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pH-Response Optimization of Amino-Substituted Tetraphenylporphyrin Derivatives as pH-Activatable Photosensitizers Hiroaki Horiuchi,*,†,‡ Ryota Kuribara,† Atsuki Hirabara,† and Tetsuo Okutsu† †

Division of Molecular Science, Graduate School of Science and Technology, and ‡International Education and Research Center for Silicon Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan S Supporting Information *

ABSTRACT: Amino-substituted tetraphenylporphyrin derivatives have been designed as pH-activatable photosensitizers for photodynamic cancer therapy. The photophysical processes of the monoamino-substituted derivative N1 and nonsubstituted derivative N0 have been studied. The quantum yields of the fluorescence and photosensitization of singlet oxygen by N1 were very low in the neutral condition (OFF state), but these quantum yields were recovered by adding acid (ON state). These changes were not observed for N0; therefore, N1 is expected to be applicable as a pH-activatable photosensitizer. The ON/ OFF switching mechanism of N1 has also been clarified. To optimize the pH response, tri- and tetraamino-substituted derivatives (N3 and N4) have also been explored. The pH response intensified as the number of amino groups increased. Furthermore, the ON/OFF switching ratio of N3 was 100, which is quite high.

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INTRODUCTION Photodynamic therapy (PDT) is a promising treatment for cancer that is based on the selective accumulation of the photosensitizer in the tumor tissue and the photosensitization of reactive oxygen species such as singlet oxygen (1O2). The development of PDT requires improvements in photosensitizer performance. Tetraphenylporphyrin (TPP) analogues have shown absorption in the red region of the electromagnetic spectrum and a high quantum yield for singlet oxygen sensitization (ΦΔ). Thus, TPP analogues are among the most fundamental photosensitizers and have been widely studied as photosensitizers for PDT. Improving the PDT activity of photosensitizers is one of the major challenges in their development. To this end, many chemical modifications of TPP analogues have been conducted, such as the introduction of functional groups to the phenyl moieties of TPP analogue,1−5 insertion of central metals,6−11 and modification of the porphyrin ring.12 The suppression of photoinduced side effects is also very important for the development of PDT photosensitizers. Many types of ligands4,5 and carriers for cancer cells13−15 have been studied to suppress the distribution of photosensitizers in normal tissue. Activatable photosensitizers are another promising strategy for suppressing photoinduced side effects.16 These photosensitizers show low ΦΔ under normal conditions (OFF state). However, one or more trigger(s) change their chemical properties, leading to the recovery of ΦΔ (ON state). As activation triggers, the binding to DNA,17−19 enzyme,20−22 low pH,23−28 and external stimuli such as ultrasound29 have attracted much attention. pH-activatable photosensitizers have the potential to realize tumor-selective damage with low photoinduced side effects. Because tumor tissue is more acidic than normal tissue, tumor tissue can serve as a target for pH-activatable photosensitizers.23−28 © 2016 American Chemical Society

Furthermore, lysosome is also an acidic environment, and thus, the lysosome of cancer cells has been suggested as a target for pH-activatable fluorescence probes.30 Therefore, lysosome can also be a target for pH-activatable photosensitizers. Several pH-activatable photosensitizers have been reported for BF2chelated azadipyrromethanes,24 BODIPY derivatives,25 phthalocyanine derivatives,27,28 and rubyrin derivatives.23 Some TPP derivatives were known to be selectively accumulated in tumor tissue3,31,32 and were localized in lysosome.3,33,34 Therefore, TPP derivatives are expected to be good candidates for the backbone of pH-activatable photosensitizers. However, to the best of our knowledge, there are few reports on pH-activatable TPP derivatives.26 Therefore, the development of pH-activatable TPP derivatives is very important. Optimization of the pH response is also very important in the development of pH-activatable photosensitizers. In this study, we developed novel pH-activatable TPP derivatives and optimized their pH response. For some of the pH-activatable photosensitizers and/or pH-activatable fluorescence probes, the electron transfer quenching by aromatic aniline unit(s) is used to realize the OFF state in the neutral condition. Therefore, we replaced a phenyl moiety of the TPP derivative with an aniline unit (N1, Figure 1) and demonstrated that N1 is applicable as a pH-activatable photosensitizer. Furthermore, we have also synthesized porphyrins with three (N3) and four (N4) aniline units to optimize the pH responses (Figure 1). We found that N3 showed a sharp pH response and very high ON/OFF switching ratio. Received: May 18, 2016 Revised: June 23, 2016 Published: June 24, 2016 5554

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Figure 1. Molecular structures of the studied photosensitizers.

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EXPERIMENTAL SECTION

sample solutions at the excitation wavelength (355 nm) was set to 0.1. DFT Calculations. Density functional theory (DFT) calculations were performed using Gaussian 09 at the B3LYP level with the 6-31G(d) basis set.

Materials. The detailed synthesis procedures for N0, N1, N3, and N4 (Figure 1) are presented in the Supporting Information. Briefly, N,N-dimethylamino-2,6-dimethylbenzaldehyde was synthesized according to the procedure reported by Killoran et al.35 N1 was synthesized using N,N-dimethylamino-2,6-dimethylbenzaldehyde, mesitaldehyde, and pyrrole via similar procedures reported by Lindsey et al.36 N0, N3, and N4 were also synthesized using a similar procedure. Dimethyl sulfoxide (DMSO), water, ethanol (EtOH), methanol (MeOH), acetonitrile (MeCN), and N,N-dimethylformamide (DMF) were used as solvents. Hydrochloric acid was used as an acid. Measurements. UV−vis absorption spectra were recorded on a Hitachi U3310 spectrophotometer. Fluorescence emission and excitation spectra were measured using a Horiba FluoroMax 4p fluorescence spectrometer. The fluorescence quantum yields were determined using an absolute photoluminescence (PL) quantum yield spectrometer (Hamamatsu C9920-02). The fluorescence lifetimes were measured using a Horiba FluoroCube (nano-LED-390 [388 nm], pulse width 1.2 ns, repetition rate 1 MHz). For the phosphorescence measurements of singlet oxygen, 355 nm light from a Nd3+:YAG laser (Tokyo Instruments Lotis II, 1.0 mJ/pulse, pulse width 8 ns, repetition rate 10 Hz) was used as the excitation light source. Phosphorescence was detected using a photomultiplier tube for the NIR region (Hamamatsu R5509-42) after dispersion with a monochromator (Ritsu MC-10N, blaze wavelength: 1250 nm, slit width 0.7 mm). The signals from the photomultiplier tube were fed to a digitizing oscilloscope (Tektronix, TDS-380P). The absorbance of the

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RESULTS AND DISCUSSION ON/OFF Switching of N1. The pH-activatable photosensitizer was designed based on DFT calculations. To suppress the photosensitization, a phenyl moiety of the TPP derivative was replaced by an aniline unit (N1, Figure 1). Figure 2a shows the energy levels of the molecular orbitals of N1. In the HOMO of N1, the electron was localized on the aniline moiety; this orbital is called HOMOA in this paper. The electron in the second HOMO of N1 was localized in the porphyrin moiety; thus, this orbital is called HOMOP in this paper. These findings indicate that the conjugation between the porphyrin and aniline moieties is expected to be negligible. The electron in the LUMO of N1 was localized in the porphyrin moiety (LUMOP in this paper). The energy level of HOMOA was higher than that of HOMOP; thus, HOMOA is expected to transfer an electron to HOMOP after the excitation of the porphyrin moiety. This electron transfer process is thought to quench the first excited singlet (S1) state to produce the charge-transfer (CT) state, and the quantum yield of the fluorescence and photosensitization of 1 O2 may be low (an OFF state, Figure 3). In the acidic condition, the aniline moiety should be protonated to form N1-H+. The energy levels of the molecular orbitals of N1-H+ are also shown in Figure 2b. The energy levels of the HOMOP and LUMOP of N1-H+ were almost the same as those of N1. Meanwhile, as a 5555

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Figure 2. Energy levels of the molecular orbitals of (a) N1 and (b) N1-H+ calculated by DFT (B3LYP 6-31G(d)).

Figure 3. Expected mechanism of the ON/OFF switching of the photosensitization of singlet oxygen (1O2) induced by pH change.

result of the protonation, the energy of HOMOA decreased below that of HOMOP. This finding suggests that the electrontransfer quenching does not proceed, and the quantum yield of the fluorescence and photosensitization of 1O2 may be recovered (an ON state, Figure 3). Therefore, we synthesized N1 as a pH-activatable photosensitizer and N0 (Figure 1) as a control molecule. UV−vis absorption and fluorescence spectra of N0 and N1 were recorded in the mixed solvent of dimethyl sulfoxide (DMSO) and water (9:1 v/v) at room temperature (Figures 4a and 4b, solid lines), as these photosensitizers are not soluble in water. The absorption spectrum of N1 is almost the same as that of N0, indicating that the electronic interaction between the aniline and porphyrin moieties of N1 is negligibly small, as expected. This negligible interaction may be due to the

perpendicular structure between the aniline and porphyrin moieties. The fluorescence of N0 was observed with peaks at 647 and 717 nm, and the fluorescence quantum yield Φf was determined to be 0.048, which is on the same order as that of TPP (Φf = 0.091). However, the fluorescence intensity of N1 was much smaller than that of N0, despite their nearly identical fluorescence peaks. The Φf value of N1 was determined to be 0.002 in this solvent, indicating that the S1 state of N1 is quenched by the aniline moiety. To clarify this quenching mechanism, the solvent effects were studied. Figure 5a shows the fluorescence spectra of N1 in various solvents. The absorbance of these solutions at the excitation wavelength (419 nm) was set to 0.10. The fluorescence intensity strongly depends on the solvent used, though the spectral shape does not. Figure 5b presents the fluorescence intensity of N1 as a function of the dielectric 5556

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function with a lifetime of 12.4 ns, which is similar to that of TPP (10.3 ns1). In the case of N1, a very fast fluorescence decay was observed, almost reaching completion within the time resolution of our instrument (ca. 0.5 ns). Thus, the rate constant of the electron-transfer quenching is expected to exceed 2 × 109 s−1, indicating that electron-transfer quenching proceeds efficiently in DMSO/water (9:1 v/v). Because the electron-transfer quenching by the aniline moiety is expected to suppress intersystem crossing to the T1 state and the photosensitization of 1O2, the photosensitization efficiency was investigated. Figures 4c and 4d show the phosphorescence spectra of 1O2 sensitized by N0 and N1, respectively (open circles). The phosphorescence intensity observed for N1 was much smaller than that observed for N0, indicating that N1 is in an OFF state in the neutral DMSO/water (9:1 v/v). The absolute quantum yield of 1O2 sensitization ΦΔ was determined to be 0.03 and 0.74 for N1 and N0, respectively, using perinaphthenone as a standard (ΦΔ = 0.9837). The ΦΔ value of N1 was 16-fold lower than that of N0. Next, the effects of acid on the absorption and fluorescence spectra were studied (Figures 4a and 4b). The fluorescence intensity of N1 was increased by adding 0.06 M HCl, whereas the fluorescence spectral shape was not affected. The absorption spectrum of N1 at this acid concentration was almost the same as that in the neutral condition. In the case of N0, no change was observed in either the absorption or fluorescence spectrum. These findings indicate that the activation of the fluorescence was achieved by adding the acid; i.e., ON/OFF fluorescence switching is possible for N1. Therefore, N1 may be applicable as a pH-activatable fluorescence probe. To confirm the ON/OFF switching of the photosensitization, the phosphorescence spectra of 1O2 were measured with and without the acid (Figures 4c and 4d, respectively). Acid addition increased the phosphorescence intensity of 1O2 in the case of N1 but not N0. Therefore, we successfully demonstrated that N1 is applicable as a pH-activatable photosensitizer. To clarify the mechanism of the ON/OFF switching, the acid concentration dependence was studied in detail (Figure 6a).

Figure 4. Absorption and fluorescence spectra of (a) N0 and (b) N1 in DMSO/water (9:1 v/v) without (broken line) and with HCl (0.06 M, solid line) at room temperature. The solution absorbances at the excitation wavelength (419 nm) were set to 0.10. Phosphorescence spectra of singlet oxygen sensitized by (c) N0 and (d) N1 in DMSO/ water (9:1 v/v) without (open circles) and with HCl (0.06 M, filled circles) at room temperature. The N1 solution absorbances at the excitation wavelength (355 nm) were set to 0.10.

Figure 5. (a) Fluorescence spectra of N1 in EtOH, MeOH, MeCN, DMF, and DMSO at room temperature. The N1 solution absorbances at the excitation wavelength (419 nm) were set to 0.10 for each solvent. (b) Fluorescence intensity at 649 nm as a function of the solvent dielectric constant.

Figure 6. (a) Fluorescence quantum yield of N0 (open circles) and N1 (filled circles) in DMSO/water (9:1 v/v) as a function of minus common logarithm of [HCl] (−log[HCl]). (b) The N1 solution absorbances at the excitation wavelength (419 nm) were set to 0.10. Molar ratio of the protonated form of N,N,3,4-tetramethylaniline in DMSO/water (9:1 v/v) as a function of the acid concentration.

constant of the solvent (εsolv). The fluorescence intensity decreased with increasing εsolv. The electron transfer from the aniline to porphyrin moieties is expected to be faster in polar solvents because of the stabilization of the CT state. Thus, this result supports the electron-transfer quenching mechanism. We attempted to determine the rate constant of the electron-transfer quenching by fluorescence lifetime measurements. The fluorescence decay of N0 could be analyzed using a single-exponential

The fluorescence quantum yield Φf of N1 was 0.002 in the neutral condition, as described above. With increasing acid concentration, Φf increased gradually and peaked (Φf = 0.034) 5557

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dependence of Φf of N1 could be analyzed based on its K1 of 3.8 × 10−3 M (pK1 = 2.4) and Kp of 2.1 M2 (pKp = −0.33) in DMSO/water (9:1 v/v). In this analysis, we assumed that the fluorescence quantum yield of H2N1-H+ is zero because the fluorescence quantum yield of the protonated form of tetraphenylporphyrin derivative was much smaller than that of the free base form. By using these acid dissociation constants, the molar ratio of N1, N1-H+, and H2N1-H+ was estimated and compared with the acid concentration dependence of the fluorescence quantum yield of N1 (Figure S1). The fluorescence quantum yield well corresponds to the molar ratio of N1-H+. The acid dissociation constant K1 of N,N,3,4-tetramethylaniline was also estimated to be 2.3 × 10−3 M (pK1 = 2.6) in DMSO/water (9:1 v/v) by a similar analysis. This value is similar to the K1 value of N1. N,N,3,4-Tetramethylaniline is soluble in water, and the acid dissociation constant K1 of N,N,3,4-tetramethylaniline was estimated to be 6.3 × 10−3 M (pK1 = 5.2) in water. Therefore, the pK1 of N1 is expected to be approximately 5.0 in water, if N1 can be dissolved in water. Because the pH of lysosome is approximately 5, N1 is expected to be partially activated in lysosome. The protonation process of N0 is shown in Scheme S1, and the molar ratio of N0 is described by eq S1. The Kp of N0 was also estimated to be 0.11 M2 (pKp = 1.0). Thus, the Kp of N1 is greater than that of N0, which may be due to the electrostatic repulsion between N1-H+ and H+. Based on the fitting curve of the acid concentration dependence of Φf for N1 shown in Figure 6a, the maximum Φf of 0.031 was estimated to occur at −log[HCl] = 0.81. Based on the Φf of N1 in the neutral condition (0.002), the ON/OFF switching ratio was estimated to be 16. This value indicates that a desirable ON/OFF switching ratio can also be obtained for porphyrin derivatives as well as other pH-activatable photosensitizers.23−25,27,28 The sharpness of the ON/OFF switching response curve of N1 will be discussed later. Based on the fitting curve of the acid concentration dependence of Φf, the maximum Φf was obtained at −log[HCl] = 0.81, and 10% of the maximum Φf was obtained at −log[HCl] = 3.80. Based on these values, the acid concentration change required to change Φf by a factor of 10 (Δlog[HCl]10) was estimated to be 2.99. This value is considered to be large, while smaller Δlog[HCl]10 values are desirable for the application of pH-activatable photosensitizers to PDT.

at −log[HCl] = 0.92. To determine whether this OFF → ON switching is induced by the protonation of the aniline moiety, the protonation of the N,N,3,4-tetramethylaniline was studied by UV−vis absorption spectroscopy. N,N,3,4-Tetramethylaniline shows an absorption band at around 300 nm, and its intensity decreased upon acid addition due to the protonation of the amino group. By analyzing this absorption spectral change, the molar ratio of the protonated form was estimated (Figure 6b). The protonation of N,N,3,4-tetramethylaniline was observed in the −log[HCl] region of 1.0−4.0, which is similar to the region of the Φf change for N1. This finding supports the hypothesis that the protonation of the aniline moiety of N1 suppresses the electron-transfer quenching of the S1 state of the porphyrin moiety to induce the ON/OFF switching of fluorescence. The fluorescence lifetime of N1 was also estimated as 12.5 ns in 0.06 M HCl. This lifetime is much longer than that of N1 in the neutral condition (less than 0.5 ns) and is similar to that of N0 (12.4 ns). This finding also supports the hypothesis that the protonation of the aniline moiety of N1 suppresses the electrontransfer quenching of the S1 state of the porphyrin moiety. Below −log[HCl] = 0.9, the Φf value of N1 decreased with increasing acid concentration, and a similar decrease was also observed for N0 (Figure 6a). It is known that the pyrrole nitrogens of porphyrin are protonated in strongly acidic solutions.38 The UV−vis absorption spectra of N0 and N1 in the strongly acidic condition were similar to that of the protonated form of tetra(p-carboxyphenyl)porphyrin (a doubly charged diacid).38 Thus, both the aniline moiety and pyrrole nitrogens of N1 are considered to be protonated, and the formation of this triprotonated molecule causes Φf to decrease below −log[HCl] = 0.9 (Scheme 1). Quantitative analysis was also conducted. The protonation processes of N1 are shown in Scheme 1. The monoprotonated N1 (N1-H+) is in an ON state, and the molar ratio of N1-H+ can be described by the following equation: K p[H+] [N1‐H+] = [N1]0 K1K p + K p[H+] + [H+]3

(1)

where [N1]0 is the initial concentration of N1, K1 is the acid dissociation constant of the aniline moiety, and Kp is the acid dissociation constant of the pyrrole nitrogens. The acid concentration Scheme 1. Protonation Processes of N1

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A similar analysis was also conducted for N4 using a similar set of assumptions. A good fitting was obtained using a K1 of 3.8 × 10−3 M, K2 of 0.01 M, K3 of 0.026 M, K4 of 0.044 M, and Kp of 7.0 M2 (Figure 7c). From this fitting curve, the Δlog[HCl]10 of N4 was estimated to be 1.64. Based on these analyses, it is concluded that the sharpness of the ON/OFF switching response curve is higher for N3 and N4 than for N1. The switching sharpness of N4 is similar to that of N3, but the acid dissociation constant in the final protonation step (formation of an ON state) is higher for N4 than for N3; i.e., switching requires a higher acid concentration for N4. Therefore, we concluded that N3 is a more promising pH-activatable photosensitizer for PDT applications. Finally, the ON/OFF switching ratio will now be discussed. Surprisingly, the fluorescence of N3 in the neutral condition was negligibly small. Thus, the ON/OFF switching ratio was estimated to be 100. In the case of N4, weak fluorescence was observed in the neutral condition, and the ON/OFF switching ratio was estimated to be 20. Based on these results, N3 possesses both a sharp pH response and an extremely high ON/OFF switching ratio. Thus, we concluded that N3 is the best pH-activatable photosensitizer among the candidates investigated in this study.

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CONCLUSIONS The fluorescence and photosensitization efficiencies of singlet oxygen exhibited by amino-substituted tetraphenylporphyrin derivatives could be controlled by adjusting the acid concentration. Furthermore, the fluorescence quantum yield of the monoamino-substituted derivative N1 decreased by increasing the dielectric constant of the solvents. This decrease could be explained by the quenching of the first excited singlet state by the electron transfer from the aniline to the porphyrin moiety. The quantum yield of the singlet oxygen sensitization of N1 was also very low in polar solvents. These fluorescence and photosensitization quantum yields were recovered by adding acid. The change in acid concentration required to change Φf by a factor of 10 (Δlog[HCl]10) was estimated to be 2.99, and the pK1 of N1 in water was expected to be approximately 5.0. To improve the pH response, triamino (N3)- and tetraamino (N4)-substituted derivatives were also synthesized. Strong acid concentration dependencies were observed for the fluorescence and photosensitization of N3 and N4, and the Δlog[HCl]10 of N3 and N4 were both 1.64. Thus, ON/OFF switching is possible under a smaller pH change for N3 and N4. In addition, the ON/OFF switching ratio of N3 was found to be extremely high. Therefore, amino-substituted tetraphenylporphyrin derivatives are promising pH-activatable photosensitizers for PDT.

Figure 7. Relative fluorescence (filled circles) and photosensitization (open circles) quantum yield of (a) N1, (b) N3, and (c) N4 in DMSO/water (9:1 v/v) as a function of minus common logarithm of [HCl] (−log[HCl]). The photosensitizer solution absorbances at the excitation wavelengths (419 nm for the fluorescence measurements, 355 nm for the photosensitization measurements) were set to 0.10.

photosensitization is similar to that of the fluorescence, supporting the idea that the ON/OFF switching of photosensitization is induced by the suppression of the electron transfer in the S1 state of N1. ON/OFF Switching of N3 and N4. The photosensitization of N1 can switch from an OFF to an ON state upon acid addition, but the ON/OFF switching response curve was broad. To improve the sharpness of the ON/OFF switching response curve, we also studied TPP derivatives with three and four aniline moieties (N3 and N4). In the case of N3 and N4, the protonation of the aniline moieties is multistep, and the photosensitization efficiency is only recovered when all the aniline moieties are protonated (Scheme S1). In these cases, a sharp response is expected. The acid concentration dependencies of the quantum yields of the fluorescence and photosensitization of N3 and N4 are shown in Figures 7b and 7c, respectively. For both N3 and N4, the acid concentration dependencies of the photosensitization quantum yield are similar to those of the fluorescence quantum yield, similarly to the case of N1 (Figures 7b and 7c). Therefore, the ON/OFF switching of photosensitization is also induced by the suppression of the electron transfer in the S1 state. Based on the protonation processes shown in Scheme S1, the molar ratio of the photosensitizer in an ON state can be described by the eqs S2 and S3 for N3 and N4, respectively. Because of the impractically high number of fitting parameters for N3, the acid concentration dependence of N3 was analyzed by various K1 and K2 values. Thus, we assumed that the K1 of N3 is similar to that of N1 (3.8 × 10−3 M), and K2 is intermediate between the K1 and K3 values because of the electrostatic repulsion between the protonated N3 and proton. Based on these assumptions, a good fitting was obtained using a K1 of 3.8 × 10−3 M, K2 of 0.01 M, K3 of 0.026 M, and Kp of 2.6 M2 (Figure 7b). From this fitting curve, the Δlog[HCl]10 of N3 was estimated to be 1.64.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.6b05019. Detailed synthesis procedures for N0, N1, N3, and N4; protonation processes of N0, N3, and N4 (Scheme S1); molar ratios of photosensitizers in an ON state for N0, N3, and N4 (eqs S1−S3) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*(H.H.) E-mail [email protected], Tel +81 277 30 1241. Notes

The authors declare no competing financial interest. 5559

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ACKNOWLEDGMENTS This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture Sports, Science, and Technology (MEXT) of the Japanese government. H.H. also thanks the Element Innovation Project and Gunma University Medical Innovation Project of Gunma University.

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DOI: 10.1021/acs.jpca.6b05019 J. Phys. Chem. A 2016, 120, 5554−5561

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DOI: 10.1021/acs.jpca.6b05019 J. Phys. Chem. A 2016, 120, 5554−5561