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The lack of accurate and robust photodynamic therapy dosimetry is one of the obstacles for the widespread clinical applications. In this study, we propose a methodology to monitor the production of reactive oxygen species in real-time using the phosphorescent spectra of metalloporphyrin based photosensitizer. The correlation among the phosphorescence intensity, the 1O2 quantum yield (ΦΔ) and the oxygen concentration [O2] was established. A method of determining ΦΔ with different [O2] was studied based on comparative spectrophotometry, and the quantum yield ΦΔ of gadolinium metalated hematoporphyrin mono ether (Gd-HMME) in methanol was determined for different [O2]. With our method, both [O2] and ΦΔ could be monitored simultaneously using the phosphorescence spectra. The photochemical reactions in a liquid phantom composed of Gd-HMME and 1O2 capture 1,3-diphenylisobenzofuran (DPBF) were correlated using the kinetics equations of singlet oxygen generation and reaction. Using our method, the 1O2 quantum yield becomes observable and the 1O2 dose rate could be calculated by the product of photosensitizer absorption and its 1O2 quantum yield. Moreover, this 1O2 dosimetry could be observed by spectral imaging intuitively without complex analysis, and is especially suitable for precise customized photodynamic treatment.
© 2015 Optical Society of America
1. Introduction
Photodynamic therapy (PDT) is a promising theranostic modality for many diseases in the areas of oncology, dermatology and ophthalmology [1,2]. Its therapeutic effect is based on the cytotoxic singlet oxygen (1O2), which is generated by the photochemical reaction among the photoactivatable photosensitizer (PS), light of the appropriate wavelength and molecular oxygen. Compared with conventional surgery and radiation therapy, PDT is a selective and noninvasive treatment that can destroy localized diseased tissue with minimal side-effect [3,4]. However, its widespread clinical application is obstructed by the lack of accurate and robust dosimetry. A precise and real-time dosimetry could help better control of the operation and provide accurate estimation of the outcome.
There are mainly three approaches for PDT dosimetry, singlet oxygen luminescence dosimetry (SOLD), implicit dosimetry and explicit dosimetry [5,6]. SOLD uses the luminescence emission of 1O2 at 1270 nm to measure the production of 1O2 and predict the PDT efficacy. It has been widely accepted as the gold-standard of dosimetry for PDT [7,8]. Some clinical applications of SOLD on cells and dermatology have been realized [8–11]. However, due to the low transmission probability and the short lifetime of 1O2, it is challenging to use SOLD for clinical applications of deeper lesions. The implicit dosimetry uses the fluorescence measurements of photosensitizer photobleaching or photoproduct generation to predict the PDT efficacy [12,13]. It is more clinically feasible for deeper lesions, as the distributions of the light fluence rate, the tissue optical parameters and photosensitizer are measurable with fluorescence diffuse optical tomography (FDOT) when interstitial PDT is utilized [14]. The implicit dosimetry functions well for 1O2 dominant photosensitizers, like mTHPC when the tissue is well oxygenated [7]. However, the implicit dosimetry does not function well when non-1O2 induced photobleaching exists due to hypoxia or intrinsic property of some photosensitizers, such as ALA-PpIX [15,16]. The explicit dosimetry involves measurements of the light fluence rate, tissue optical parameters, photosensitizer distribution and tissue oxygenation. The commonly used explicit dosimetry rate is usually defined as the product of the local photosensitizer concentration and the light fluence rate or the product of the local photosensitizer concentration, the light fluence rate and the tissue oxygenation. The former one works well with stable tissue oxygenation. But the oxygen consumption and vascular destructions always cause hypoxia, leading to less effective PDT treatment [17]. The later one needs to make a correction by introducing the tissue oxygenation. To date, tissue oxygenation is usually estimated with total hemoglobin concentration (THC) and blood oxygen saturation (StO2). This method has achieved certain success and is used for deeper lesions [18]. However, they do not directly offer complete tissue oxygenation information. There is still need for complex and dynamic models due to the complex capillary and the nonlinear binding rate of oxygen to hemoglobin. Some microscopic and macroscopic models have been set up for this purpose based on kinetics equations of 1O2 generation and its reaction, and oxygen diffuse equation respectively [19–23].
To characterize the singlet oxygen dosimetry completely, it is necessary to determine the 1O2 quantum yield and study its relationship with oxygen molecule concentration. The 1O2 quantum yield, usually defined as the number of 1O2 molecules generated for each photon absorbed by photosensitizer, is an important quantitative character evaluating the ability of a photosensitizer to generate 1O2. The singlet oxygen dosimetry rate could be the product of light absorption of photosensitizer and the 1O2 quantum yield, which is a kind of figure of merit [24,25]. However, this dosimetry is seldom adopted in scientific study or clinical practice due to the following reasons: First, the 1O2 quantum yield is dependent on oxygen concentration and changes accordingly as the oxygen depletes. The reported data of most photosensitizers is acquired in a certain air-saturated or oxygen-saturated solution [24]. The theoretical relationship between the 1O2 quantum yield and oxygen had been established [24], but it is not intuitive enough for practical applications. Second, the 1O2 quantum yields of photosensitizers are not directly measurable. Most photosensitizers, such as porphyrins, have high efficiency of intersystem crossing. However, they are fluorescent rather than phosphorescent [26]. This guarantees a relatively high efficiency of photosensitization, but makes it hardly possible to estimate the oxygen concentration with phosphorescence spectra. The most common methods to determine the 1O2 quantum yields are direct measurements of luminescence of 1O2, the calorimetric techniques like time-resolved photoacoustic calorimeter and quantitative analysis of photooxidation reactions. Oxygen-sensitive phosphorescence quenching is perhaps most suitable for biological applications [27–29]. It is reliable, minimally invasive and feasible for 3-dimensional measurement in-vivo [30,31]. Some metalloporphyrins and metallobacteriochlorophylls of noble metal, such as Pt(II)-, Pd(II), Ru(II)- and Ir(III)- complexes, have been validated in measuring molecule oxygen based on phosphorescence quenching [29,32]. They are intrinsically photosensitive but most of them are less potent because of the competition between phosphorescence and photosensitization. Their phototoxicity has been taken care of when used as oxygen probes [33]. Nevertheless, a series of palladium bacteriochlorophyll derivatives have been used as photosensitizers, such as Padoporfin (Tookad) [34,35]. Therefore, it is possible to find some metalloporphyrins functioning as both oxygen probe and photosensitizer. In our previous study, gadolinium labelled hematoporphyrin mono ether Gd-HMME has been synthesized and proved to be oxygen sensitive with a 1O2 quantum yield of 0.4 in air-saturated methanol solution [36]. The generations of phosphorescence and singlet oxygen are both relevant with the triplet state of the photosensitizer. Their competition relationship in quenching the triplet state of photosensitizer indicates that they may follow a relatively simple relationship and this would help a lot in the determination of oxygen concentration, 1O2 quantum yield and therefore the singlet oxygen production.
In this study, we propose a new method to monitor the 1O2 dosimetry rate using luminescence spectra of phosphorescent metalloporphyrin, such as Gd-HMME. The kinetics equations describing the photophysical and photochemical reactions in the mixture solution of photosensitizer and singlet oxygen capture 1,3-diphenylisobenzofuran (DPBF) will be discussed theoretically. Based on that, a relationship between the quench of phosphorescence and the 1O2 quantum yield can be established. Then, the theoretical basis for determining the 1O2 quantum yield in different oxygen concentrations was extended from the comparative spectrophotometric method for the same oxygen concentration. The dependences of phosphorescence quench and the 1O2 quantum yield of Gd-HMME on oxygen concentration were measured spectrophotometrically and their relationship was determined. The photochemical processes of liquid mixture solution composed of Gd-HMME and DPBF under illumination were described by the kinetics equations of photochemical reactions with the parameters determined above to investigate the feasibility of monitoring the singlet oxygen generation using phosphorescent photosensitizers.
2. Theoretical analysis and experiments
2.1 The relationship between singlet oxygen quantum yield and phosphorescence quenching
The photophysical and photochemical processes during type-II photodynamic reaction were illustrated by Wilkinson [24]. The dominant processes relevant with analyzing the interrelationship between the phosphorescence intensity IP, the 1O2 quantum yield ΦΔ and oxygen concentration [3O2] are shown in Fig. 1 and all definitions of variables are listed in Table 1.
Table 1. Definitions of variables describing photophysical and photochemical interactions between photosensitizer, oxygen and 1O2 capture DPBF
The quantum yield of the phosphorescence ΦP and the singlet oxygen ΦΔ are described by Eqs. (1) and (2), respectively,
where ; ΦT, ΦP and ΦΔ represent the quantum yield of triplet state, phosphorescence and 1O2, respectively; is the fraction of T1 quenched by 3O2 that generates 1O2 and denotes the proportion of T1 quenched by 3O2.The dependence of the phosphorescence intensity and lifetime on oxygen concentration follows the Stern-Volmer equation [28],
where , and ; IP0 and τP0 are the phosphorescence intensity and lifetime without oxygen; IP and τP are the phosphorescence intensity and lifetime with oxygen and KSV represent the Stern-Volmer oxygen quenching rate.As shown by Fig. 1 and Eqs. (1) and (2), the generation of phosphorescence emission and singlet oxygen share the common process, the population of the triplet state of photosensitizer. The ΦΔ of photosensitizer is usually reported as a constant in certain circumstance, but in reality, it is dependent on the environmental variables, such as oxygen concentration, temperature and the pH value. The relationship between ΦΔ and [3O2] is described by Eq. (2), but it is not convenient for observation. The relationship between ΦΔ and the phosphorescence intensity could be derived from Eqs. (2) and (3) and expressed as
which could be used for monitoring the ΦΔ through the phosphorescence intensity as long as the product is determined. The chemical reaction between singlet oxygen and DPBF is also shown in Fig. 1. 1O2 reacts with 1,3-diphenylisobenzofuran (DPBF) rapidly and yields the intermediate products endoperoxide. Then each endoperoxide molecule transforms to o-dibenzoylbenzene (DBB) and releases 1/2 oxygen molecule [37].2.2 The method for determination of singlet oxygen quantum yields
The temporal concentrations of photosensitizer and oxygen at each state are described by the kinetics equations of photochemical reactions as follows [24]
where v is light speed in solution, ρ is the photon number density, σPS is the absorption cross section of photosensitizer; [1PS], [1PS*] and [3PS*] are the photosensitizer concentrations in ground state, lowest singlet state and lowest triplet state; [3O2] and [1O2] are the oxygen concentrations in ground state and lowest singlet state; [DPBF] is the concentration of DPBF.The steady-state approximation can be applied to 1PS, 3PS* and 1O2. By solving the quasi-steady state equations, the consumption rate of DPBF k may be described by
If the irradiance on photosensitizer is relatively low, [O2] and [PS] do not change apparently, the chemical reaction between DPBF and 1O2 could be regarded as pseudo-first-order. Then the degradation rate of DPBF, k, can be determined byThis study deals with the photophysical and photochemical processes in uniform solutions without scattering. The photosensitizer absorption of laser irradiation per unit area could by calculated by Beer-Lambert’s law and illustrated bywhere the laser power intensity is expressed as , h is the Planck constant, NA is the Avogadro's constant, is the optical frequency and L is the optical path length. The approximation in this equation holds well when the concentration of photosensitizer is low enough. Considering the laser spectra distribution, the photosensitizer absorption Iabs in optical measurement could be determined byBy regulating Eqs. (10) and (12), replacing the photon density ρ and the absorption cross section σPS with the PS absorption Iabs and putting the constants and detectable variables on different sides, a new equation can be derived,where NA and h are physical constants; L and are constants for a certain experiment; kc and kd depend only on the property of the solvent and temperature, which are independent of the type of photosensitizer and its concentration. Since all the physical quantities on the left side of Eq. (14) are independent of oxygen concentration, the right side of Eq. (14) does not vary with oxygen concentration either. Base on this, the ΦΔ of different photosensitizer in solutions with different oxygen concentration could be determined.2.3 Measurements of phosphorescence and singlet oxygen quantum yields
Gd-HMME was synthesized as described in a previous work [36] and its methanol solution was preserved from air and light. The dependence of phosphorescence intensity on oxygen concentration was studied first. The beaker contained with the sample of Gd-HMME in 100 μM methanol solution was put into a closed chamble connected with oxygen and nitrogen. The oxygen concentration was controlled by tuning the flow ratio between oxygen and nitrogen above the liquid surface using mass flowmeters and monitored with Clark electrode. The sample was inilluminated with 532 nm laser (CLO Laser DPGL-500L, China) whose power density was calibrated to be 20 mW/cm2 by the laser powermeter (Ophir Photonics Group, Israel). The luminescence spectra was collected with optical fiber and recorded with miniature fiber optic spectrometer USB2000 (Ocean Optics, USA) when the oxygen concentration and the phosphorescence intensity have got stable.
The ΦΔ of Gd-HMME air-saturated methanol solution was determined by a comparative spectrophotometric method using DPBF as chemical capture of 1O2 and Rose Bengal (RB) as reference photosensitizer. The oxygen concentration was determined to be 94 μM with a Clark-type electrode. Three groups of mixture solution of DPBF and photosensitizers were prepared: (1) DPBF 30 μM only; (2) DPBF 30 μM; RB 0.5 μM, 1.0 μM, 1.5 μM or 2.0 μM; (3) DPBF 30 μM; Gd-HMME 1.0 μM, 2.0 μM. They were put in silica curette of 1 cm length and illuminated with 532 nm laser at the power density of 1 mW/cm2. The irradiation spectrum of 532 nm laser was measured with miniature fiber optical spectrometer USB2000 and the absorption spectra of Gd-HMME and Rose Bengal of the same concentrations in the mixture solution were determined by a spectrometer. The photosensitizer absorptions Iabs were determined by Eq. (13). DPBF has strong absorption at 415 nm in methanol solution and this absorption peak vanished after photo-oxidation. The degradation rate of DPBF was monitored using the absorption spectra of DPBF in the range from 400 nm to 430 nm, and the degradation rate k was determined by Eq. (11). RB has a 1O2 quantum yield of ΦΔ = 0.80 in air-saturated methanol solution [24]. The constant term was determined first and the ΦΔ of Gd-HMME in air-saturated methanol solution was determined by Eq. (14).
To determine the relationships of ΦΔ with oxygen concentration and the phosphorescence intensity, the ΦΔ values of Gd-HMME in methanol solutions were determined for different oxygen concentrations. The curette contained with 3 mL methanol solution of 1 μM Gd-HMME and 30 μM DPBF and a beaker of 20 mL methanol were put into a chamber connected with oxygen and nitrogen. The proportion of oxygen in chamber was adjusted with mass flowmeters and the oxygen concentration in solution changed accordingly. The oxygen concentration of methanol in the beaker was measured with the Clark electrode and used to represent the oxygen concentration in the curvette when the display of the electrode got stable for a while. The curvette was exposed to 532 nm laser at the power density of 1 mW/cm2. The degradation of DPBF was recorded for each oxygen concentration. All other conditions were kept the same and all measurements were taken at atmosphere pressure and room temperature.
2.4 Numerical simulations on the photooxidation process of DPBF
Considering the chemical reaction between DPBF and 1O2 illustrated in Fig. 1 and the oxygen supply, the time dependence of oxygen could be illustrated as
where the second term is related with the oxygen supply through the oxygen diffusion from air, which is a simplified form of Fick’s law and used the in the same way as [22]. [O2]0 is the initial oxygen concentration before light irradiation under the balanced condition; g denotes the maximum oxygen supply rate and g is 0 for a closed system. To illustrate the necessity of monitoring the changes of [O2] and ΦΔ, and to investigate the feasibility of monitoring 1O2 generation level by optical measurement, numerical simulations were performed to estimate the photo-oxidation of DPBF in liquid solution. The situations for air close system and air open system were also compared. The phantoms are assumed to be the methanol solution of mixture of 1 μM Gd-HMME and 90 μM DPBF in 4 ml silica cuvette, of which one group is exposed to air and the other group is isolated from air. The value of g is assumed to be 1 μM/s for air open system. They were illuminated by a 532 nm laser with a power density of 10, 20 and 50 mW/cm2 respectively. The time dependences of phosphorescence intensity IP/IP0, oxygen concentration [3O2], the quantum yield of singlet oxygen ΦΔ and DPBF degradation rate k were calculated numerically based on Eqs. (9) and (15), and the predetermined constant . The necessary light dose for a degradation of DPBF by 99.9% was calculated by .3. Results and discussion
3.1 Stern-Volmer relationship
Figure 2 shows the relationship between the luminescence spectra of Gd-HMME and the dissolved oxygen concentrations [3O2]. As shown in Fig. 2(a), the phosphorescence intensity at 710 nm decreases dramatically as the oxygen concentration increases, and in contrast, the fluorescence intensity at 625 nm remains a constant. The ratio between the phosphorescence intensity and fluorescence intensity was determined to be IP0/F = 5.1 ± 0.1 in oxygen-free methanol solution. The Stern-Volmer quenching plot of Gd-HMME in methanol at room temperature is shown in Fig. 2(b). The Stern-Volmer quenching constant was fitted to be KSV = 15.25 mM−1. The stable fluorescence intensity could be used not only to determine the photosensitizer distribution but also to estimate the phosphorescence intensity in anaerobic condition IP0. Since IP0 is usually not measured directly, the ratio IF/IP is used to determine oxygen concentration instead of IP0/IP in practical applications. Therefore, Gd-HMME could be used as ratiometric oxygen indicator.
Fig. 2 (a) The luminescence spectra of Gd-HMME at oxygen concentrations of 100 μM and 0. (b) The relationship between IP0/IP (IF/IP) and 3O2 concentration.
3.2 Dependence of the singlet oxygen quantum yield ΦΔ on oxygen concentration
The ΦΔ of Gd-HMME was determined by the comparative spectrophotometric method. The main procedure to estimate the ΦΔ in air-saturated methanol solution with a dissolved oxygen concentration of 94 μM is shown in Fig. 3. The normalized irradiation spectrum of 532 nm laser and the absorbance of RB and Gd-HMME are shown in Fig. 3(a). The laser wavelength of 532 nm corresponds to the lowest electronic excited state of Gd-HMME, which is outside of the range of DPBF absorption. Therefore, the degradation of DPBF was completely induced by 1O2. The photosensitizer absorptions of excitation light Iabs were calculated with Eq. (13). Figures 3(b) and 3(c) show the degradations of DPBF in the presence of RB and Gd-HMME, respectively, illuminated with a power density of 1 mW/cm2. The degradation rates k were calculated using Eq. (11). The values of Iabs and k are listed in Table 2. The term was determined to be a constant of 15.8 ± 0.1 mJ/cm2 using the values of Iabs, k and ΦΔ of RB. The ΦΔ of Gd-HMME in air-saturated methanol solution is determined to be 0.40 ± 0.1 with the constant value of and Iabs, k of Gd-HMME. These results are also listed in Table. 2.
Fig. 3 (a) Normalized irradiation spectra of 532 nm laser and absorbance of Gd-HMME and DPBF. (b) Time dependence of DPBF concentration on irradiation time in presence of Rose Bengal. (c) Time dependence of DPBF concentration on irradiation time in presence of Gd-HMME.
Table 2. PS, PS concentrations, PS absorption Iabs, degradation rate of DPBF k, singlet oxygen quantum yield ΦΔ and the constant term.
Figure 4 presents the photo-degradations of DPBF with the same concentration of Gd-HMME but different oxygen concentrations. The degradation rate k increases with the oxygen concentration. The ΦΔ values of Gd-HMME with different dissolved oxygen concentrations were determined based on the fact that the term does not vary with oxygen concentration. Figs. 5(a) and 5(b) show the relationships b ΦΔ with oxygen concentration and phosphorescence intensity, respectively. For Gd-HMME, the product is determined to be 0.73 ± 0.02. This means that the quantum yield of the triplet state ΦT does not change with oxygen concentration. Therefore, the ΦΔ of Gd-HMME follows a simple relationship with oxygen concentration and could be monitored in real-time by the luminescence spectra. This is beneficial for the estimation of the singlet oxygen production, and the singlet oxygen dosimetry can be defined as the time integral of the product of the photosensitizer absorption and its ΦΔ without having to analysis the complex photochemical process that generates 1O2.
Fig. 4 Photodegradation of DPBF in methanol solutions with different dissolved oxygen concentrations.
Fig. 5 (a) The relationship between ΦΔ of Gd-HMME and [3O2]. (b) The relationship between ΦΔ of Gd-HMME and IP/IP0.
3.3 Numerical results of Photochemical Reactions and Monitoring of DPBF consumption and singlet oxygen dosage using luminescence spectra
The main photochemical reactions in the liquid phantom were numerically calculated. Figure 6 shows the temporal distributions of [3O2], the phosphorescence intensity IP/IP0, ΦΔ, [DPBF] and k, as well as the necessary light doses for certain depletions of DPBF. Higher fluence rate results in higher 1O2 generation rate and faster photochemical depletion of O2 and DPBF. The oxygen concentration decreases continuously without external supply of oxygen (g = 0) until DPBF, the insufficient chemicals had been exhausted in this simulation. If given a certain amount of oxygen supply, such as g = 1μM/s, the oxygen concentration undergoes a temporary decrease then recovers to the initial concentration because the oxygen depletion rate decreases as the DPBF degrades. The photodegradation of DPBF is faster with an oxygen supply compared with the situation in a concealed environment. As the oxygen concentration varies, the intensity of phosphorescence and 1O2 quantum yield changes simultaneously. Conversely, both [3O2] and ΦΔ levels can be analyzed by luminescence spectra when the parameters KSV and are determined. For this specific numerical calculation of liquid phantom, the DPBF degradation rate k could be predicted based on the ΦΔ value using the relationship of = 15.8. Generally speaking, the light fluence rate could be designed for surface or deeper tissue, the distributions of photosensitizer and 1O2 quantum yield could be determined by spectra imaging or fluorescence diffuse optical tomography (FDOT) for 3-dimentional cases. The photochemical reaction rate could be determined by spectra imaging in this method. The targeting dosimetry in this simulation is to make DPBF decreases by 99.9% and the corresponding light exposures in different conditions are shown in Fig. 6(f). Without oxygen supply, the necessary light doses are the same, which is in contrast to the case with oxygen supply. The lower is the fluence rate, the less is light dose needed in completing the targeting process. At lower fluence rate, the light dosimetric rate is more than efficient due to the reperfusion of oxygen, which compensates its consumption.
Fig. 6 (a) Temporal distributions of [O2]. (b) Temporal distributions of IP/IP0. (c) Temporal distributions ΦΔ. (d) Temporal distributions of [DPBF]. (e) Temporal distributions of DPBF degradation rate k. (f) Dependence of light dosimetry on irradiance. (It is assumed that g = 1μM/s for air open system.)
4. Conclusion
In summary, the relationship among the oxygen concentration, the phosphorescence intensity and the 1O2 quantum yield has been established by analyzing the photophysical and photochemical processes during the photochemical reactions. Their relationships were determined with two parameters respectively, the Stern-Volmer constant KSV and , which is the product of the triplet state quantum yield and the fraction of triplet state quenched by oxygen to generate singlet oxygen. The phosphorescence intensity and 1O2 quantum yield of Gd-HMME in methanol solutions were studied by comparative spectrophotometry in methanol solutions with various dissolved oxygen concentrations, and their relationship was in accordance with the theoritical model. The Stern-Volmer constant was determined to be KSV = 15.25 mM−1 and the parameter of Gd-HMME in methanol was determined to be a constant 0.73 ± 0.01 at room temperature. The photophysical and photochemical processes in the liquid phantom composed of Gd-HMME and singlet oxygen capture DPBF in irradiance were simulated with the kinetics equations of the photochemical reactions. The temporal distributions of oxygen concentration, singlet oxygen quantum yield, DPBF concentration, DPBF degradation rate and and their relationships state that it is feasible to monitor the 1O2 production rate using luminescence spectra in real time. Therefore, the singlet oxygen dosage could be estimated by the product of the absorption of photosensitizer and its singlet oxygen quantum yield. However, futhur work is necessary to establish its applications for 1O2 dosimetry in PDT, as to the toxicity, tissue localization of photosensitizer and the relationship between tissue depth and detection yield of phosphorescence signal.
Acknowledgments
This work was financially supported by the National Key Basic Research Program of China (973 Program) under Grant No. 2013CB632900, the China Postdoctoral Science Foundation funded project (No. 2014M561342), and the Fundamental Research Funds for the Central Universities and Program for Innovation Research of Science in Harbin Institute of Technology (No. B201415).
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