**2. Electron transfer oxidation as a mechanism of photosensitized biomolecule damage**

In general, photosensitized biomolecule damage can be explained by oxygenindependent mechanism (Type I mechanism) and oxygen-mediated mechanism (Type II mechanism) (**Figure 1**) [31–33]. Because the electron transfer-mediated biomolecule oxidation does not absolutely require oxygen, this mechanism is categorized as Type I mechanism. On the other hand, biomolecule oxidation through 1 O2 generation is defined as Type II mechanism (Type II, major). Another ROS-mediated process, superoxide (O2 •−)-mediated biomolecule oxidation is also categorized as the Type II mechanism (Type II, minor). Although O2 •− is produced through electron transfer from photoexcited photosensitizer, it's not categorized as the Type I mechanism. The initial process of electron transfer-mediated biomolecule oxidation is an electron extraction from the targeting biomolecule, such as protein, to the photoexcited photosensitizer.

#### **2.1 Driving force dependence of electron transfer**

The driving force of electron transfer, Gibbs energy (Δ*G*), is determined by the excitation energy of photosensitizer (photon energy) and the redox potential of photosensitizer and targeting biomolecule. The electron transfer is a relaxation process of photoexcited photosensitizer. Fast electron transfer is advantageous for an efficient electron transfer. Due to the Marcus theory [34, 35], the rate constant of electron transfer (*k*ET) is expressed using Δ*G* as follows:

$$k\_{\rm ET} = \sqrt{\frac{4\pi^3}{h^2 \mathcal{A} K\_\mathcal{B} T}} V\_{\rm DA}{}^2 \exp\frac{-\left(\Delta G^\circ + \lambda\right)^2}{4\mathcal{A} K\_\mathcal{B} T},\tag{1}$$

*Electron Transfer-Supported Photodynamic Therapy DOI: http://dx.doi.org/10.5772/intechopen.94220*

#### **Figure 1.**

*Relaxation process of photoexcited state of photosensitizer and the typical photosensitized biomolecule damaging mechanisms.*

where *h* is Plank constant, *λ* is the reorganization energy, *K*B is the Boltzmann constant, and *V*DA is the effective electronic Hamiltonian matrix element. The *λ* can be calculated from the following equation:

$$\mathcal{A} = \frac{e^2}{4\pi\varepsilon\_0} \left(\frac{\mathbf{1}}{2r\_D} + \frac{\mathbf{1}}{2r\_A} + \frac{2}{d}\right) \left(\frac{\mathbf{1}}{n^2} - \frac{\mathbf{1}}{\varepsilon}\right),\tag{2}$$

where *e* is the elementary charge, *ε*0 is the vacuum permeability (8.854 × 10−12 F m−1), *r*D and *r*A are the radius of the electron donor and that of acceptor, respectively, *d* is the distance between electron donor and acceptor, *n* is the refractive index, and *ε* is the static dielectric constant of surrounding material. Since the *V*DA is determined by the overlap between wavefunctions of electron donor and acceptor, the electron transfer rate strongly depends on the *d*, and decreased exponentially with an increase in *d*. Therefore, association between photosensitizer and targeting biomolecule is very important. The Δ*G*, driving force of electron transfer, is expressed as follows:

$$
\Delta \mathbf{G} = \mathbf{e} \left( E\_{\text{rad}} - E\_{\text{ox}} \right) - E\_{\text{0-}0}, \tag{3}
$$

where *E*red is the redox potential of a one-electron reduction of photosensitizer, Eox is the redox potential of a one-electron oxidation of targeting biomolecule, and *E*0–0 is the 0–0 energy (singlet excited (S1) energy) of photosensitizer. The Eq. (1) indicates that *k*ET becomes maximum at Δ*G* = *λ*. However, in general, large -Δ*G* is

advantageous for fast electron transfer. Therefore, small (small absolute value) *E*red and/or large (large absolute value) *E*ox is appropriate for effective electron transfer. To evaluate the electron transfer in the triplet excited (T1) state, the "*E*0–0" term in Eq. (3) is replaced with the T1 state energy. Because T1 state energy is smaller than *E*0–0, in general, electron transfer oxidation by T1 state photosensitizer becomes difficult.

#### **2.2 Excitation energy and electron transfer**

Excitation energy (photon energy) strongly affects the electron transfer rate and efficiency as the Eq. (3). Indeed, an ultraviolet photosensitizer can oxidize DNA, which is relatively resistant to the electron extraction, through photoinduced electron transfer [32, 33]. However, ultraviolet radiation is harmful for human tissue. Furthermore, long wavelength visible light or near infrared radiation can penetrate human tissue deeply as mentioned above as the optical window [18]. Therefore, visible light (or near infrared) photosensitizer, such as porphyrins and phthalocyanines, are important for PDT. To realize the electron transfer photosensitizer, which can be excited by long wavelength light, the design and synthesis of photosensitizer molecules with small *E*red value are required. However, a molecule with small *E*red has tend to decay through reduction by surrounding molecules, and small *E*red is not appropriate for stability of molecule.

#### **2.3 Kinetics of electron transfer**

In general, electron transfer can be demonstrated by a transient absorption spectrum measurement [36, 37] and a time-resolved electron paramagnetic resonance measurement [38, 39]. The *k*ET values can be determined by the analysis of transient absorption spectra. Fluorescence lifetime measurement is also an important method [40]. Although fluorescence lifetime is affected by various factors other than electron transfer, it is sensitive and convenient method. If other factors can be excluded, this method is advantageous for the kinetic evaluation of electron transfer. The *k*ET value can be obtained using fluorescence lifetime by the following equation:

$$k\_{ET} = \frac{\mathbf{1}}{\tau\_{\mathbf{f}}} - \frac{\mathbf{1}}{\tau\_{\mathbf{f}}^{\rm o}},\tag{4}$$

where *τ*f is the observed fluorescence lifetime of photosensitizer with electron donor (targeting biomolecule) and *τ*<sup>f</sup> 0 is that without electron donor. In general, *k*ET becomes larger than 108 ~ 109 s−1 in the case of electron transfer in the S1 state, because lifetime of most of porphyrin S1 state is order of several nanosecond. In the case of T1 state, the lifetime is order of microsecond and the rate constant becomes relatively small. As mentioned above, the T1 state is not appropriate for electron transfer oxidation from the thermodynamic point of view.

#### **3. Phosphorus(V) porphyrin photosensitizer**

Porphyrin derivatives have been used as clinical photosensitizer for PDT [8–11]. Porfimer sodium [12, 13] and Talaporfin sodium [13] are famous examples of clinically used photosensitizers. The PDT mechanism of these porphyrins is 1 O2 generation. The photochemical property of porphyrin can be changed by the replacement of the central atom and substitution. It has been reported that phosphorus(V)

porphyrin can oxidize biomolecules, such as nucleobase [41], protein [42–48], and other biomolecules [49, 50] through electron transfer.
