Near-Infrared Absorbing Conjugated Polymer Dots ... - ACS Publications

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Near-Infrared (NIR)-Absorbing Conjugated Polymer Dots as Highly Effective Photothermal Materials for In Vivo Cancer Therapy Shengliang Li,† Xiaoyu Wang,† Rong Hu,† Hui Chen,† Meng Li,† Jianwu Wang,† Yunxia Wang,† Libing Liu,† Fengting Lv,† Xing-Jie Liang,*,‡ and Shu Wang*,† †

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China ‡ Chinese Academy of Sciences Center for Excellence in Nanoscience, CAS Key Lab for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, People’s Republic of China S Supporting Information *

ABSTRACT: Photothermal therapy (PTT) holds great promise for noninvasive cancer treatment. To fulfill this goal, highly effective and low-risk photothermal agents have been intensively explored. Here, we present a new PTT material based on conjugated polymer dots (Pdots) that exhibit strong near-infrared (NIR) absorption and high photostability. The Pdots result in a thermal response upon illumination with a NIR laser, leading to a high photothermal conversion efficiency of 65%. Thus, the photothermal ablation of cancer cells using the Pdots both in vitro and in vivo can be achieved, highlighting the potential of Pdots as a nanoplatform for clinical therapy. They also open up a new avenue to develop new photothermal therapeutic materials.

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INTRODUCTION Conjugated polymers (CPs), characterized by electrondelocalized backbones and rapid exciton diffusion, also along the backbone, have been widely used in optoelectronic devices, such as organic field-effect transistors,1−3 organic solar cells,4,5 and organic light-emitting diodes.6,7 Recently, because of their excellent light-harvesting and light-amplifying properties, the application of CPs is further being expanded into biomedical fields, including optical and electronic biosensors,8−11 bioimaging,12−15 and anticancer and antimicrobial therapies.16−19 In particular, conjugated polymer dots (Pdots) of small sizes have drawn extensive attention, because of their intriguing optical characteristics and nontoxic features for living systems.20−23 There are enormous efforts to develop Pdots that have multicolor and near-infrared (NIR) emission as fluorescent probes for bioimaging and sensor design. Moreover, Pdots have begun to see development as a light-activated agent, and they have been applied for anticancer and antimicrobial phototherapy.24−26 However, these light-activated activities mainly rely on visible light; therefore, the penetration ability and phototoxicity of visible light prevents further biomedical applications. Through altering the donor−acceptor (D-A) construction units in Pdots, their absorption and fluorescence emission can be finely regulated, providing a strategy to address the above limitations.27,28 The extension of absorption and emission of Pdots to NIR (λ = 700−1350 nm) will ensure their potential applications in biomedical area, such as NIR imaging and NIRactivated phototherapy.29,30 Moreover, taking advantage of © 2016 American Chemical Society

noninvasive and spatiotemporal-controlling modes, the biodegradable Pdots with NIR-induced photoactivity exhibit great potential for in vivo cancer therapy. Herein, four photothermal Pdots are developed using diketopyrrolopyrrole (DPP)-containing CPs bridged with different thiophene units (see their chemical structures in Figure 1), which display strong NIR absorbance and high photothermal conversion efficiency for in vivo photothermal therapy of tumors. Particularly, the relationship of D-A backbone structures in Pdots with their optical and photothermal properties is studied. These Pdots exhibit efficient conversion ability from photon energy into heat, leading to a high photothermal conversion efficiency of 65%. A proof-ofconcept application of Pdots as good photothermal materials is thus demonstrated for in vitro and in vivo tumor treatments.

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RESULTS AND DISCUSSION Synthesis and Characterization of CP1−CP4. The electron-deficient feature of DPP provides a possibility to adjust its optical band gap into NIR region via copolymerization with electron-rich aromatic heterocycles.31−34 Based on this strategy, four D-A CPs containing DPP and various thiophene derivatives (monothiophene, thienothiophene, bithiophene, and benzodithiophene) were synthesized by Stille coupling reaction (Figures S1−S4 in the Supporting Received: September 5, 2016 Revised: October 28, 2016 Published: November 2, 2016 8669

DOI: 10.1021/acs.chemmater.6b03738 Chem. Mater. 2016, 28, 8669−8675

Article

Chemistry of Materials

Figure 1. (a) Schematic illustration of preparation for Pdots. (b) Molecular structures of CP1−CP4. (c) UV-vis-NIR absorption spectra of CPs 1−4 in chloroform. (d) Band diagram representing the HOMO and LUMO levels of CP1−CP4 determined by cyclic voltammetry. (e) Representative TEM images of Pdot-1. (f) Size distribution histogram of Pdot-1 by DLS measurement. (g) Photographic images of Pdots 1−4 in aqueous solutions (25 μg/mL) after one month of storage at 4 °C.

Information). Their molecular structures are depicted in Figure 1b. Because of the strong electron-withdrawing ability of DPP, these CPs exhibit broad absorption spectra, ranging from 600 nm to 900 nm in chloroform solution, as shown in Figure 1c. Advantageously, the energy band and optical property could be regulated effectively by changing thiophene donors, and the maximim absorption peaks of CP1−CP4 are 816, 810, 790, and 750 nm, respectively (see Figure 1d, as well as Figure S5 in the Supporting Information). To evaluate their NIR absorbing capability, the corresponding mass extinction coefficients at 808 nm were further measured, which is 72.9, 60.6, 55.6, and 33.0 L mg−1 cm−1, respectively (Table 1). Meanwhile, all CPs showed almost no fluorescence emission, indicating that the nonradiative decay is the main pathway for excited-state deactivation.

Table 1. Molecular Weight and Photophysical Properties of CPs 1−4

polymer

numberaverage molecular weight, Mn (kg/mol)

polydispersity index, PDI

λMax, abs (nm)

CP1 CP2 CP3 CP4

64.1 37.3 52.8 45.1

2.3 2.5 1.9 3.6

816 810 790 750

ε808 −1 −1

(cm

g

72.9 55.6 60.6 33.0

L)

quantum yield, QY (%) 0.1 0.2 0.2 0.1

Preparation and Characterization of Pdots. For further PTT application, Pdots 1−4 were respectively prepared from the hydrophobic CP1−CP4 via a nanoprecipitation method 8670


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Figure 2. (a) Infrared thermographs and (b) temperature elevation of water and Pdot-1 aqueous solutions with different concentrations, as a function of irradiation time. (c) Photothermal response of Pdot-1 aqueous solution (25 μg/mL) under irradiation for 5 min with an NIR laser (808 nm, 0.5 W/cm2) and then the laser was shut off. (d) Temperature profiles of Pdot-1 aqueous solution for five ON/OFF cycles.

using a previously reported method,35 which is higher than those of Au NRs (21%),35 CuS nanocrystals (25.7%),36 black phosphorus (28.4%),37 and melanin nanospheres (40%).38 The photothermal conversion efficiencies of Pdots 2−4 were also calculated to be ∼55%, 42%, and 34%, respectively. Compared with other reported conjugated polymers or their nanoparticles, Pdots in this work show higher photothermal conversion efficiency, because of the reduced energy loss from the excitation state.39−41 As we known, the photothermal stability is an important parameter in photothermal therapy. In order to further investigate the photothermal stability of Pdots, the samples were irradiated by the 808 nm laser for 5 min and then turned off, to allow the system to cool to room temperature, and the ON/OFF cycle was repeated five times. ICG, the FDAapproved NIR dye widely used for clinical phototherapy, was chosen as control. As shown in Figure 2d, after five ON/OFF cycles of irradiation at 0.5 W/cm2, Pdots still maintain a high photothermal effect, while that of ICG loses mostly under the same conditions. It is noted that the NIR absorbing ability of Pdots does not change in this process, while that of ICG disappears completely after five cycles (see Figure S9 in the Supporting Information). Importantly, after five ON/OFF cycles of irradiation, the size of Pdots maintain their narrow size distribution, with an average size of 48.7 nm (see Figure S10 in the Supporting Information). The above results confirm the high and stable photothermal performance of Pdots and highlight their good potential as photothermal materials for PTT treatment. In Vitro Photothermal Ablation of Cancer Cells. The potential of Pdots as PTT materials for in vitro ablation of cancer cells was evaluated because of their favorable photothermal effect, as demonstrated above. As a proof-of-concept experiment, 4T1 cells were chosen as cancer cells model. 4T1 cells were incubated with Pdot-1 and then irradiated by 808 nm laser at 0.5 W/cm2 for 5 min, and then the live/dead cells were determined after treatment by calcein AM and propidium

(Figure 1a). The morphologies of Pdots were determined by transmission electron microscopy (TEM) (Figure 1e), and the results showed that Pdots were uniformly spherically shaped, with a diameter of ∼30 nm. Dynamic light scattering (DLS) measurement presents a hydrodynamic diameter of 49 ± 3 nm with a polydispersity index (PDI) value of 0.19, indicating the monodisperse preference of Pdots in aqueous solution (Figure 1f). Besides, these Pdots did not show any aggregation behavior and maintained a homogeneous size, even storage at 4 °C for one month, indicating their good stability (Figure 1g). Photophysical properties of Pdots were also investigated, and the results showed that the extinction coefficient and fluorescence quantum yield of Pdots were similar to those of CPs in chloroform solution. Photothermal Performance of Pdots. In consideration of the strong NIR absorption of these Pdots, we further studied their photothermal performances. Sharp temperature increases were observed upon irradiation with an 808 nm laser at 0.5 W/ cm2 for 5 min, indicating that the Pdots possess good photothermal response (Figure S6 in the Supporting Information). Moreover, Pdot-1 shows the best photothermal performance among these Pdots, possibly because of its higher mass extinction coefficient at 808 nm (Table S1 in the Supporting Information). Thus, the photothermal conversion capacity of Pdot-1 was chosen and further investigated in the following experiments (Figures 2a and 2b). The temperature of the Pdot-1 aqueous solution increases with irradiation time extension and concentration increase. At low concentration (50 μg/mL) of Pdot-1, the temperature increased up to 61.4 °C after 5 min of irradiation, while that of the pure water slightly changed, confirming the fast and high-efficient photothermal conversion capacity of Pdots (Figure 2b). The photothermal response of Pdot-1 under various laser densities was also investigated and showed a laser-density-dependent profile (Figure S7 in the Supporting Information). The photothermal conversion efficiency of Pdot-1 was calculated to be ∼65% (see Figure 2c, as well as Figure S8 in the Supporting Information), 8671


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Figure 3. (a) Thermal images of the 4T1 cell culture dish after incubation with Pdot-1 and laser irradiation (0.5 W/cm2) for 5 min; (b−d) fluorescence images of cells stained with calcein AM (live cells, green fluorescence) and PI (dead cells, red fluorescence). (e) Cell viability of 4T1 cells after incubation with various concentrations of Pdot-1 for 24 h. (f) Relative viabilities of 4T1 cells after treatment with Pdot-1 under 808 nm laser at 0.5 W/cm2 for 5 min.

groups of mice included untreated mice, mice administered with Pdots without laser irradiation, and mice irradiated with only a laser. The tumor sizes were measured by an electronic digital caliper on every other day. As shown in Figures 4c and 4e, after Pdots injection and laser irradiation, the tumors were effectively ablated and only black scars were left at tumor lesions. Notably, no recurrent was found in a Pdots-induced PTT treatment group, even for 14 more days of feeding. Nevertheless, other three control groups have homologous tumor growth ratio, which indicates that neither Pdots nor laser irradiation could hinder the tumor growth. More importantly, all mice in the treated group had life spans of >30 days, while the mice in the three control groups just survived 14−25 days, on average (Figure 4d). These findings confirm that Pdots has great potential for in vivo PTT cancer treatment.

iodide (PI) (Figures 3a−d). After irradiation, the distinct boundary between green (live cells) and red (dead cells) was detected under confocal laser scanning microscopy (CLSM), and the cells within the laser region displayed red fluorescence, indicating that the cells were killed completely after PTT treatment. The standard MTT was employed to confirm and quantify the photothermal ablation effect. As shown in Figure 3e, after incubation with various concentrations of Pdot-1 for 24 h in darkness, no obvious cytotoxicity and proliferation inhibition of 4T1 cells were observed even the concentrations of Pdots up to 100 μg/mL. However, the 4T1 cells were efficiently killed by Pdots under irradiation, and more than 90% cells were ablated, even under concentrations as low as 25 μg/ mL (Figure 3f). These results indicate that Pdots have potential as highly efficient and low-toxicity PTT materials for in vivo cancer treatment. In light of the good NIR absorption and photothermal conversion of Pdots, we then carried out in vivo PTT treatment using Pdots in the 4T1 tumor-xenograft model. The mice bearing tumors were intratumorally injected with Pdots (0.5 mg/mL, 40 μL) and then irradiated under 808 nm laser. The temperature change in tumors under laser irradiation was monitored by an infrared thermal imager. As shown in Figures 4a and 4b, upon irradiation at the power densities of 0.25 and 0.5 W/cm2, the tumor temperature increased to 53−68 °C within 5 min, which is high enough to kill the tumor in vivo. As a control, the tumor temperature is slightly altered under the same laser condition when the mice were treated by saline injection. In Vivo Photothermal Therapy. We then studied the in vivo photothermal therapeutic efficacy of Pdots. After the tumor size reached ∼60 mm3, the 4T1 tumor-bearing mice (6 mice per group) were divided into four groups. In the treatment group, the mice were intratumorally injected with Pdot-1 (0.5 mg/mL, 40 μL) and followed with 5 min of irradiation by the 808 nm laser at a power density of 0.5 W/cm2. Other control

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CONCLUSION In summary, we have successfully designed and synthesized a series of Pdots as effective photothermal materials. Because of the high mass extinction coefficient at 808 nm and lower excitation energy loss, Pdots show photothermal conversion efficiency up to 65%. Moreover, Pdots possess good stability in solution and photostability, compared to ICG. Using Pdots as PTT materials, the in vitro cancer cells ablation effect was obtained, even using low concentration and low laser power. In vivo PTT treatment of Pdots was also studied and ∼100% tumor elimination was realized under irradiation at the laser power density of 0.5 W/cm2, and no recurrent was observed. The work provides a new way to design and synthesize Pdots with excellent biocompatibility and photothermal effect as photothermal therapy materials, which highlights the good potential of Pdots for tumor therapy.

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MATERIALS AND METHODS

Materials. All the reagents and solvents used were commercially available and used as received. Poly(styrene-co-maleic anhydride) 8672


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Figure 4. (a) Thermal images of tumor-bearing mice exposed to the 808 nm laser irradiation for 5 min after the injection of saline and Pdot-1. (b) Time-dependent photothermal heating curves of tumor upon laser irradiation, as a function of irradiation time. (c) Tumor growth curves in different groups of tumor-bearing mice after various treatments. Relative tumor volumes were normalized to their initial sizes. Error bars represent the standard deviation of six mice per group. Asterisk indicates P < 0.01. (d) Survival curves of tumor-bearing mice after various treatments, as indicated in panel (c). (e) Representative photos of tumor-bearing mice after photothermal therapy. (PSMA, average molecular weight (Mw) of ∼1700, styrene content = 68%) was purchased from Sigma−Aldrich (St. Louis, MO, USA). 5,5′Bis(trimethylstannyl)-thiophene, 5,5′-bis(trimethylstannyl)-2,2′-bithiophene,1 2,5-bis(trimethylstannyl)thieno[3,2-b]thiophene,2 2,6-bis(trimethyltin)-4,8-bis(5-hexy-lthiophene-2-yl) benzo[1,2-b:4,5-b́]dithiophene,3 and 3,6-bis(5-bromo-2-thienyl)-2,5-dihydro-2,5-di(2′hexyldecyl)-pyrrolo-[3,4c]pyrrolo-1,4-dione4 were synthesized according to literature procedures. For the animal experiments, permission was obtained from the National Center for Nanoscience and Technology. Measurements. The 1H NMR spectra was recorded on Bruker Avance 400 MHz spectrometers. Gel permeation chromatography (GPC) measurement was performed on a Waters 410 system against polystyrene standards. UV-vis-NIR absorption spectra were taken on a Jasco Model V-570 spectrophotometer. Fluorescent quantum yields (FLQY) were measured on Quantaurus-QY Absolute PL quantum yield spectrometer. The morphology of the nanoparticles was determined via transmission electron microscopy (TEM) (Model HT7700, Hitachi). Dynamic light scattering (DLS) was performed on the Malvern ZetaSizer Nano ZS90. Confocal images were captured via confocal laser scanning microscopy (Model FV1200-IX83, Olympus, Japan). Cell viability analysis was recorded on a microplate reader (BIO-TEK Synergy HT, USA). Synthesis of CP1. 5,5′-Bis(trimethylstannyl)-thiophene (40 mg, 0.098 mmol) and 3,6-bis(5-bromo-2-thienyl)-2,5-dihydro-2,5-di(2′hexyldecyl)-pyrrolo-[3,4c]pyrrolo-1,4-dione (100 mg, 0.098 mmol)

was poured into a two-neck flask, and 10 mL of degassed toluene was added and flushed with N2 for 20 min; then, Pd(PPh3)4 (20 mg) was added. After being flushed with N2 for another 10 min, the reaction mixture was vigorously stirred at 110 °C for 24 h under N2 atmosphere. The resulted polymer was precipitated by 50 mL of methanol after being cooled to room temperature. The precipitate then was filtered through Soxhlet extraction with methanol, hexane, and chloroform, respectively. The polymer was purified via precipitation in methanol/water (10:1) again. CP1 was recovered as a dark blue solid (74.8 mg, 53%). 1H NMR (400 MHz, CDCl3): δ (ppm) 9.41−8.55 (b, 2H), 7.47−6.81 (b, 4H), 4.38−3.19 (m, 4H), 2.44−0.59 (bm, 78H). GPC: Mn = 64.1 kDa, PDI = 2.3. Synthesis of CP2. 5,5′-Bis(trimethylstannyl)-2,2′-bithiophene (46 mg, 0.098 mmol) and 3,6-bis(5-bromo-2-thienyl)-2,5-dihydro-2,5di(2′-hexyldecyl)-pyrrolo-[3,4c]pyrrolo-1,4-dione (100 mg, 0.098 mmol) were used as the monomers to prepare CP2 following the same procedure as that used to synthesize CP1. CP2 was obtained as a dark blue solid (81 mg, 56%). 1H NMR (400 MHz, CDCl3): δ (ppm) 9.40−8.72 (b, 2H), 7.68−6.34 (bm, 6H), 4.37−3.10 (m, 4H), 2.45− 0.38 (bm, 78H). GPC: Mn = 37.3 kDa, PDI = 2.5. Synthesis of CP3. 2,5-Bis(trimethylstannyl)thieno[3,2-b]thiophene (48 mg, 0.098 mmol) and 3,6-bis(5-bromo-2-thienyl)-2,5dihydro-2,5-di(2′-hexyldecyl)-pyrrolo-[3,4c]pyrrolo-1,4-dione (100 mg, 0.098 mmol) were used as the monomers to prepare CP3 following the same procedure as that used to synthesize CP1. CP3 was obtained as a dark blue solid (120 mg, 81%). 1H NMR (400 MHz, 8673



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CDCl3): δ (ppm) 9.38−8.72 (b, 2H), 7.58−6.46 (bm, 4H), 4.32−3.23 (m, 4H), 2.51−0.49 (bm, 78H). GPC: Mn = 52.8 kDa, PDI = 2.9. Synthesis of CP4. 2,6-Bis(trimethyltin)-4,8-bis(5-hexylthioph ené dithiophene (90 mg, 0.098 mmol) and 3,62-yl) benzo[1,2-b:4,5-b]bis(5-bromo-2-thienyl)-2,5-dihydro-2,5-di(2′-hexyldecyl)-pyrrolo[3,4c]pyrrolo-1,4-dione (100 mg, 0.098 mmol) were used as the monomers to prepare CP4 following the same procedure as for CP1. CP4 was obtained as a dark blue solid (122 mg, 64%). 1H NMR (400 MHz, CDCl3): δ (ppm) 9.84−8.42 (b, 2H), 8.04−6.28 (bm, 8H), 4.67−2.52 (bm, 8H), 2.08−0.58 (bm, 108H). GPC: Mn = 45.1 kDa, PDI = 3.6. Preparation of Pdots. Pdots were obtained using a coprecipitation method. Briefly, CPs (5 mg) and PSMA (20 mg) were dissolved in THF (10 mL) by bath sonication and the resulted solution was filtered through a syringe-driven filter (0.22 μm), respectively. Five milliliters (5 mL) of THF solution with 50 μg/mL CPs and 20 μg/mL PSMA was prepared and mixed sufficiently in order to form a homogeneous solution. Subsequently, the solution was rapidly injected to 10 mL of Milli-Q water (Millipore, Bedford, MA) and sonication for 5 min. THF that was in the mixture was then removed by bubbling nitrogen at room temperature. Finally, the resulting Pdots solution was concentrated in a 90 °C oil bath, and Pdots was obtained after filtration using a 0.22 μm syringe-driven filter. Cell Culture. 4T1 cell line was obtained from cell culture center of Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Beijing, China), and were maintained in DMEM supplemented with 10% FBS. The entire cells were cultured at 37 °C in a humidified atmosphere containing 5% CO2. Cytotoxicity Assay. The viability and proliferation of 4T1 cells were evaluated by MTT assay. Typically, 4T1 cells were seeded in 96well plates at a density of 4 × 103 cells/well. After cultured overnight, the cells were incubated in fresh culture medium containing various concentrations of Pdots and incubated for 24 h. Ten microliters (10 μL) of MTT (5 mg/mL) solution was added and incubated for another 3 h. The absorbance at 450 nm was measured using microplate reader (BioTek Synergy HT, USA). All experiments were conducted in triplicate and presented as a mean ± standard deviation (SD), compared to the OD values of untreated cells. Photothermal Ablation of Cancer Cells In Vitro. To assess the photothermal effect on cancer cells, 4T1 cells (4 × 103 cells/well) were seeded in 96-well plates and incubated overnight. After washing by PBS (pH 7.4), the cells were incubated with various concentrations of Pdots for 6 h at 37 °C, and then irradiated with an 808 nm laser at a power density of 0.5 W/cm2 for 5 min. After illumination, cells were incubated for another 24 h. The standard MTT assay was used to determine the relative viabilities of cancer cells with various treatments. To further confirm the photothermal effect on cancer cells, after various treatments, 4T1 cells were co-stained by calcein AM (calcein acetoxymethyl ester) and PI (propidium iodide) to differentiate live (green) and dead (red) cells, respectively. Animal Experiments and Tumor Models. Female BALB/c nude mice (each 16−18 g) were purchased from Vital River Company (Beijing, China) and raised under the principles of care and use of laboratory animals. The 4T1 tumors models were generated by subcutaneous injection of 3 × 106 cells in 100 μL saline medium into the right flank of each mouse. The mice were used for further experiments when the tumor size had grown to ∼60 mm3. In Vivo Photothermal Therapy. 4T1 tumor-bearing mice were divided into 4 groups to determine tumor growth rate. For the treatment groups (n = 6/group), mice bearing 4T1 tumors were intratumorally injected with 40 μL of Pdots (0.5 mg/mL) and irradiated by the 808 nm laser at power density of 0.5 W/cm2 for 5 min. For control groups, mice were either treated with the same volume of saline, saline with laser irradiation, or injected with Pdots without laser irradiation. Infrared thermal images were used to record the tumor temperatures by Ti400 Thermal Imaging Camera. The tumor sizes were measured by an electronic digital caliper every other day after treatments and calculated as follows: volume = 0.5 × (tumor length) × (tumor width).2 The relative tumor volumes were normalized to their initial sizes.

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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.chemmater.6b03738. Procedure of measurement of photothermal performance, synthesis routes of CPs 1−4 (Figures S1−S4), HOMO/LUMO levels for repeat units of CPs 1−4 (Figure S5), photothermal performances of Pdots (Figures S6−S8), UV-vis-NIR absorption spectra of ICG and Pdots before and after five ON/OFF cycles (Figure S9) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (L. Liang). *E-mail: [email protected] (S. Wang). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the National Natural Science Foundation of China (Nos. 21533012, 21473220, 21473221, 91527306), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA09030306).

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REFERENCES

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