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Biological and Medical Applications of Materials and Interfaces

Utilizing Intramolecular Photoinduced Electron Transfer to Enhance Photothermal Tumor Treatment of Aza-BODIPY-Based NIR Nanoparticles Yunjian Xu, Teng Feng, Tianshe Yang, Huanjie Wei, Huiran Yang, Guo Li, Menglong Zhao, Shujuan Liu, Wei Huang, and Qiang Zhao ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b03568 • Publication Date (Web): 20 Apr 2018 Downloaded from http://pubs.acs.org on April 20, 2018

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ACS Applied Materials & Interfaces

Utilizing Intramolecular Photoinduced Electron Transfer to Enhance Photothermal Tumor Treatment of Aza-BODIPY-Based NIR Nanoparticles Yunjian Xu,†, || Teng Feng,†, || Tianshe Yang,† Huanjie Wei,† Huiran Yang,† Guo Li,† Menglong Zhao,† Shujuan Liu,†,* Wei Huang,†,‡,* and Qiang Zhao†,* †

Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory

for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts & Telecommunications, 9 Wen yuan Road, Nanjing 210023, China. E-mail: [email protected], [email protected]. ‡

Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU),

Xi'an 710072, P.R. China. E-mail: [email protected]. ||

Y. J. Xu and T. Feng contributed equally to this work.

KEYWORDS: intramolecular photoinduced electron transfer, photothermal agent, azaBODIPY, photothermal therapy, photoacoustic imaging

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ABSTRACT

Photothermal therapy (PTT) as a kind of noninvasive tumor treatment has attracted increasing research interest. However, the efficiency of existing PTT agents in the near-infrared (NIR) region is the major problem that has hindered further development of PTT. Herein, we present an effective strategy to construct the efficient photothermal agent by utilizing an intramolecular photoinduced electron transfer (PeT) mechanism, which is able to dramatically improve photothermal conversion efficiency in NIR region. Specifically, a NIR dye (A1) constructed with dimethylamine (DMA) moiety as electron donor and aza-BODIPY core as electron acceptor is designed and synthesized, which can be used as a class of imaging-guided PTT agents via intramolecular PeT. After encapsulation with biodegradable polymer DSPE-mPEG5000, nanophotothermal agents with small size exhibit excellent water solubility, photostability and longtime retention in tumor. Importantly, such nanoparticles exhibit excellent photothermal conversion efficiency of ~35.0%, and the PTT effect in vivo still remains very well even with a low dosage of 0.05 mg kg-1 upon 808 nm NIR laser irradiation (0.5 W cm-2). Therefore, this reasonable design via intramolecular PeT offers a guidance to construct excellent photothermal agents and subsequently may provide a novel opportunity for future clinical cancer treatment.

1. Introduction Cancer is a major disease that threats the survival of human across the world as the migration of cancer cells.1 Therefore, cancer treatment is at the forefront of all human concern. Traditional methods for cancer treatment including surgery,2,3 chemotherapy,4-7 and radiotherapy,8-10 however, have high potential for accessional damages to healthy cells and tissues. For example,


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surgery as invasive therapy usually leads to serious harm to organism. Chemotherapy can result in severe side effect, such as naupathia, emesis, etc. Radiotherapy may lead to excessive radiation. Hence, photothermal therapy (PTT), as a noninvasive tumor therapy method, has attracted tremendous research interest in recent years.11-14 In PTT, photothermal agents can convert the absorbed light into thermal energy to ablate localized cancer cells.15-18 Generally, ideal photothermal agents should have strong absorption and excellent photothermal conversion in the near-infrared (NIR) region, which allows deep-tissue therapy.4 Image-guided photothermal therapeutic platforms exhibit superiority of precision therapy in photo-regulated cancer therapy, because they can visualize the tumor before and during the therapy. These therapeutic platforms can improve the therapeutic accuracy, decrease the side effects and subsequently boost the therapeutic effects.19,20 Image-guided PTT agents mainly contain two parts, namely imaging and photothermal therapeutic units. However, the incorporation of additional imaging agent within PTT agents can result in a binary or more complex composition. It is highly desired to construct a facile platform with one component that can provide synergistic effect of both cancer imaging and photothermal therapy. When compared to those of conventional optical imaging, photoacoustic imaging (PAI), a nonionizing and noninvasive imaging technique, takes advantage of NIR light excitation and ultrasonic instead of optical detection for deeper imaging depth and higher spatial resolution with three-dimensional images.21-25 Especially, PA signal is produced by photon absorption and thermoelastic expansion.26,27 Therefore, PA signal and photothermal effect can be synergistically bound into theranostics for boosting the tumor therapy accuracy and subsequently improve tumor therapeutic effects.28,29 Up to now, many photothermal agents including organic dyes,30-33 metallic nanoparticles,34-39 and porphysomes,40,41 have been used for PAI-guided PTT. For


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example, inorganic nanotubes or nanorods have been widely used as excellent PTT agents due to their high NIR absorption and photothermal conversion efficiency.42 For organic dyes, they exhibit easily tunable chemical structures and optical properties. Hence, nanoparticles based on NIR organic dyes are also promising candidates as theranostic agents with PA imaging and PTT capabilities.43-49 However, the poor photothermal conversion efficiency, photostability and water solubility of existing organic dyes have been the major hurdles that have hindered their practical applications.50,51 Aza-BODIPY derivatives are an important class of organic dyes, and show high absorbance and easily tunable absorption from visible to NIR region.52-57 Moreover, when compared to BODIPY dyes with the similar structure, aza-BODIPY exhibit the longer-wavelength absorption,58,59 which makes them as promising PTT agents. However, most aza-BODIPY derivatives display non-negligible radiative transition and poor water solubility. The nonnegligible radiative transition can generally result in the generation of ﬂuorescence,43 which, of course, impairs nonradiative transition and subsequently decrease photothermal conversion efficiency. These features hinder aza-BODIPY as PTT agent for biomedical application in vivo. As far as we know, only few works have been reported about aza-BODIPY derivative as PTT agent for tumor treatment.60,61 Therefore, new and effective strategies to develop efficient photothermal agent based on aza-BODIPY dyes are highly desirable. In this work, we propose an effective strategy to construct the efficient photothermal agent by utilizing an intramolecular PeT mechanism. PeT is defined as an electron transfer process from a donor to an acceptor, leading to the formation of a charge separated state composing of the radical ions of the donor and the acceptor.62,63 Especially, intramolecular PeT is believed to be responsible for the quench of fluorescence.64 Therefore, it is beneficial for the nonradiative


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transition process and facilitates the photothermal conversion. As a proof of concept, herein, we designed and synthesized an aza-BODIPY dye (A1) with excellent photothermal performance. Aza-BODIPY core as electron acceptor was conjugated with electron-donating dimethylamine (DMA) unit to construct the NIR dye A1 (Scheme S1). Intramolecular PeT process in A1 can be demonstrated by theoretical calculation, steady-state and time-resolved photoluminescence (TRPL) spectra. These results confirm that intramolecular PeT mechanism helps to increase nonradiative decay probability and consequently offers more opportunity to improve photothermal conversion efficiency. Furthermore, encapsulation of hydrophobic A1 with amphiphilic polymer DSPE–mPEG5000 can obtain water-dispersible nanoparticles A1-NPs. This class of aza-BODIPY-based nanotheranostic agent exhibits the enhanced resistance to photobleaching, negligible dark toxicity and preferable tumor retention. Finally, the nanotheranostics agent has been used for imaging-guided cancer treatment, showing excellent PAI performance and improved PTT effect for tumor ablation.

2. Results and Discussion 2.1. Design Strategy of Aza-BODIPY Intramolecular photoinduced electron transfer (PeT) usually increases the non-radiative transition probability, which is beneficial for the improvement of photothermal conversion efficiency. To study how the intramolecular PeT enhances the photothermal conversion efficiency of aza-BODIPY, we introduced electron-donating DMA unit into aza-BODIPY core (as electron acceptor), and synthesized a NIR dye A1. We investigated the molecular energy levels and photophysical properties by theoretical calculation, steady-state and time-resolved photoluminescence spectra. In addition, dye A2 without DMA unit was also synthesized as a


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control compound. The synthetic routes and chemical structures of A1 and A2 were shown in Scheme S1, and the compounds have been fully characterized by the mainly methods, including NMR and MS spectra. We first investigated the energy levels of A1 and A2 by theoretical calculations. As is shown in Figure 1a, the highest occupied molecular orbital (HOMO) energy level of benzene was calculated to be -6.75 eV, which is lower than that of aza-BODIPY core (-5.18 eV). However, the energy level of HOMO for DMA unit was calculated to be -4.90 eV, which is well within those of HOMO (-2.97 eV) and the lowest unoccupied molecular orbital (LUMO) (-5.18 eV) of aza-BODIPY core. Thereby, the energy levels of DMA and aza-BODIPY dye are ideally aligned to promote intramolecular PeT. That helps to decrease radiative transition probability and consequently reduce fluorescence quantum yield, as well as increase nonradiative transition probability and offer more chance for photothermal conversion. Furthermore, the energy gap between the HOMO and LUMO of A1 (calculated as 1.93 eV) was lower than that of A2 (2.06 eV). Comparing to that of A2, the energy gap of A1 was narrower, which is in accordance with the red-shift of absorption (Figure 2c). As expected, after conjugated with DMA, A1 showed weak emission (Figure 1d), and the radiative quantum yields (QYs) of A1 was smaller in comparison to that of A2. In addition, the relative photoluminescence QYs of A2 and A1 are measured to be 0.068 and 0.003, respectively. The TRPL measurement also confirmed the intramolecular PeT in A1. The photoluminescence lifetimes were measured to be 4.5 ns for A2 and 1.4 ns for A1, respectively (Figure 1b). Thus, the lifetime of A1 was shorter than that of A2. In addition, A1 exhibited the smaller rate constant of radiative transition (kr = 2.1 × 106 s-1) and the larger rate constant of nonradiative transition (knr = 7.2 × 108 s-1) compared with that of A2 (kr = 1.5 × 107 s-1, knr = 2.4 × 108 s-1). Furthermore, under the same condition, A1 showed the


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higher temperature change, suggesting the enhanced photothermal effect (Figure S1). Taken together, the above results revealed that the intramolecular PeT process occurs between DMA moiety and aza-BODIPY, resulting in the enhanced nonradiative decay probability. Hence, the excited-state energy of A1 could be consumed through the nonradiative decay channel, showing improved photothermal conversion efficiency. 2.2. Synthesis and Characterization of A1-NPs A1 is insoluble in water, which is not suitable for biomedical applications. Hence, we convert A1 into hydrophilic nanoparticles by enveloping it with amphiphilic polymer DSPE–mPEG5000 according to the previous work.65 From the transmission electron microscopy (TEM) images (Figure 2a), we can see that A1-NPs were dispersed well, which show an average diameter of ~43.0 nm. Dynamic light scattering (DLS) also confirmed the well dispersion of A1-NPs in PBS with size distribution centered at 60.1 nm (Figure 2b). Compared to TEM result, the slightly larger diameter measured from DLS is related to the core and the swollen corona of the nanoparticles. The size distribution of A1-NPs changed slightly within 24 hours in PBS (Figure S2), showing good stability in aqueous solution. The ultraviolet-visible (UV-Vis) absorption spectrum of A1 in N,N-dimethyl formamide (DMF) is shown in Figure 2c. Two absorption bands are observed at visible region of 653 nm and NIR region of 788 nm with high molar absorption coefficients, which is 47500 mol-1 cm-1 for 653 nm, and 44800 mol-1 cm-1 for 788 nm, respectively. Upon formation of blue-green solution of A1-NPs (Figure 2d), the absorption spectrum shows the obviously red-shifted and broadened absorption bands for NIR region compared to that of A1 in DMF. This result can be attributed to the aggregation with π–π stacking formed within the micellar cores. The result also


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helps to the strong intramolecular charge transfer characteristics for both the ground state and excited state of A1, which is consistent with previous reports.65 For PTT application, the photostability of PTT agent should be considered firstly. Thus, the photostability of A1-NPs was investigated by monitoring the absorbance decrease of absorption peak upon 808 nm laser irradiation. As shown in Figure S3, the maximal absorption intensity of the free A1 decreased to almost half of initial value after 808 nm laser irradiation for 20 min with laser power of 0.3 W cm-2 (Figure S3a). Compared to free A1, the maximal absorption of A1NPs in PBS showed negligible decrease even with the laser power up to 1.0 W cm-2, suggesting the excellent photostability of A1-NPs. This result may be due to the protection of polymer DSPE-mPEG5000. Thus, the excellent stability and water solubility made A1-NPs as promising photothermal agent used in vivo. 2.3 Photothermal and Photoacoustic Properties of A1-NPs Owing to the excellent light absorption and photostability of A1-NPs in the NIR region discussed above, A1-NPs could be used as excellent photothermal agent to convert NIR light into local heat. Next, the photothermal property of A1-NPs was examined by monitoring the temperature change of A1-NPs in PBS solution vs sample concentration (0-30 µM) or vs laser power (0.1-0.7 W cm-2) under 808 nm laser irradiation. As shown in Figure 3a, with the increase of NIR laser power from 0.1 to 0.7 W cm-2, the temperature amplitude of the A1-NPs solution elevated from 8.5 to 33.0 °C after 7 min irradiation. That showed a clear power-densitydependent temperature increasing. The temperature of the A1-NPs in PBS solution elevated with the concentration of A1-NPs increasing, at given laser power of 0.5 W cm-2. The increase value of temperature was 8.4, 15.7, 20.1 and 28.3 °C for the A1-NPs concentration at 5, 15, 20 and 30 µM, respectively (Figure 3b), which is higher than that of A1 in PBS, respectively (Figure S4).


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While no obvious temperature increase was monitored for the control sample of PBS only. That was to say, the temperature of 20 µM A1-NPs solution could increase up to 55 °C after laser irradiation for 7 min, which could effectively burn tumor cells, given that the original temperature is 35 °C.66-68 To further study the photothermal conversion efficiency, a photothermal generation-dissipation curve was recorded and depicted in Figure S5 and S6. Then the photothermal conversion efficiency of A1-NPs was calculated to be ~35.0%. Compared with free A1, which was calculated as ~25.0%, A1-NPs exhibited superior photothermal property. The excellent photothermal stability of A1-NPs was further confirmed, even with the higher laser power (0.6 W cm-2), in about four cycles of laser irradiation within 80 min (Figure 3c). That helped for photo-irradiation repeatedly in the process of photothermal therapy. The high photothermal conversion efficiency and photothermal stability of A1-NPs made them a promising photothermal agent. Besides, due to their strong NIR light-absorption and photothermal effect, the PA signals of A1-NPs at 815 nm were measured vs concentration in PBS. A linear change of PA intensity with increasing sample concentration was obtained (Figure 3d). The inset showed the PA intensity images of A1-NPs with different concentrations in PBS. These results provided the chance to quantitatively analyze the distribution of photothermal agents, which indicated that A1-NPs were suitable as contrast agent for PA imaging. 2.4 Cytotoxicity Assay and PTT of A1-NPs in Vitro In order to explore the biomedical application of A1-NPs in vivo, we first investigated cell uptake of samples and their potential cytotoxicity. We incubated HeLa cells with A1-NPs and free A1 at the concentration of 10 µM for 4 h, respectively. Then the cell imaging was measured using confocal laser scanning microscope. As shown in Figure 4a-4f, the images showed weak


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fluorescent signal in the cytoplasm, indicating that A1-NPs and free A1 could be taken in by HeLa cells. The potential cytotoxicity of A1-NPs to tumor cells was tested by standard methyl thiazolyl tetrazolium (MTT) assay. HeLa cells were incubated with different concentrations of A1-NPs for 24 h. Then their relative viabilities were monitored (Figure 4g). Cell viability kept 85% even with the concentration of 100 µM, which revealed that A1-NPs showed negligible dark cytotoxicity to HeLa cells below 100 µM. However, free A1 showed a considerable cytotoxicity to HeLa cells. When HeLa cells were incubated with free A1 at a concentration of 75 µM, the cell viability decreased to 60%. The low cytotoxicity of A1-NPs might be attributed to biological friendly polymer DSPE-mPEG5000, and the negligible dark cytotoxicity to HeLa cells of A1-NPs made them as promising agents for biological application. In order to choose ideal laser power for the next biological experiments, MTT assay was performed to study the relative cell viabilities after treatment by different laser power without or with A1-NPs incubation. As shown in Figure 4h, it demonstrated that the decreased cell viabilities were observed with increasing NIR laser irradiation after they were incubated with 20 µM of A1-NPs, while the cell viabilities without A1-NPs incubation showed little change. For example, HeLa cells treated with A1-NPs even decreased to 40% of original number when the laser power reached up to 0.5 W cm-2, while HeLa cells with laser irradiation only still reached up to 90% of original number. The concentration of A1-NPs at 20 µM and the laser power of 0.5 W cm-2 were chosen for our next cell experiments. Considering the excellent cell uptake and photothermal efficiency of A1-NPs, the PTT of A1NPs in vitro was further carried out. Fluorescence live/dead cell labelling imaging was used to visualize the PTT process. Apoptotic cells were labelled with green emissive annexin V-FITC,


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while dead cells were stained with red emissive propidium iodide (PI). The group treated with the A1-NPs plus laser irradiation acted as the positive control. The group treated with A1-NPs only, laser irradiation only or PBS only acted as the negative control. As shown in Figure 5a-5j, as expected, in both the light only and A1-NPs only groups, no obvious apoptotic and dead cells could be observed, suggesting that laser irradiation only or A1-NPs incubation had little destruction to the cells. When the cells were incubated with A1-NPs and exposed to laser, the images showed green and red signal, indicating that most of cells in the laser irradiated region were apoptotic or dead. As expected, these results were in consistence with the MTT assay results shown in Figure 4h, suggesting excellent photothermal effect of A1-NPs under irradiation of NIR light. In addition, cells beyond the region of the laser edge remained alive (Figure 5d, 5h, 5i, 5j), which further confirmed the negligible dark cytotoxicity of A1-NPs to HeLa cells. Furthermore, flow cytometry experiments were also carried out to measure the photothermal effect of A1-NPs to HeLa cells. The experimental conditions were similar to those above. In both the laser irradiation only and A1-NPs only groups, only 1.56% and 3.23% Hela cells were dead, respectively (Figure 5l, 5m). The results further indicated that laser and samples showed negligible dark toxicity to HeLa cells. For the group subjected to A1-NPs plus laser irradiation, the percentages of dead cells and apoptotic cells were above 60.00% (Figure 5n), which was consistent with the results of MTT assay and cell imaging experiments. These results collectively revealed that A1-NPs were highly efficient PTT agents. 2.5 Photothermal and Photoacoustic Imaging of A1-NPs in Vivo On the basis of the photothermal and photoacoustic effects of A1-NPs under NIR irradiation, we next tested the retention of A1-NPs in the tumor site by photothermal and photoacoustic imaging. BALB/c mice bearing tumor were intratumorally injected with PBS (as control) and


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A1-NPs (0.05 mg kg-1), and irradiated under 808 nm laser at 0.5 W cm-2. The temperature variation of tumor site was recorded by an IR thermal camera, as shown in Figure 6a. The temperature of the tumor injected with PBS only increased to 40 ± 1 °C with 808 nm laser irradiation for 5 min. The temperature of the tumor part injected with A1-NPs increased rapidly to 53 ± 1 °C under the same condition, indicating their excellent photothermal conversion performance. Even 15 days later, the temperature of tumor could still reach to 50 ± 1 °C, showing the long-time retention of A1-NPs in tumor. The long-time retention of A1-NPs in tumor was further confirmed by PA imaging. We carried out the PA imaging for A1-NPs within tumor site in mice. Mouse intratumorally injected with A1-NPs showed an enhanced PA signal, comparing with that of the mouse intratumorally injected with PBS. After 15 days, obvious PA signals could still be observed, further confirming the long-time retention of A1-NPs in tumor. In vivo PA imaging ability makes A1-NPs promising theranostics agent for imaging guided photothermal therapy. 2.6 Photothermal Therapy in Vivo Inspired by the excellent photothermal efficiency and long-time retention of A1-NPs in tumors, PTT efficacy in vivo on HeLa tumor bearing mice was further studied. When the tumor volume reached 200 mm3 or so, we randomly divided 12 BALB/c mice with HeLa tumor into 4 groups, including experimental group (A1-NPs plus laser irradiation) and control groups (blank group for PBS only, irradiation control group for laser only, and material control group for A1-NPs only). PTT efficacy in vivo was monitored by NIR laser irradiation on tumor site (808 nm, 0.5 W cm-2, 5 min) every day. In general, tumor cells were damaged when their local temperature was higher than 42 °C. On the basis of the result of photothermal imaging (Figure 6), the temperature of tumor sites of mice treated with A1-NPs rapidly increased to be high enough to


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ablate tumor with 808 nm laser irradiation for 5 min. We measured the variation of tumor size every day after treatment. As shown in Figure 7a, an obvious growth inhibition of tumor was observed for the mice treated with A1-NPs and 808 nm laser irradiation after 15 days. And the black burn marks, as well as negligible size in naked eye were located at tumors. The tumors of each group were taken out after the PTT for 15 days (Figure S8). The tumors in the other three groups all grew in size of 2~4 times volume comparing with the initial tumor after 15 days (Figure 7a, 7c). The body weights of all mice were monitored every day during the PTT period (Figure 7b). During the period of 15 days, the body weight of all the mice exhibited similar increase, indicating the low side effects of A1-NPs injection or laser irradiation at 0.5 W cm-2 to mice. All the results showed that A1-NPs had low side effects in vivo and excellent photothermal effect to tumors. And A1-NPs could serve as an effective photothermal agent for imaging-guided photothermal therapy of tumor. 2.7 Ex Vivo Histology Examination To further assess the potential toxicity of A1-NPs in vivo, the pathomorphology study of the tumor and major organs (heart, liver, spleen, lung, muscle, kidneys) were carried out by hematoxylin and eosin (H&E) staining for one mouse of each group after 15 days. As shown in Figure 8, the tumor cells shrank and the interspace between cells increased in the tumor with A1-NPs and NIR laser irradiation. The results suggested the extensive necrosis of tumor, which was resulted from apoptosis damaged by heat from A1-NPs. The results above were in accordance with the fact that the photothermal performance of A1-NPs in vitro could also lead to cells shrink (Figure S7), which were in line with previous reports.71,72 In addition, no obvious necrosis was observed in the other three control groups, revealing negligible toxicity of laser radiation or A1-NPs to tumors. For the major organs, the histochemical results of PTT


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administration all showed no obvious abnormality compared with the other three control groups. It verified that A1-NPs had low side effects in vivo in the PTT period.

3. Conclusion In summary, a new strategy was proposed to construct the aza-BODIPY-based efficient NIR photothermal agent by utilizing an intramolecular PeT mechanism. As a proof of concept, dye A1 was constructed by conjugating DMA moiety with aza-BODIPY core. PeT mechanism in A1 has been examined by theoretical calculation, steady-state and time-resolved photoluminescence, revealing that the enhanced nonradiation results in high photothermal conversion efficiency. Furthermore, nano-photothermal agents A1-NPs was fabricated by encapsulating A1 with biodegradable polymer DSPE-mPEG5000, which exhibits small size, excellent water solubility and photostability, and negligible dark cytotoxicity. As its broad and strong NIR photoabsorption, A1-NPs also show excellent photoacoustic signal. Through photothermal and photoacoustic imaging, it was confirmed that A1-NPs have a long-time retention in tumor. Moreover, A1-NPs achieved effective tumor ablation through photothermal therapy with a NIR wavelength laser (808 nm, 0.5 W cm-2) at a low dosage 0.05 mg kg-1 in vivo after intratumoral injection of A1-NPs. Meanwhile, our results verify that A1-NPs have low side effects in vivo in photothemal therapy period. Therefore, it has great potential as theranostics agent in nanomedicines. More importantly, based on the intramolecular PeT mechanism of this work, the development of other highly efficient theranostics agent in NIR region can be predictable. And our further work will focus on multifunctional nano-platform based on aza-BODIPY for multimode imaging guided in vivo therapy including PTT, photodynamic therapy, and drug delivery.


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4. Experimental 4.1. Experimental Information The details of materials, instruments and methods, cell culture and imaging and so on can be found in Supporting Information. 4.2. Synthesis of A1 and A1 Nanoparticles (A1-NPs) Synthesis of intermediate products and A2 were described in the Supporting Information. Synthesis and characterization of N-BODIPY-DMA (A1). A mixture of dry CH2Cl2 (0.25 mL)/dry diisopropylethylamine (DIEA) (0.7 mL), aza-dipyrrin c1 (0.17 g, 0.20 mmol) and BF3·OEt2 (0.39 mL, 3.12 mmol) were reacted at room temperature for overnight. Then column chromatography with 60% CH2Cl2/petroleum ether gave the blue-green solid A1 0.16 g (Yield: 89 %). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.08 (d, J = 8.4 Hz, 4H), 8.02 (d, J = 8.4 Hz, 4H), 7.00 (d, J = 8.0 Hz, 4H), 6.82 (s, 2H), 6.79 (d, J = 8.4 Hz, 4H), 4.20 (t, J = 4.8 Hz, 4H), 3.89 (t, J = 4.8 Hz, 4H), 3.76 (t, J = 4.4 Hz, 4H), 3.71-3.67 (m, 8H), 3.56 (t, J = 8.4 Hz, 4H), 3.39 (m, 3H),3.08 (m, 3H).

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C NMR (100 MHz, CDCl3) δ (ppm): 160.46, 156.85, 150.89, 145.11,

143.02, 131.11, 130.73, 125.12, 121.33, 114.91, 114.57, 114.93, 71.94, 69.65, 67.45, 59.05, 40.27, 29.69, 18.97. MALDI-TOF-MS m/z: 907.46. Aza-BODIPY NPs with water solubility was obtained referring to previous report.69,70 The solution of A1 (2.0 mg in 2 mL THF) was quickly poured into 10 mL DSPE-mPEG5000 (5.0 mg) aqueous solution under sonication. The solution was blown by argon on the surface to clean up THF at 45 oC, then obtained a bright blue-green aqueous solution. The aqueous solution was concentrated with a centrifugal-filter at 5000 r for 5 min repeated several times. The resultant


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products were concentrated and stored at 4 oC in PBS (pH = 7.4) and filtered through a 0.22 µm filter for next experiments. The diagram of concentration-dependent absorption of A1 in CH2Cl2 was obtained via a pointto-point method. To dry 1 ml of A1-NPs solutions, and to get the absorption of dry A1-NPs in 1 ml CH2Cl2. Then, the final concentration of A1-NPs solution was obtained as 2.5 × 10-4 mol L-1.

ASSOCIATED CONTENT Detailed description about instruments, testing methods and cell experiments; Synthetic procedure, NMR and MS results of A2 and intermediate products; Absorption spectra of A1, A2 and A1-NPs; Photothermal conversion performance of A1, A2 and A1-NPs; Photothermal therapy of cancer cells in vivo and vitro. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected].

Author Contributions ||

Y. J. Xu and T. Feng contributed equally to this work.

Notes


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The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (51473078, 21501098, 21671108 and 21401108), National Program for Support of TopNotch Young Professionals, Scientific and Technological Innovation Teams of Colleges and Universities in Jiangsu Province (TJ215006), and Priority Academic Program Development of Jiangsu Higher Education Institutions (YX03001).


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Figure 1. Schematic illustration of intramolecular PeT. (a) The highest occupied molecular orbital and lowest unoccupied molecular orbital of BODIPY core, N,N-dimethylaniline part, benzene, A1 and A2, respectively. (b) Time-resolved photoluminescence decay at the specific emission ranges. The optical excitation is performed with 630 nm pump pulses. (c) Absorption spectra of samples in toluene with a concentration of 10 µM. The dashed shows the excitation position at 630 nm. (d) Photoluminescence spectra of samples in toluene (10 µM). The relative intensities are normalized by the absorbance values at 630 nm.


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Figure 2. Characterization of A1-NPs. (a) TEM image of A1-NPs. (b) DLS examination for size distribution of A1-NPs in PBS (pH = 7.4). (c) UV-Vis absorption spectra of A1 in DMF (black line) and A1-NPs (red line) in PBS (pH = 7.4) (10 µM). (d) Photographs of A1 in DMF and PBS, and A1-NPs in PBS (pH = 7.4) (20 µM).


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Figure 3. Photothermal and photoacoustic studies of A1-NPs. (a) Temperature rise after 7 min laser irradiation for A1-NPs solutions (20 µM) of different laser powers. (b) Temperature rise after 7 min laser irradiation (808 nm, 0.5 W cm-2) of different concentrations of A1-NPs and PBS. (c) Photothermal stability study of A1-NPs solution (20 µM, 808 nm, 0.6 W cm-2). The starting temperature above of the solution before the light irradiation is 20 oC. (d) Photoacoustic signal amplification for A1-NPs of different concentrations (0, 5, 25, 50, 75, 100 and 200 µM). Inset: The photograph of photoacoustic signal for A1-NPs solutions of different concentrations.


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Figure 4. In vitro cell experiments. Confocal microscopy images of HeLa cells incubated with A1-NPs (10 µM) or A1 (10 µM) for 4 h. (a) and (d) are the corresponding bright field images of fluorescent images (b) and (e), respectively. (c) is the overlap of (a) and (b). (f) is the overlap of (d) and (e). All the images shared the same scale bar of 30 µm. Images were taken at 25 °C. (g) Relative viability of cells incubated with various concentrations of A1-NPs or A1. (h) Relative viability of HeLa cells after incubated with A1-NPs (20 µM) or not for 4 h, and then treated with laser irradiation by 808 nm laser for 5 min.


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Figure 5. The photothermal therapy of HeLa cells in vitro. The HeLa cells were treated with PBS (a, e), A1-NPs only (b, f), laser only (c, g), A1-NPs plus laser (d, h), respectively. And then they were stained by Annexin V-FITC/propidium iodide (PI). (i) is the overlap of (d) and (h). (j) is the image of marked segments. All the images shared the same scale bar of 300 µm. Images were taken at 25 °C. (k-n) Flow cytometry quantification of annexin V-FITC and PI-labeled HeLa cells treated with PBS, A1-NPs only, laser only, A1-NPs plus laser, respectively. (20 µM, 808 nm, 0.5 W cm-2, 5 min).


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Figure 6. Photothermal and photoacoustic imaging of A1-NPs in HeLa tumor mice. (a) Temperature recording of HeLa tumor mice treated with PBS or A1-NPs upon 5 min laser exposure, respectively. (b) Representative photos of HeLa tumor mice at different days after 5 min laser exposure (808 nm, 0.5 W cm-2). (c) Photoacoustic signals of HeLa tumor mice at different days after 5 min laser exposure (808 nm, 0.5 W cm-2). The tumor sites are marked by the segments in imaginary line.


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Figure 7. Photothermal therapy in vivo. (a) Representative photos of HeLa tumor mice at different days after treatment. Change of (b) body weight and (c) tumor volume during therapy.


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Figure 8. H&E stained images of tumors and major organs (heart, liver, spleen, lung, and kidney) for different groups. All the images shared the same scale bar of 300 µm. Images were taken at 25 °C.


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