therapy

Bamba Kafoumba^*, Ouattara Lamoussa, Massapihanhoro Pierre Ouattara, Ouattara Wawohinlin Patrice, Diarrassouba Fatogoma, N’guessan Kouakou Nobel, Ehouman Ahissan Donatien, Ziao Nahossé

Laboratoire de Thermodynamique et Physico-Chimie du Milieu, Université Nangui Abrogoua, Abidjan, Cote d’Ivoire.

DOI: 10.4236/cmb.2022.122007                

Abstract

This work was undertaken to see how Ru II complexes can be suitable for photodynamic therapy through theoretical prediction. For that, four Ru II complexes, α-RuCl₂(Azpy)₂, ,  and  were used in unrestricted state by providing with no more energy than 2.68 eV. The unrestricted state allows the complex molecule to display each of its electrons in one orbital. All the calculations such as optimization, frequency and TD-DFT calculations were performed at WB97XD/Lanl2dz level. It resulted from this investigation that Ru II complexes are active for both mechanisms suitable for photodynamic therapy in presence or absence of ³O₂. Moreover, this reaction was assumed to take place only with Guanine DNA base as demonstrated in literature. Therefore, Guanine is admitted as the base most reacting with ruthenium complexes for photodynamic therapy. This work confirms our prediction regarding metallic complexes that are assumed to be photosensitized in condition that an electron must be isolated to favor the excitation. Nevertheless, Ru II complexes are found suitable for superficial therapy while Ru III must be active for deep therapy.

Keywords

TD-DFT, Ru(II), Photo-Dynamic Therapy (PDT), (Un)restricted Model

1. Introduction

Since discovered as cytotoxic agents, Ru complexes are of great interest [1] [2] [3]. Even if they differ from the nature of the ligand, most of them remain competitive comparatively to other metallic complexes like cisplatin and its derivative molecules [4]. Then, in our previous article, we made a comparison regarding activity of Ru(II) and Ru(III) complexes irrespective of their ligands [5]. We found that both group of complexes are cytotoxic. In addition, we could not make any distinction between the charges of the central metal Ruthenium. However, concerning the photodynamic therapy (PDT) properties, they were obtained assuredly by Ru(III) complexes. We found out furthermore that the inactivity of Ru(II) complexes was certainly due to the couple paired of valence electrons. Therefore, they had failed to display a triplet state. Besides, within the present work that is a continuity of the previous one, we have selected four ruthenium II complexes that we will excite first in a triplet state to permit the separation of pair electrons and find out their cytotoxic effect as photodynamic therapeutic agent. It means that all calculations will be performed in unrestricted model. These complexes are α-RuCl₂(Azpy)₂, $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$, $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$ indicated by Figure 1. All of them are active cytotoxically except for $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$.

The diagram of Jablonski highlights the principle of photodynamic therapy [6]. It states that the molecule responsible for the therapy must be irradiated first. Thus, this molecule is known as a photo-sensitizer (PS). Actually, the irradiation triggers a transition in the PS from the state of singlet (S1) to triplet state (T1) through intersystem crossing. Here, the triplet state is essentially responsible for the therapy as long as it allows the formation of species reactive oxygen [7].

2. Methods

DFT and TD-DFT calculations were performed at WB97XD/Lanl2dz level thanks to Gaussian 09 packages [8]. WB97XD is one of the widespread hybrid functional used for DFT calculations. Its advantage is that it is more accurate and displays better the symmetry of complex molecules [9] [10]. It means that the optimizations and the frequency calculations were performed with symmetry constraints. That process produces an accurate result close to reality. Lanl2dz is the pseudo basis set suitable for heavy elements and it minimizes the relativity effect [11] [12]. TD-DFT was calculated both at ground state and at first excited state to investigate the absorption properties of the Ru II complexes. The energy of the molecules was determined both in restricted and in unrestricted states.

3. Results and Discussion

3.1. Energy of Restricted and Unrestricted States

Both the restricted and unrestricted states can belong to fundamental state. The difference between them stems from the spin of the complex. In the restricted state known as close shell model, we have absolutely an even numbers of electrons. The electrons are coupled with opposite spin thereby giving the complex a singlet spin. In addition, every coupled electrons are in the same orbital. Whereas the unrestricted state, it regards the open shell model. In this case, electrons are unpaired, they are divided in spin up and spin down, and each electron is in a separate orbital. The lowest spin in this case for the molecule is triplet. The

Figure 1. Structure of Ru (II) complexes, a-RuCl2(Azpy)₂, $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$, Fac and $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$.

unrestricted model can naturally be encountered especially when the molecule has odd numbers of electrons in fundamental state and in the excited state [13]. Thus, it can be imposed for the even numbers electrons. Figure 2 displays both models regarding an even electron numbers.

When we look Figure 2, we figure out that from close shell to the open shell, energy of the molecule must increase and the molecule becomes unsteady. Therefore, Table 1 shows the energy recorded from restricted and unrestricted states of the four Ru II complexes.

Table 1 presents the difference of energy between close shell molecules and open shell molecules. We can see that the difference of energy ΔE_S→T between both states is positive. This means that the open shell molecule is more unstable and more reactive than the close shell molecule. Moreover, $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$ requires the highest energy with 2.68 eV to dissociate electrons and create two high occupied molecular orbitals (HOMO) with different energy. Besides, α-RuCl₂(Azpy)₂ requires the least energy to unpair electrons with 1.21 eV. Always in Table 1, we present the difference energy between the highest HOMO and its corresponding LUMO. In this case, the gap energy ΔE_H→L (in eV) is the lowest in the isomers $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ with respectively 4.64 eV and 4.81 eV thereby making them the most reactive complexes. Furthermore, the total energy required for a molecule with close shell electrons to be excited is the sum of both ΔE_S→T and ΔE_H→L. This energy shows that both isomers $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ are the most active with respectively 6.60 and 6.72 eV. $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$ presents the highest energy with 8.14 eV. Henceforth, since the low value noticed between close shell and open shell statute, all calculations will take place at unrestricted state. Figure 3 displays the structure of the four Ru II complexes calculated at unrestricted state after optimization.

3.2. Photophysical Properties of Complexes at Unrestricted State

Table 2 and Table 3 display the 20 first singlets and triplets excited states with the unrestricted model at wb97xd/b3lyp level.

Figure 2. Close shell and open shell models known respectively as restricted and unrestricted states.

Figure 3. Structures from left to right of α-RuCl₂(Azpy)₂, $\text{FAC-Ru}{\left(\text{Azpy}\right)}_3^{2+}$, $\text{MER-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$ calculated at unrestricted state at wb97xd/Lanl2dz level.

Table 1. Energy of close and open shells models and energy of frontiers orbitals of unrestricted state of the Ru(II) complexes calculated at WB97XD/Lanl2dz level.

Total energy required = ΔE_S→T + ΔE_H→L.

Table 2. The 20 lowest singlet excitation energies (eV), wavelength (nm) and oscillation strength (f) of Ru II complexes under unrestricted model calculated at WB97XD/Lanl2dz level.

Table 3. the 20 lowest triplet excitation energies (eV), wavelength (nm) and oscillation frequencies (f) of Ru II complexes under unrestricted models calculated at WB97XD/Lanl2dz level.

Regarding Table 2 that shows up the singlet states of the complexes, we can notice that α-RuCl₂(Azpy)₂ presents two bands at S5 and S9. The lowest energy here is 1.703 eV. This energy corresponds to the wavelength at 727.9 nm and to the transition ${\text{t}}_{\text{2g}}\to {\pi }^{*}$. The last band is observed for the excitation state S9. The energy required for that band is 2.12 eV, which is known suitable for deep phototherapies. Both isomers $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ present their first singlet band at respectively 2.55 eV and 2.41 eV. However, these energies correspond respectively to wavelengths 486.21 and 514.6 nm showing that the first isomer is qualified for deep therapy and the last one can be used for superficial tumors [14] [15]. These bands correspond to the fifth excited state of the molecules. Whereas $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$, its first singlet excitation appears at S11 with 3.23 eV as energy required. The corresponding wavelength is 383.3 nm. Nevertheless, we can see many other bands at high energy and low wavelength. Anyhow, this cation displays only transitions suitable for deep tumors [16] [17].

Table 3 records all information of the 20 first triplets states for each complex calculated at Wb97xd/lanl2dz level in the unrestricted model. We can see therefore that all the complexes show significant wavelengths corresponding to oscillation forces higher than 0.001. Thus, α-RuCl₂(Azpy)₂ displays fourteen important wavelengths where the first is 6328.88 nm and the energy corresponding is 0.20 eV. Regarding $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$, its first triplet wavelength appears at 3335.95 nm and the energy necessary for this excitation is 0.37 eV. In the case of $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ we can see that its first excitation wavelength is set at 2257.76 nm. The energy required for this transition is 0.55 eV. For the last molecule $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$, its first transition is shown at the wavelength 2885.42 nm and the energy necessary is 0.43 eV. Contrary to the close shell state, we can see that the molecules in unrestricted state display actually E_T energy [5]. This witness their abilities to be therapeutically active. By comparison of their first energy of the triplet state, we have: E_T1(α-RuCl₂(Azpy)₂) < E_T1( $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ ) < E_T1( $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$ ) < E_T1( $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ ). Besides, Figure 4 and Figure 5 show the spectra relative to previous tables regarding the wavelengths of the complexes respectively at singlet and triplet states.

Figure 4. Electronic spectra of Ru II complexes calculated at wb97xd/lanl2dz level in unrestricted singlet state.

Figure 5. Electronic spectra of Ru II complexes calculated at wb97xd/lanl2dz in unrestricted triplet state.

We can see in Figure 4 that actually, only α-RuCl₂(Azpy)₂ presents a wavelength higher than 700 nm that comprises the therapeutic window. We notice the same fact for $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ which main wavelength is higher than 500 nm. This means that only these complexes can probably be active for deep cancers. Besides, the two other complexes such as $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$ can be active for superficial tumors regarding their wavelength lower than 500 nm. In Figure 5, we can see that all complexes display electronic spectra meaning that they can be active for phototherapy dynamic.

3.3. Vertical Electron Affinity VEA and Vertical Ionization Potential VIP

The photosensitizing process depends in the attitude of the photosensitizer to give or to accept electrons. Therefore, VEA and VIP of the ruthenium complexes have been predicted at unrestricted state and recorded at both ground and excited states in Table 4 and Table 5.

At ground state S₀, we can see in Table 4 that the energies necessary for ruthenium to receive electrons (VEA_S0) is negative for all the ruthenium complexes. Besides, the most molecule able to accept electrons with the lowest energy are both isomers Fac and $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and their energy is −0.350 eV. Whereas the vertical ionization potential VIP_S0, its lowest energy is displayed by α-RuCl₂(Azpy)₂ with 0.208 eV meaning that this complex is the most capable to liberate electron. Regarding the excited state in Table 5, we can notice that all the energy regarding VAE_T1 is negative. Here, $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ presents the lowest energy necessary to accept electron. Whereas VIP_T1, its lowest energy is still presented by $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ with −0.086 eV.

Actually, photodynamic therapy can be performed only if PS can exchange electron with DNA bases of the cancer cells. These DNA bases are Adenine, Cytosine, Guanine, Thymine and Uracil. As explained in our previous article and in literature, they are assumed to give electron to the PS. Therefore, Table 6 displays the VEA and VIP of the DNA that react with the photosensitizer PS [5] [18] [19].

Table 4. Electronic energies of parent molecule (E_p, (in hartree)), anion radical (E_a, (in hartree)), cation radical (E_c, (in hartree)), vertical electronic affinity (VEA, eV) and vertical ionization potential (VIP, eV) of ruthenium complexes at unrestricted state calculated at Wb97xd/Lanl2dz level.

^aVEA_S0 = E_a − E_p. ^bVIP_S0 = E_c − E_p.

Table 5. Vertical electronic affinity (VEA eV), vertical ionization potential (VIP, eV) both at ground and excited states and the lowest energy at excited state E_T1 (eV) of ruthenium complexes at unrestricted state at Wb97xd/Lanl2dz level.

^aVEA_T1 = VEA_S0 − E_T1. ^bVIP_T1 = VIP_S0 − E_T1.

Through Table 6, we realize that the DNA base that most needs least ionization energy is Guanine with 0.297 eV. Besides, Uracyl is known to accept electron with the lowest energy through vertical electronic affinity.

Furthermore, it is admitted that photodynamic therapy takes place according to two possible steps as mechanisms.

3.3.1. Mechanism I

The first mechanism is assumed to occur directly between the PS and the DNA base either by exchange of electron or energy without oxygen molecule. The following equations show up all possibilities for PS to oxidize the DNA bases.

$\left[Ru-K\right]\left(T_1\right)+B\to {\left[Ru-K\right]}^{\cdot -}+B^{\cdot +}$ (1)

$\left[Ru-K\right]\left(T_1\right)+\left[Ru-K\right]\left(S_0\right)\to {\left[Ru-K\right]}^{\cdot -}+{\left[Ru-K\right]}^{\cdot +}$ (2)

$\left[\text{Ru}-\text{K}\right]\left({\text{T}}_1\right)+\left[\text{Ru}-\text{K}\right]\left({\text{T}}_1\right)\to {\left[\text{Ru}-\text{K}\right]}^{\cdot -}+{\left[\text{Ru}-\text{K}\right]}^{\cdot +}$ (3)

${\left[\text{Ru}-\text{K}\right]}^{\cdot +}+\text{B}\to \left[\text{Ru}-\text{K}\right]\left({\text{S}}_0\right)+{\text{B}}^{\cdot +}$ (4)

Equation (1) shows that PS at an excited state T₁ can receive directly electron from the DNA base that is known to be at a ground state S₀. This reaction is characterized by the sum of VEA_T1 and VIP_S0 (base) so that their sum is negative. In fact, the negative sum is at the stake of reaction thermodynamically feasible [20]. Moreover, a cation PS can receive electron from the DNA base (Equation (4)). The cation PS is actually produced through auto-ionization by combination of two excited PS at T1 state (Equation (3)) or by reaction between the excited PS and the PS at a fundamental state (Equation (2)). These reactions are respectively expressed by the sum either VEA_T1 + VIP_S0 or VIP_T1 + VEA_S0 for Equation (2) and by the sum VEA_T1 + VIP_T1 (Equation (3)). Table 7 shows the results from these reactions.

Table 7 shows us that the reaction regarding Equation (1) of all the complexes is possible insofar that the sum of VEA_T1(C) and VIP(G) is negative meaning that the PS at excited and unrestricted state can actually receive electron from the DNA base. Moreover, the reaction related to the auto-ionization to produce radical cation of the PS is possible. In fact, all the sums are also negative. It means that in unrestricted state, the ruthenium II complexes are active and can

Table 6. Vertical electronic affinity (VEA, eV) and vertical ionization potential (VIP, eV) calculated on DNA and RNA bases at wb97xd/Lanl2dz level.

Table 7. Sum of the VEA_T1 parameters of the complex and VIP parameters of the Guanine reflecting the interactions according to Equation (1), Sum VEA_T1 + VIP_S0 or VIP_T1 + VEA_S0 both reflecting the auto ionization reaction and VIP_T1 + VEA_T1, all performed at B3lyp/wb97xd level over the unrestricted complexes.

react with the Guanine weather directly or through auto-ionization for cation production. Therefore, we can conclude that Ru II complexes at unrestricted state are active as photosensitive molecules through mechanism I.

3.3.2. Mechanism II

Regarding the second mechanism, it is an indirect reaction between DNA and the PS molecule. It requires a presence of oxygen molecule in a third state ³O₂. It is characterized by the Equation (5).

$\left[Ru-K\right]\left(T_1\right)+{}^{3}O{}_2\to \left[Ru-K\right]\left(S_0\right)+{}^{1}O{}_2$ (5)

The oxygen molecule in the third state must be shifted in singlet that is assumed to be active as destructor of the tumor cell. To obtain the singlet oxygen molecule, the energy of triplet state of PS must be higher than the energy necessary to change the state. According to literature, this energy required is estimated to 1.06 eV [21] [22] [23]. Therefore, in Table 3 that displays the first twenty triplet states, we can see that T1 is not suitable for this reaction in any complex. However, even though it is possible, only high transitions are admitted. For instance, with α-RuCl₂(Azpy)₂, T4 is suitable with 1.694 eV. With $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$, T6 is the first transition necessary for 1.246 eV. Regarding $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$, T6 is the transition acceptable for energy 1.148 eV. Whereas $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$, the first transition necessary is T7 with the energy 1.212 eV. Anyway, $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ presents the lowest energy required to transform ³O₂ at the state ( ${}^3\Sigma {}_g^{-}$ ) in to ¹O₂ with the state ( ${}^1\Delta {}_g$ ).

Table 8. Sum of VIP_T1 of Ru complex and AEA(O₂) of oxygen in eV calculated at Wb97xd/lanl2dz level.

Furthermore, mechanism II can be also described by production of peroxide radical anion $O_2^{\cdot -}$ with the triplet oxygen molecule ³O₂. This reaction takes place between the triplet state of ruthenium complex and the triplet oxygen molecule. Equation 6 highlights this reaction.

$\left[Ru-K\right]\left(T_1\right)+{}^{3}O{}_2\to {\left[Ru-K\right]}^{\cdot +}+O_2^{\cdot -}$ (6)

Thermodynamically, this reaction means summation of VIP_T1 for the ruthenium complex and the adiabatic electron affinity AEA(O₂) of the oxygen. This latter energy is given in vacuum as −0.59 eV [14] [20]. Table 8 shows the sum of both VIP_T1 of PS and AEA(O₂).

The result of the sum of VIP_T1 and AEA(O₂) is negative for each complex, it means the reaction is also thermodynamically possible. Therefore, we can retain that Ru II complexes can generate the superoxide anion $O_2^{\cdot -}$. Moreover, they are active as photosensitizer in photodynamic therapy through mechanism II provided they be in unrestricted state.

4. Conclusions

Ruthenium complexes at oxidation state II were investigated in this work as photodynamic therapy photosensitizers at unrestricted state. This is a state where electrons occupy lonely their orbitals. It required that the optimization and frequency calculations be performed in that abovementioned state. In our previous paper in which we compared state II and III of ruthenium complexes, we discovered that Ru complexes with the state II are naturally in restricted state. Therefore, it is very hard for them to liberate electron when they are excited to yield triplet state. Thus, they are not active for PDT.

Here, the use of Ru II begins by dissociating first the pair electrons for open shell model. Then excitation to a singlet and triplet is performed. The total energy required was comprised between 6.60 and 8.14 eV. These two extreme energies are respectively given by $\text{Fac-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ and $\text{Ru}{\left(\text{Bipy}\right)}_3^{2+}$. TDDFT calculation in singlet state shows henceforth that α-RuCl₂(Azpy)₂ and $\text{Mer-Ru}{\left(\text{Azpy}\right)}_3^{2+}$ can be active for deep cancer as they display therapeutic windows. Whereas the two other complexes, they are assumed to neutralize superficial cancers. Besides, there are all discovered to bind with Guanine DNA base.

Regarding phototherapy dynamic, Ru II complexes at unrestricted state are assumed to be active for both mechanisms either in presence or in absence of O₂. In addition, they do not require much energy to shift from restricted to open shell state. This tremendous result is showing that Ru II complexes can of course be used as Photosensitizer for photodynamic therapy providing that they be in unrestricted model. Therefore, our upcoming work will consist of synthetizing the Ru II complexes at unrestricted state and find out the difference with the restricted state complexes.

Conflicts of Interest

The author declares no conflicts of interest regarding the publication of this paper.

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