BODIPY Derivatives for Photodynamic Therapy

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BODIPY Derivatives for Photodynamic Therapy: Influence of Configuration versus Heavy Atom Effect Jianhua Zou,† Zhihui Yin,† Kaikai Ding,† Qianyun Tang,† Jiewei Li,† Weili Si,† Jinjun Shao,† Qi Zhang,*,‡ Wei Huang,*,† and Xiaochen Dong*,† †

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Centre for Advanced Materials (SICAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China ‡ School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China S Supporting Information *

ABSTRACT: Heavy atom effect and configuration are important for BODIPY derivatives to generate singlet oxygen (1O2) for photodynamic therapy. Herein, a series of BODIPY derivatives with different halogens were synthesized. 1O2 quantum yields (QYs) and MTT assay confirm that incorporation of more heavy atoms onto dimeric BODIPY cannot effectively enhance the 1O2 QYs. Rather, the dark toxicity increases. This phenomenon can be attributed to the competition of heavy atom effect and configuration of dimeric BODIPY. In addition the BODIPY derivative with two iodine atoms (BDPI) owns the highest 1O2 QYs (73%) and the lowest phototoxicity IC50 (1 μM). Furthermore, an in vivo study demonstrates that BDPI NPs can effectively inhibit tumor growth and can be used as a promising threanostic agent for photodynamic therapy in clinic. KEYWORDS: BODIPY, heavy atom effect, configuration, Hela, photodynamic therapy

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BODIPY derivatives also show high 1O2 QYs. For example, Akkaya et al. reported the design of BODIPY derivatives to achieve high 1O2 QYs. The derivatives with orthogonal configuration went through excited states coupling and generating triplets efficiently.29,30 However, the highest 1O2 QYs is only 51%, and there is still much space to improve the 1 O2 QYs for better PDT efficacy. Nevertheless, the relationship between the heavy atoms and structural configuration on the effect of 1O2 QYs of the photosensitizers is not clear. It is of great importance to design the BODIPY derivatives to exhibit high 1O2 QYs, low dark toxicity for PDT, as well as to illuminate the competition of heavy atoms effect and configuration. Herein, a series of BODIPY derivatives with one or two BODIPY units connected with a benzene ring and their corresponding halogenated (Br and I) derivatives have been designed and synthesized (Scheme 1). Di-iodinated BDPI presents the highest 1O2 QY of 73% with the lowest half maximal inhibitory concentration (IC50) of only 1.0 μM on Hela cells. More heavy atoms were incorporated onto the dimeric BODIPY, and MTT assay indicated that the dark toxicity of BBDPI NPs is much higher than that of BDPI NPs

INTRODUCTION Contemporary society bears the burden of cancer, and a growing number of individuals die of cancer every year. Therefore, it is urgent that more therapies should be developed to treat cancer. Among the multiple therapies against cancer, photodynamic therapy (PDT) is a promising one due to its advantages of low systemic damage, noninvasion, and controllable characteristics. Thus, various photosensitizers have been developed for PDT.1−12 Among these photosensitizers, boron dipyrromethene (BODIPY) derivatives are recognized as potential candidates for dual-use as bioimaging and PDT therapeutic agents owing to their excellent photostability and high molar extinction coefficient. 13−27 These BODIPY derivatives, however, usually suffer from low singlet oxygen (1O2) quantum yield (QYs, ΦΔ), which is one key factor to determine the performance of photosensitizers. As is widely acknowledged, heavy atoms are able to enhance the spin−orbital coupling (SOC) and thus facilitate the intersystem crossing (ISC) rate and improve the 1O2 QYs of photosensitizers, which is called “heavy atom effect”.12,17,20,28 In addition, the iodine atom shows higher efficiency than the bromine atom does in most cases.14 To design BODIPY derivatives for highly efficient photosensitizers, it is common to incorporate halogen atoms for efficient triplet-sensitization. Rational design of the BODIPY configuration is another approach to enhance the 1O2 QYs. Heavy atom free dimeric © XXXX American Chemical Society

Received: May 31, 2017 Accepted: September 6, 2017 Published: September 6, 2017 A

DOI: 10.1021/acsami.7b07569 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces Scheme 1. Synthetic Routine for BODIPY Derivativesa

a

(i) (a) 2,4-dimethylporrole, DCM. (b) NEt3, BF3·OEt2. (ii) NBS, CHCl3/HOAc (3:1). (iii) NIS, CHCl3/HOAc (3:1). was determined by colorimetric MTT assay. A solution of 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in distilled water (5 mg/mL, 20 μL) was added to each well followed by incubation for 4 h under the same conditions at 37 °C. Then the medium was discarded and 200 μL of DMSO was added. At ambient temperature, the plate was agitated on a Bio-Tek microplate reader before the absorbance at 490 nm was measured. The average absorbance of the blank well (no cells) was subtracted from the readings of the other wells. The cell viability was then determined by the following equation: viability (%) = {∑[(Ai/Acontrol) × 100]}/n, where Ai is the absorbance of the corresponding data (i = 1, 2, 3, ..., n), Acontrol is the average absorbance in control wells where the nanoparticles were absent, and n is the data points. Cellular Uptake and Fluorescence Image of Cellular ROS. Hela cells were incubated with BDPI NPs (0.6 μg/mL, 2 mL) in a confocal dish for different times (24 h) in the dark, the mother liquid was discarded, and the cells were washed with PBS (3 mL), followed by the addition of 1 mL of polyoxymethylene for 25 min. Then polyoxymethylene was discarded, and the cells were washed with PBS for three times. The sample with BDPI NPs for 24 h was further incubated with 10 μM of 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) for another 3 min, which was washed with 1 mL of PBS three times. This sample was irradiated by xenon lamp (>510 nm, 40 mW/cm2) for 3 min. The fluorescence images were observed by an Olympus IX 70 inverted microscope. For the samples with BDPI NPs for 24 h and they were excited at the wavelength of 540 nm and collected fluorescence from 550 to 600 nm. While the one was incubated with DCF-DA under irradiation, it was excited with a 488 nm laser and collected fluorescence from 490 to 600 nm. In Vivo Tumor Treatment Histology Examination and Bioimage. The animal ethic approval was obtained from Animal

while its photo toxicity is lower than that of BDPI NPs. Moreover, in vivo study demonstrates that BDPI NPs exhibit high phototoxicity, low dark toxicity, as well as good biocompatibility.

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EXPERIMENTAL SECTION

Materials and Apparatus. All chemicals were purchased from Sigma and used without further purification. The 1H NMR and 13C NMR spectra were recorded on Bruker DRX NMR spectrometer (500 MHz) in CDCl3 solution at 298 K with solvent residual (CDCl3, δ = 7.26 ppm) as the internal standard. UV−vis spectra were recorded on a spectrophotometer (UV-3600 UV−vis−NIR, Shimadzu, Japan). The fluorescence spectra were measured on an F-4600 spectrometer (HITACHI, Japan). Preparation of BODIPY Derivatives Nanoparticles. The nanoparticles of the six compounds were prepared by reprecipitation. Taking BDPI as example, 200 μL of BDPI (5 mg/mL−1) in tetrahydrofuran (THF) was added into 5 mL of water under vigorous stirring at room temperature. After the mixture was stirred for 20 min, THF was removed by nitrogen bubbling. BDPI NPs in the solution were obtained by centrifugation. Cell Culture and MTT Assay. Hela cell lines (Institute of Biochemistry and Cell Biology, SIBS, CAS (China)) were cultured in a regular growth medium consisting of Dulbecco’s modified Eagle’s medium (DMEM, Gibco), supplemented with 10% fetal bovine serum under an atmosphere of 5% CO2 at 37 °C. Cell viability assays of the nanoparticles of the six compounds were first dissolved in distilled water, which were diluted with DMEM to various concentrations and put in the 96-well plate, respectively. Then the 96-well plate was irradiated with a xenon lamp (40 mW/cm2) for 8 min. Cell viability B


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ACS Applied Materials & Interfaces

Figure 1. (a) Normalized absorption spectrum of BDPI in DCM and its NPs in water. (b) Normalized emission spectra of BDPI in DCM and its NPs in water. (c) The absorbance degradation of DPBF under Xe lamp irradiation of BDPI. (d) Linear fitting of absorbance degradation.

Table 1. Summary of Absorption, 1O2 QYs, and IC50 of Compounds 1-6

Center of Nanjing Medical University (NJMU, Nanjing, China) for pharmacokinetic study (SCXK-2012−004). Fifteen nude mice were purchased and then injected with Hela cells into the armpit as the tumor source. When the tumor volume reached about 100 mm3, the mice were divided into three groups randomly. Groups I and II were tail vein injected with BDPI NPs (60 μg/mL, 100 μL) in PBS solution, respectively. Similarly, group III was injected with saline in the same way as the control one. After 24 h, the tumors of the first and third group were irradiated by xenon lamp for 8 min while the mice in the second group were not irradiated exceptionally. The process above was conducted for 20 days, the tumor volume and body weight of mice was recorded every 2 days. These nude mice were killed followed by histology analysis. The main organs (heart, liver, spleen, lung, and kidney) and the tumor from each mouse was isolated and fixed in 4% formaldehyde solution. After dehydration, the tissues were embedded in paraffin cassettes and stained with hematoxylin and eosin (H and E), the images were recorded on a microscope. The bioimages of tumor, heart, liver, spleen, liver, and kidney were recorded on PerkinElmer IVIS Lumina K.

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compound

abs in DCM (nm)

BDP BDPBr BDPI BBDP BBDPBr BBDPI

501 527 533 502 528 540

1

O2 QYs (%)

IC50 (μM)

0.8 31 73 7.1 47 68

77 5.2 1 53 3.3 2.8

known compounds, while compounds 5 and 6 are new compounds. Figures 1a and S1 show the absorption spectra of the six compounds. The maximum absorption of BDP is 501 nm, while that of BBDP is 502 nm, indicating the two BODIPY units are not conjugated so well and a great distortion angle exists between the two BODIPY units. After incorporation of halogen atoms, the absorbance shows a red-shift of 26 and 32 nm for the brominated and iodinated BODIPY, respectively. This phenomenon maybe comes from the fact that Br- and Iatoms can serve as an electron acceptor to conjugate with BODIPY core and result in a corresponding red shift. While the heavier iodine atom shows a little stronger electron-accepting ability than bromine atom does, the iodinated BODIPY presents more red-shift than the brominated one. The 1O2 QYs of the six compounds were quantitatively measured by using DPBF (1,3-diphenylisobenzofuran) as the probe and methylene blue (ΦΔ = 0.57 in DCM) as the standard.20 As shown in Figure 1c, it can be seen that the absorbance of DPBF degrades gradually under the irradiation of

RESULTS AND DISCUSSION

Scheme 1 shows the synthetic routines of the six BODIPY compounds. Generally, reactions of benzoyl chloride or terephthaloyl chloride with 2,4-dimethylporrole in DCM, followed by the addition of triethylamine and BF3·OEt2 give BDP or BBDP. Then, BDP or BBDP were treated with NBS (N-bromosuccinimide) and NIS (N-iodosuccinimide) in a mixture of CHCl3/HOAc, respectively, to obtain halogenated BDPBr, BDPI, BBDPBr, and BBDPI, respectively. The structures of these compounds were confirmed by 1HNMR, 13 C NMR spectra, and mass spectroscopy. Compounds 1−4 are C


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Figure 2. (a) TEM image of BDPI NPs. (b) DLS result of BDPI NPs. (c) 1O2 QYs of compounds 1−6 in DCM. (d) IC50 results of compounds 1−6 by MTT assay on Hela cells.

phenomenon can be explained by “heavy atom effect” as mentioned before. However, it is supposed that after incorporation of more Br or I atoms onto BBDP may further improve the 1O2 QYs. On the contrary, the 1O2 QYs of BDPI with two I atoms can reach 73%, which is higher than that of BBDPBr (47%) with four Br atoms or even that of BBDPI (68%) with four I atoms. It can be concluded that two more heavy atoms incorporated is not effective enough to improve the 1O2 QYs. To verify these results and investigate the cell toxicity and biocompatibility of the six compounds, MTT (3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay were performed. To improve the water solubility, a reprecipitation method was applied to achieve hydrophilic nanoparticles (NPs). Compared with the spectrum of BDPI in DCM, its NPs in water present a red shift of 27 and 32 nm for the maximum absorption and emission spectra, respectively (Figure 1b). The absorption spectra of BDP, BDPBr, BBDP, BBDPBr, and BBDPI in DCM are shown in Figure S1a,b, while those of their NPs are shown in Figure S1c,d, respectively. Transmission electron microscopy (TEM) image and dynamic light scattering (DLS) results show that the BDPI NPs have spherical morphology with the diameter of approximate 45−160 nm (Figure 2a,b). DLS of NPs of BDP, BDPBr, BBDP, BBDPBr, and BBDPI show similar size distribution (mean diameter ∼130 nm; Figure S4). To investigate the stability of BDPI NPs, time dependent DLS were reported (Figure S5a−f). It can be found that BDPI NPs are stable because negligible diameter change was observed even at 48 h. Figure S5g−h are the DLS of BDPI NPs in PBS and saline, which indicate that such NPs are also stable toward PBS and saline. High phototoxicity is crucial for a photosensitizer used as a PDT agent. As expected, IC50 of BDP NPs is the highest (Figure S6a, 25 μg/mL), while that of BDPI NPs is the lowest (0.6 μg/mL), which is consistent with the results of the 1O2 QYs mentioned above. BBDPI NPs have relatively low IC50 (Figure S6e, 3 μg/mL), but it shows considerable dark

Figure 3. (a) Cellular uptake of BDPI NPs in Hela cells (0.6 μg/mL). (b) Fluorescence images of Hela cells incubated with BDPI NPs with DCF-DA as probe under light irradiation. Scar bar: 10 μm.

a Xe lamp. For example, the degradation slope of BDPI is around 0.0803 (R2 = 0.9995), indicating a linear degradation process. 1O2 QYs of such compounds were calculated and are listed in Table 1. For BDP, the 1O2 QY is 0.8%, which is almost negligible. This is a well-established fact that the nonhalogenated BODIPY has a very low ISC rate. For BBDP, two BODIPY units connected with one benzene ring presents singlet oxygen QYs of 7.1%, which is much higher than that of BDP but relatively lower than the reported orthogonal BODIPY dimer (46% and 21%).29 It is probably due to the distorted structure of BBDP, which could have excited states coupling, but not as efficient as the reported orthogonal BODIPY dimers. When the pyrrole hydrogen atoms in BDP are substituted with halogen atoms (Br- or I-), a dramatic increase of the 1O2 QYs is observed. The 1O2 QYs of BDPBr (31%) or BDPI (73%) is approximately 38- or 91-fold to that of BDP (0.8%), respectively. Similarly, an obvious increase of 1O2 QYs is observed for BBDPBr and BBDPI (Figure 2c). This D


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Figure 4. (a) MTT assay of BDPI NPs with different concentrations. (b) Tumor volume change during the treatment, pink arrows indicate injection. (c) Body weight change of the control, no illumination, and illumination groups.(d and e) H and E stained images of the tumor histologic section of control and no illumination group, respectively. (f) The mice tumors of the control group and no illumination group.

Figure 5. H and E stained images of main organs (heart, liver, spleen, lung, and kidney) of control, no illumination, and illumination groups, respectively.

toxicity at the same concentration of BDPI NPs (Figure S7). Therefore, it can be concluded that not all iodine atoms in BBDPI are effective for the generation of singlet oxygen. Instead, with more iodine atoms, the dark toxicity of the photosensitizer increases greatly.

Generally, heavy atom and orthorgonal configuration can enhance 1O2 QYs of the BODIPY. It can be assumed that incorporation of another BODIPY core onto the BDP makes BBDP undergo triplet generation effectively, thus increasing the 1 O2 QYs, but not so high as the reported one.29,30 For BDPBr, E


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and in vivo studies show BDPI NPs can efficiently inhibit tumor growth and may be a potential candidate for photodynamic therapy.

BDPI, BBDPBr, and BBDPI, incorporation of heavy atoms can enhance the SOC and thus facilitate the intersystem ISC and improve the 1O2 QYs. However, heavy atoms may also limit the distortion of cores, decreasing the ability of triplet generation of the four compounds. As a result, the 1O2 QYs of BBDPBr and BBDPI do not increase sharply. The phenomenon may be ascribed to the competition of the heavy atom and the molecular configuration of BODIPY derivatives. The heavier the halogen atom is and the more reduction of the 1O2 QYs BODIPY will show, the less effective the heavy atoms will be. All in all, BDPI NPs are the most promising candidate for clinical PDT application with high phototoxicity and low dark toxicity. To assess its suitability for PDT in vitro, cellular uptake of BDPI NPs was measured, as shown in Figure 3. It indicates that BDPI NPs could be used as an agent for cell imaging. A 2′,7′-dichlorofluorescein diacetate (DCF-DA) probe was selected to detect the singlet oxygen generation under the irradiation of 488 nm (the excitation wavelength of DCF-DA). It is found that BDPI NPs is able to generate singlet oxygen efficiently in vitro due to the observed strong fluorescence (Figure 3). The PDT efficacy of BDPI NPs in vivo were further investigated. Fifteen Hela tumor-bearing nude mice were divided into three groups, and BDPI NPs were injected into the no illumination and illumination groups, respectively. As shown in Figure 4b, the tumor volumes of the control group increase sharply, while that of the illumination-free group increased a little slowly due to the fact that inevitable irradiation of room light generate of 1O2 to inhibit the tumor growth. For the illumination group, the tumor volume remains almost unchanged for the first 6 days and began to decrease for the next 14 days. After treatment for 24 days, the tumor disappears. After another 6 days, no obvious tumors were observed, indicating the tumor growth can be inhibited completely. The mice after treatment are shown in Figure S8. The body weight change of mice indicates that the mice in the control group decrease while those in the no illumination and illumination groups increase, demonstrating the low dark toxicity and good biocompatibility of BDPI NPs (Figure 4c). The biodistributions of BDPI NPs in tumor, heart, liver, spleen, lung, and kidney is illustrated in Figure S9. It can be observed that BDPI NPs can still accumulate in the tumor and liver after injection of 24 h. The hematoxylin and eosin (H and E)-stained images of the tumor histologic section of control and no illumination group (Figure 4c,d) show the nuclei of the cells remain almost unchanged, suggesting its low dark toxicity. After treatment, these mice were sacrificed, and the tumors of the former two groups are shown in Figure 4f. No obvious difference between the images of the main organs (heart, liver, spleen, lung, and kidney, Figure 5) in no illumination and illumination groups were observed, indicating BDPI NPs cause little damage to normal tissues.19,21

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b07569. Associated experimental details, characterization of compounds 1−6, normalized absorption spectra of compounds 1−6 in DCM and their nanoparticles in distilled water (Figure S1). Degradation of DPBF at 414 nm under the irradiation of xenon lamp for (a) methylene blue, (b) BDP, and (c) BDPBr (Figure S2). Degradation and linear fitting of the absorption of DPBF at 414 nm under the irradiation of xenon lamp for (a) BBDP, (b) BBDPBr, and (c) BBDPI (Figure S3). DLS of the nanoparticles of (a) BDP, (b) BDPBr, (c) BBDP, (d) BBDPBr, and (e) BBDPI in distilled water (Figure S4). Time dependent DLS of BDPI NPs for (a) 2, (b) 4, (c) 6, (d) 12, (e) 24, and (f) 48 h in water, DLS of BDPI NPs in (g) PBS and (h) saline, respectively (Figure S5). MTT assay on Hela cells for the NPs of (a) BDP, (b) BDPBr, (c) BBDP, (d) BBDPBr, and (e) BBDPI (Figure S6). Cell viability of BDPI and BBDPI NPs at high concentration without irradiation (Figure S7). Photographs of tumor-bearing mice treated after 30 days (Figure S8). (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jinjun Shao: 0000-0001-6446-8073 Wei Huang: 0000-0001-7004-6408 Xiaochen Dong: 0000-0003-4837-9059 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work was supported by the NNSF of China (61525402, 61775095, and 61604071), Key University Science Research Project of Jiangsu Province (15KJA430006), and Natural Science Foundation of Jiangsu Province (BK20161012).

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CONCLUSIONS In summary, a series of BODIPY derivatives with one or two BODIPY cores were straightforwardly synthesized via two-pot reaction. The 1O2 QYs measurement indicate that too much heavy atoms cannot effectively improve the generation of 1O2, instead, high dark toxicity of the photosensitizer itself would be detected. The results were confirmed by MTT assay on Hela cells. BDPI has the highest 1O2 QYs (73%) and lowest IC50 on Hela cells (0.6 μg/mL), indicating a strong competition between configuration and heavy atom effect. Both in vitro F


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