Small-Molecule Porphyrin-Based Organic Nanoparticles with

May 23, 2019 - Herein, a new organic compound, [porphyrin–diketopyrrolopyrrole ... ONPs with high PCE demonstrated promising application in photoaco...
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Biological and Medical Applications of Materials and Interfaces

Small-Molecule Porphyrin-Based Organic Nanoparticles with Remarkable Photothermal Conversion Efficiency for in Vivo Photoacoustic Imaging and Photothermal Therapy Fengshou Wu, Li Chen, Liangliang Yue, Kai Wang, Kai Cheng, Jun Chen, Xiaogang Luo, and Tao Zhang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • Publication Date (Web): 23 May 2019 Downloaded from http://pubs.acs.org on May 24, 2019

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ACS Applied Materials & Interfaces

Small-Molecule

Porphyrin-Based

Organic

Nanoparticles

with

Remarkable Photothermal Conversion Efficiency for in Vivo Photoacoustic Imaging and Photothermal Therapy Fengshou Wu a*, Li Chena, Liangliang Yue,a Kai Wang,c* Kai Cheng,e Jun Chen,b* Xiaogang Luo, a and Tao Zhang d a

Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical

Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430072 P. R. China. E-mail: [email protected]; [email protected]. b

School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan,

430073, Hubei, P. R. China. E-mail: [email protected]. c

Hubei Callaborative Innovation Center for Advanced Organic Chemical Materials, Hubei

University, Wuhan, 430062 P.R. China. E-mail: [email protected]. d

MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of

Biophotonics, South China Normal University, Guangzhou, 510631, China. e

College of Life Science and Technology, Huazhong University of Science and Technology,

Wuhan, 430074, Hubei, P. R. China.

Abstract Near-infrared (NIR)-absorbing organic nanoparticles (ONPs) were emerging candidates for “one-for-all” theranostic nanomaterials with considerations of safety and formulation in mind. However, facile fabrication methods and improvements in the photothermal conversion efficiency and photostability are likely to be needed before a clinically viable set of candidates emerges. Herein, a new organic compound (Por-DPP) with donor-acceptor (D-A) structure was synthesized, where the porphyrin was used as a donor unit while diketopyrrolopyrrole as an acceptor unit. Por-DPP exhibited efficient absorption extending from visible to near-infrared regions. After self-assembling into nanoparticles (∼120 nm), the absorption spectrum of Por-DPP NPs broadened and red-shifted to some extent, relative to that of organic molecule. Furthermore, the architecture of nanoparticles enhanced the acceptor-donor structure, leading to emission quenching and facilitating nonradiative thermal generation. The photothermal conversion efficiency (PCE) of Por-DPP NPs was measured and calculated to be 62.5%, higher than most of ONPs. Under a 808 nm-laser irradiation, the Por-DPP NPs possessed a distinct PTT effect in vitro and can damage cancer cells efficiently in vivo without significant side effects after phototherapy. Thus, the small-molecule porphyrin-based organic nanoparticles with high PCE demonstrated the

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promising application in photoacoustic imaging-guided photothermal therapy.

Keywords: porphyrin, self-assembly, photoacoustic imaging, photothermal therapy, organic nanoparticles

Introduction Cancer has become a great challenge to human beings’ life and health in the world. The traditional cancer therapies, such as chemotherapy, surgery, and radiotherapy, often have serious side effects on cancer patients.1-3 Therefore, the personalized noninvasive treatment of tumor is highly desired. Phototherapy, such as photodynamic therapy (PDT) and photothermal therapy (PTT), is an emerging photo-induced cancer therapy.4,

5

Among them, PTT had gained great

interest owing to its harmless, safety and efficiency in cancer elimination,2,

6-10

as the thermal

effect is only produced under the irradiation of near-infrared light in the presence of therapeutic agents. Currently, the inorganic nanomaterials were the most widely used PTT agents, which contained noble metal nanomaterials nanomaterials

13, 14

11,

transition metal dichalcogenides

12,

and carbon

because of their high photothermal stability, intense absorption in the

near-infrared region and strong surface plasmon resonance (LSPR) effect.15 However, these typical non-biodegradable inorganic nanomaterials have some problems that could not be ignored, such as poor pharmacokinetics and potential long-term toxicity.16 Thus, it is urgent to develop PTT agents with good biosafety and remarkable photothermal conversion efficiency. Moreover, the nanoagents with efficient NIR-absorbing are ideal probes for photoacoustic (PA) imaging since they could generate sound waves under irradiation.17-21 Since both of the photoacoustic imaging and photothermal therapy are derived from the heat induced by near-infrared light radiation, a single platform that integrates PA imaging and PTT has promising applications in biomedical field.22, 23 Porphyrin derivatives were widely used for fluorescence imaging, PDT,24-28 and PTT because of their large extinction coefficients,29 good biocompatibility,30 and minor adverse effects on organisms.31,

32

However, the absorption maxima of many porphyrin derivatives are generally

below 700 nm,33 and they always showed deficient photostability in NIR treatment which limits their long-term use.34, 35 One of the efficient ways to overcome these problems is to redshift the Q band

absorption

to

near

800

nm

through

enhancing

their

π-conjugated

system.

Diketopyrrolopyrrole (DPP) derivatives36-38 were extensively used in electronic devices and fluorescence probes due to their high molar absorption coefficient and photostability, planar and conjugated structure39 and unique optical properties.40 With a typical electron-deficient feature,

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diketopyrrolopyrrole

could

conjugate

with

electron-donating

components

to

form

a

donor-acceptor (D-A) structure, which enhances their near infrared (NIR) absorption41 and semiconductive effect.42 In this contribution, herein the small-molecule porphyrin-based organic nanoparticles were developed and applied in photoacoustic imaging-guided photothermal therapy. Specifically, diketopyrrolopyrrole (DPP) as an electron acceptor was conjugated with porphyrin component to form an A-D molecule. Both porphyrin and DPP are independent fluorophores, which emitted red light upon exposure to a UV lamp (365 nm). The two molecules were linked through triple bonds, which increased the π-conjugated system. Through the reprecipitation method,43 the Por-DPP can spontaneously self-assemble into nanoparticles without adding any auxiliary reagents. The Por-DPP NPs dispersed well in aqueous solutions and showed very high photothermal conversion efficiency. Because of the small size of NPs, they could selectively enter tumor sites through enhanced permeability and retention effect.44 The cellular assays and animal experiments indicated Por-DPP NPs were promising nanoagents for photoacoustic imaging-guided photothermal cancer treatment. Por-DPP NPs exhibited several remarkable features, including (1) well-defined nanostructures derived from only one small molecule (porphyrin-DPP conjugate), (2) excellent theranostic properties with remarkable PCE (62.5%), and (3) simple preparation through self-assembly without adding any other reagents. Thus, the Por-DPP NPs were applied as excellent nanoagents for PAI-guided PTT against tumor, which will open a promising way for precision phototheranostics in (pre)clinic.

Results and Discussion

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Scheme 1. Schematic illustration of the preparation of Por-DPP NPs and their applications as theranostic agents for PAI-guided PTT (insets are the photographs of the THF solutions of organic compounds and the aqueous solution of Por-DPP NPs)

The detailed preparation methods of Por and DPP-Br were listed in supporting information. In Por, two triethylene glycol chains were introduced in the 10- and 20-meso positions of porphyrin to improve its hydrophilicity. Besides, the 5- and 15-meso positions of Por were conjugated with acetylene group to extend the π-conjugated system of porphyrin core, resulting in the enhancement of the absorbance in near-infrared region. The conjugate (Por-DPP) was synthesized through a Sonogashira coupling reaction between Por and DPP-Br with yield of 70%. Owing to the amphiphilic chemical structure, the porphyrin-DPP conjugate facilitated spontaneous assembly through π-π stacking to form a robust nanostructure, with a uniform size distribution. During the preparation of NPs, the solution color of intermediates gradually deepened. Finally, the tumor-bearing mice were intravenously injected with the as-prepared Por-DPP NPs for photoacoustic imaging and photothermal therapy (Scheme 1).

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Figure 1. (a) TEM image of Por-DPP NPs; (b) DLS profile of Por-DPP NPs in water; (c) Zeta potential of Por-DPP NPs in water; (d) Absorption spectrum of DPP, Por, and Por-DPP in DCM and Por-DPP NPs in water; (e) Fluorescence spectrum of DPP (λex= 530 nm), Por (λex= 420 nm), and Por-DPP (λex= 450 nm) in DCM and Por-DPP NPs (λex= 450 nm) in water; (f) Absorption spectrum of Por-DPP NPs before and after irradiation (808 nm, 1.5 W/cm2, 10 min).

The core of nanoparticle was formed through π-π stacking between porphyrin and DPP component, while the surface was covered by the alkyl chains and ether chains. The aqueous solution of Por-DPP NPs did not show any precipitation after 30 days at room temperature, confirming the good colloidal stability (Figure S1). The mean size of Por-DPP NPs was 120 nm as indicated by transmission electron microscope (TEM) and dynamic light scattering (DLS), respectively (Figures 1a, b). This small size of NPs facilitated their biomedical applications as they could passively target the tumor sites owing to the EPR effect. The zeta potential of Por-DPP NPs was -31.3 mV (Figure 1c). Thus, the negatively charged particles in aqueous solution will repel each other to form the stable colloids.45,

46

Moreover, comparing with DPP or Por, the

absorption spectra of Por-DPP broadened and red-shifted significantly, with maximum peak at 745 nm in dichloromethane. After formation to NPs, the Por-DPP NPs displayed an obvious bathochromic-shifted and broadened absorption in water, with maximum peak moving to 807 nm, probably due to the π-π aggregation of the organic conjugate (Figure 1d). Fluorescence spectrum (Figure 1e) showed that the donor-acceptor structure favored intramolecular electron transfer to quench the fluorescence and enhance the nonradiative heat generation. Thus, the strong absorbance of Por-DPP NPs around 800 nm is expected to yield high PCE for effective photothermal therapy. To evaluate the photostability of Por-DPP NPs, the absorption spectrum of

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Por-DPP NPs were recorded before and after 808 nm laser irradiation. As shown in Figure 1f, the absorption spectrum did not display any significant variation, indicating their remarkable photostability.

Figure 2. (a) Temperature elevation of Por-DPP NPs in water in dependence of concentration (808 nm, 1 W/cm2); (b) Optical graphs and thermal images of Por-DPP NPs in water at different concentrations; (c) Temperature elevation of Por-DPP NPs in water in dependence of power density (808 nm); (d) Photothermal effect of Por-DPP NPs in aqueous solution irradiated with 808 nm laser (1 W/cm2); (e) The cooling time versus negative natural logarithm of the temperature obtained from cooling period; (f) Temperature change of Por-DPP NPs for five irradiation/cooling cycles (1 W/cm2).

The photothermal effects of Por-DPP NPs were evaluated under irradiation of a 808-nm laser with the change of NPs concentration and laser intensity. After irradiation for 10 min with laser power density of 1.0 W/cm2, the pure water did not show any significant temperature change, while the temperature of Por-DPP NPs exhibited a concentration-dependent manner (Figure 2a). As recorded in the thermal images, the solution temperature of different concentrations (0-80 μg/mL) of Por-DPP NPs increased regularly under irradiation and a high value of 50.1 °C was observed in 600 s at a concentration of 80 μg/mL (Figure 2b). Meanwhile, the Por-DPP NPs displayed the laser-power-density-dependent temperature elevation properties, as shown in Figure 2c. Under a concentration of 40 μg/mL, the temperature of Por-DPP NPs increased by 32.3°C after irradiation at 1.5 W/cm2 for 600 s. As to a photothermal agent, PCE is a very important parameter to evaluate their PTT performances. Thus, the temperature changes of Por-DPP NPs were measured under laser irradiation at 1.0 W/cm2. When the solution of NPs was continuously

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irradiated for 10 min, the laser was turned off (Figure 2d). According to the cooling stage of NPs, the curve of cooling time (t) versus negative natural logarithm of the temperature driving force (-lnθ) was acquired (Figure 2e). The time constant (τ) for heat transfer of the system was calculated to be 363.6. Based on these obtained data, the photothermal conversion efficiency of Por-DPP NPs was determined to be 62.5%, higher than most reported inorganic or organic photothermal agents.47-51 Finally, to further evaluate the photothermal stability of PPT agent, the aqueous solution of Por-DPP NPs was irradiated for multiple cycles under a 808-nm laser. As indicated in Figure 2f, there were little changes of temperature after five heating/cooling stages, confirming high photostability of Por-DPP NPs, which were suitable for multiple PTT process.

Figure 3. (a) Viability of HeLa cells treated with various concentrations of Por-DPP NPs in dark or upon exposure to laser radiation (808 nm, 1 W/cm2, 3 min); (b) PA images of Por-DPP NPs upon excitation at 800 nm at different concentrations; (c) PA amplitudes of Por-DPP NPs at 800 nm as a function of concentration; (d) PA images of tumors tissue at different time points (0, 1, 4, 8, 12, 24 h) after intravenously injection of 100 µL Por-DPP NPs (100 μg/mL); (e) PA signal intensity of tumor tissues after intravenously injection at different times. The biocompatibility and photocytotoxicity of Por-DPP NPs against HeLa cells was evaluated. As shown in Figure 3a, the survival rate of HeLa cells was still over 89% at a maximum

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concentration of 60 μg/mL in dark, demonstrating the low cytotoxicity and good biocompatibility of Por-DPP NPs. Under irradiation for 3 min (808 nm, 1 W/cm2), the cell viability significantly decreased with the increase of Por-DPP NPs concentration, and only about 28% of HeLa cells remained viable when its concentration reached 60 μg/mL. The IC50 of Por-DPP NPs against HeLa cells under 808-nm laser irradiation was calculated to be 11.6 μg/mL. Encouraged by the efficient absorption in NIR region and distinct photothermal effects, we then studied the feasibility of Por-DPP NPs as PAI agents. As shown in Figure 3b, the PA image having 100 μg/mL Por-DPP NPs was significantly brighter than the control group without NPs, indicating its remarkable PA performance. The PA signal intensity of Por-DPP NPs increased with the concentration (0-100 μg/mL). Moreover, the PA amplitudes of Por-DPP NPs displayed a relatively linear correlation versus the NPs concentrations from 0 to 100 μg/mL (Figure 3c), enabling the quantitative analysis of PA signals. Next, we investigated the PA imaging of Por-DPP NPs in tumor-bearing mice. As shown in Figure 3d, there was weak PA signal before Por-DPP NPs administration at 0 h, probably assigned to the near infrared (NIR)-absorbing properties of endogenous melanin and hemoglobin. The PA brightness of tumor site significantly increased after intravenous injection of Por-DPP NPs, revealing that Por-DPP NPs can selectively accumulate the tumor site because of the efficient EPR effect. After injection for 8 h, the PA brightness of tumor site reached the maximum, illustrating that 8 h postinjection was the optimal time for next photothermal treatment. As depicted in Figure 3e, the PA signal intensity of tumor region was 13 at 8 h, which was 4.3-fold higher than that of background of tumor. Furthermore, the PA signal in tumor region was still evident after 24 h post-injection, revealing a long-term circulation of Por-DPP NPs in vivo. In addition, the infrared (IR) thermal imaging of Por-DPP NPs was also explored in vivo at different time points. As shown in Figure S2, the brightness of thermal images in tumor site increased from 1 to 8 h and decreased after 8 h postinjection, suggesting the highest enrichment time point is about 8 h, which was in good agreement with the results from PA imaging. The passive targeting property and a long-term circulation in vivo of Por-DPP NPs were probably ascribed to their appropriate nanoparticles size, improving the efficient EPR effect.52

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Figure 4. (a) IR thermal images of HeLa tumor-bearing mice after the injection of Por-DPP NPs intravenously and irradiated by laser (808 nm, 1.5 W/cm2); (b) Mean temperature of the tumor sites as a function of irradiation time (808 nm, 1.5 W/cm2). Laser irradiation was performed after injection of Por-DPP NPs or saline for 8 h; (c) Tumor volume of the mice in different treatment groups; (d) Body weight of the mice for various treatment groups. According to the PA imaging and IR thermal imaging results, the PTT effect in vivo was then evaluated, where the mice bearing HeLa tumor were intravenously injected with Por-DPP NPs. The mice were divided into four groups (four mice for each group) as follows: “Saline”, “Saline + Laser”, “Por-DPP NPs”, and “Por-DPP NPs + Laser”. For the groups with laser, the tumor site was irradiated (808 nm, 1.5 W/cm2) for 10 min at 8 h postinjection time point. The temperature of tumor site in “Por-DPP NPs + Laser” group raised from 31.2 to 60.8°C after 6 min irradiation and was maintained at 61 °C for the remaining time (Figure 4a, b), which was high enough to damage tumor cells. In comparison, the control group (“Saline + Laser”) just increased by 6°C (to 36.7 °C) under the same irradiation, indicating that Por-DPP NPs were an efficient PPT agent in vivo. After above treatments, the tumor volume and the changes of body weight of mice were measured every two days. During the treatment period, the “Por-DPP NPs” group was similar to that the “Saline” and “Saline + Laser” groups, which totally failed to inhibit the tumor growth (Figure 4c). Remarkably, the “Por-DPP NPs + Laser” group showed high antitumor efficacy, where the tumor site experienced cell necrosis, scab over, and abscission until spontaneous healing (Figure S3).

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Figure 4d showed that there was no significant difference of the mice weight in the period of 28 days, suggesting that Por-DPP NPs or laser irradiation alone had negligible side effect on mice. The graphs of HeLa tumor-bearing mice and tumor site in each group were recorded after 28 days of PTT treatment (Figure 5a). These results in vivo further confirmed the remarkable therapeutic effect of Por-DPP NPs under laser irradiation.

Figure 5. (a) Representative photo of the excised tumors for each group; (b) H&E staining of the heart, lung, spleen, kidney, and liver from different groups at 28 days after treatment. Scale bar is 100 μm. To evaluate the biocompatibility of the PTT treatment in vivo, the inside organs (heart, lung, liver, kidney, spleen) of mice were collected and stained with hematoxylin and eosin (H&E) at the end of observation. As shown in Figure 5b, there was no obvious pathological change or tissue denaturation in the main organs after injection of Por-DPP NPs and laser irradiation, suggesting its excellent biocompatibility and minor side effects for cancer therapy. Besides, the H&E staining of tumor slices from mice treated with different groups was also implemented. As shown in Figure S4, the nucleus of tumor cells were damaged significantly in “Por-DPP NPs + Laser” group, while the tumor tissues of other three groups were in good condition and well preserved, demonstrating the distinct therapeutic effect of Por-DPP NPs under laser irradiation.

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Figure 6. Blood test parameters (a) liver function; (b) blood analysis of mice from different groups followed by dissection at the indicated times (n = 4) for 7 days and 14 days. To further evaluate the potential toxicity of Por-DPP NPs in vivo, four groups of mice were sacrificed for serum biochemistry assay after 7 days and 14 days of treatment. As shown in Figure 6a, the liver function indicators (ALT and AST) and the function markers of kidney (BUN and CREA) did not show any significant changes, suggesting no obvious hepatic disorders of mice treated by “Por-DPP NPs + Laser”. The complete blood panel assay further verified the liver and kidneys were unaffected by “Por-DPP NPs + Laser” treatment in the short term. Moreover, there were no statistical differences in these indicators (WBC, LYM, HCT, Hgb, RBC and RDW) between “Por-DPP NPs + Laser” group and the other three groups (Figure 6b). Altogether, the Por-DPP NPs displayed excellent biocompatibility and could be applied as efficient nanoagents in PAI-guided PTT against cancers.

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Conclusions In summary, we synthesized a new small molecule by the conjugation between porphyrin and diketopyrrolopyrrole to enhance the near infrared (NIR) absorption. The synthesized porphyrin conjugate (Por-DPP) can spontaneously self-assemble into nanoparticles (Por-DPP NPs) without adding any extraneous vehicle and cargo because of its amphiphilic structure. Due to the characteristics of D-A structure, Por-DPP NPs displayed remarkable photothermal effect and the photothermal conversion efficiency was calculated to be 62.5%, higher than most reported inorganic or organic NPs. Moreover, the tumor site reached the maximum PA signal at 8 h post-injection, indicating Por-DPP NPs could passively target the tumor tissue owing to its efficient EPR effect. The excellent photothermal therapeutic performance of Por-DPP NPs was further confirmed in HeLa tumor-bearing mice. The potential toxicity assay suggested the high biocompatibility and minor side effects of Por-DPP NPs during the cancer treatment. Considering the advantages of excellent photothermal therapeutic performance, facile fabrication, high photo/phothermal stability, and good biocompatibility, the Por-DPP NPs will open a promising way for precision phototheranostics in (pre)clinic.

Materials and methods Materials and apparatus. The intermediates, Por and DPP-Br, were synthesized according to the previous work (see Supporting Information).53 The absorption spectrum was measured using UV-vis spectrophotometer (HP 8453). The photoluminescence spectrum was recorded on a spectrofluorometer (Perkin-Elmer LS 55). Dynamic light scattering was recorded by ZetaSizer (Malvern, USA). The TEM images were obtained from transmission electron microscope (JEM-2010F). Synthesis of Por-DPP. DPP-Br (64 mg, 0.11 mmol) and Por (24 mg, 0.25 mmol) were dissolved in triethylamine (10 mL) and anhydrous toluene (20 mL) under an atmosphere of nitrogen. Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) and CuI (4 mg, 0.01 mmol) were then added. The resulting solution was reacted at 80 oC for 3 days under these conditions. After the completion of reaction, the solvents were evaporated under vacuum. The residue was collected and purified by silica gel column chromatography (dichloromethane/methanol (60:1)) to obtain Por-DPP as a dark brown solid 18 mg (yield, 70%). 1H NMR (400 MHz, CDCl3): δ 9.45 (d, 4H, CH), 8.85 (s, 4H, CH), 8.52 (s, 4H, Ph-H), 8.09 (s, 6H, Ph-H and CH), 7.52 (s, 2H, CH), 7.32 (s, 2H, CH), 7.18 (s, 2H, CH), 6.7 (s, 2H, CH), 4.50 (s, 4H, CH2), 4.14 (s, 4H, CH), 3.80 (m, 28H, CH2), 2.01 (s, 2H, SH), 0.84 (s, 62H, CH2 and CH3). HRMS: m/z Calcd for C112H128N8O12S4Zn [M+H]+1970.7923, found 1970.7762. UV-Vis (DMF): λ= 457, 567, 743 nm. Preparation of Por-DPP NPs. To a solution of Por-DPP in tetrahydrofuran (100 μL, 1 mg/mL),

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5 mL deionized water was added. After stirring at room temperature for half an hour, the organic solvent was removed by air blowing. The mixture was purified by centrifugation to remove agglomerated particles, yielding the clear aqueous solution of Por-DPP NPs with dark brown color. The obtained solution was then concentrated by freeze-drying to get the materials with high concentration. The concentration of nanoparticles was calculated from the standard curve of the absorbance of Por-DPP. The Por-DPP NPs was characterized through dynamic light scattering and transmission electron microscopy. Photothermal performance of Por-DPP NPs. The aqueous solution of Por-DPP NPs (3.0 mL) in a quartz cell with different concentrations (0, 10, 20, 40, 60 and 80 μg/mL) were irradiated by a 808 nm laser for 600 s at different power density (0.5, 0.75, 1.0, 1.25, 1.5 W/cm2). For comparison, pure water without NPs was used as a control sample. The temperature and the thermal images of solutions were monitored and collected every 60 s during irradiation by an IR-thermal camera. In vitro PA imaging. The aqueous solutions of Por-DPP NPs with different concentrations (0, 6.25, 12.5, 25, 50 and 100 μg/mL) were put into a phantom, which was prepared by agarose gel. The samples were scanned from 680 to 900 nm with a photoacoustic computed tomography system. The intensity of PA signal was quantified for the scanned area. Cytotoxicity assay. HeLa cells were cultured in DMEM containing 10% fetal bovine serum (FBS) at 37 °C. For in vitro therapeutic efficacy tests, cancer cells were seeded to 96-well plates with DMEM culture media. After incubation for 24 h, the cells were incubated with Por-DPP NPs (0, 3.75, 7.5, 15, 30, 60 μg/mL) for another 24 h. Subsequently, the cancer cells were washed with fresh medium and then exposed by a laser (808 nm 1.0 W/cm2) for 3 min. Finally, the cancer cells were incubated in dark for 24 h and the cell viability was evaluated with the MTT method. In vivo tumor model. All animal procedures were approved by the Institutional Animal Care Committee at Huazhong University of Science and Technology. Female BALB/c-nude mice (4-5 week) were purchased from Beijing HFK Bioscience Co. Ltd. HeLa tumor cells (6.0 × 107 cells in 100 μL PBS) were subcutaneously injected into the selected position of each mouse. The tumor dimensions were monitored using a digital balance every day. The tumor volume was recorded with the formula as: tumor volume = length × width2/2. In vivo PA imaging. 100 µL Por-DPP NPs (100 μg/mL) was intravenously injected into the tumor-bearing mice. The PA images were recorded at various time points (0, 1, 4, 8, 12, 24 h) using photoacoustic microscopy imaging system. In vivo PTT. Sixteen HeLa tumor-bearing nude mice were divided into four groups (“Saline”, “Saline + Laser”, “Por-DPP NPs”, and “Por-DPP NPs + Laser”). 200 µL saline and Por-DPP NPs (100 μg/mL) were then intravenously injected into each eight mice. After 8 h, the mice of laser groups were irradiated by a 808 nm laser at 1.5 W/cm2 for 10 min. The thermal images of mice

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were photographed, and the temperature increase of tumor tissues was recorded by an infrared thermal camera (Flir, E6). Meanwhile, the tumor volume and body weight of each mouse were measured every two days. Histological studies. After treatment for 28 days, the mice were sacrificed. The tumors and major organs (heart, lung, kidney, spleen and liver) were retrieved, cut into 5 μm sections, fixed in formalin solution (4%), dehydrated with ethanol, and embedded with paraffin after slicing and staining with H&E. The histological sections were performed through a fluorescence microscope Toxicology Evaluation. Thirty-two HeLa tumor-bearing mice were separated into four groups (“Saline”, “Saline + Laser”, “Por-DPP NPs”, and “Por-DPP NPs + Laser”). The blood of sixteen sacrificed mice from the above-mentioned four groups was collected on day 7 and day 14, and then tested with an automated hematology analyzer.

Supporting Information Experimental details of Por, calculation of photothermal conversion efficiency of Por-DPP NPs, stability of Por-DPP NPs, IR thermal images of tumors tissues, images of tumor-bearing mice at various time points after treatment, and H&E staining images of tumors harvested from mice in the four groups.

Acknowledgement The authors are grateful for the support from the National Natural Science Foundation of China (NSFC) (grant no. 21601142) and Natural Science Foundation of Hubei Province (grant no. 2018CFB159 and 2017CFB689).

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