black phosphorus nanosheet‐based drug delivery system for...

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Black Phosphorus Nanosheet-Based Drug Delivery System for Synergistic Photodynamic/Photothermal/Chemotherapy of Cancer

Wansong Chen, Jiang Ouyang, Hong Liu, Min Chen, Ke Zeng, Jianping Sheng, Zhenjun Liu, Yajing Han, Liqiang Wang, Juan Li, Liu Deng,* You-Nian Liu,* and Shaojun Guo*

W. Chen, Prof. Y.-N. LiuState Key Laboratory for Powder MetallurgyCentral South UniversityChangsha, Hunan 410083, P. R. ChinaE-mail: [email protected]. Chen, J. Ouyang, M. Chen, K. Zeng, J. Sheng, Z. Liu, Y. Han, L. Wang, Dr. J. Li, Dr. L. Deng, Prof. Y.-N. LiuCollege of Chemistry and Chemical EngineeringCentral South UniversityChangsha, Hunan 410083, P. R. ChinaE-mail: [email protected]. LiuAier Ophthalmic CollegeCentral South UniversityChangsha, Hunan 410083, P. R. ChinaProf. S. GuoDepartment of Materials Science and EngineeringCollege of EngineeringPeking UniversityBeijing 100871, P. R. ChinaE-mail: [email protected]. S. GuoBIC-ESATCollege of EngineeringPeking UniversityBeijing 100871, P. R. China

DOI: 10.1002/adma.201603864

The new discovered black phosphorus (BP) nanosheets have generated new opportunities for designing conceptually new electronic and biomedical devices. As a metal-free layered semiconductor, BP nanosheet exhibits the thickness-dependent band gap tunable from about 0.3 eV for bulk to 2.0 eV for single layer. Compared with other 2D materials such as gra-phene and MoS2, BP has much higher surface to volume ratio due to its puckered lattice configuration, which can increase the drug loading capacity. However, using BP nanosheets as drug delivery system has not been explored. On the other hand, due to its unique electronic structure, BP is found to be highly effi-cient photosensitizer, and applied as photodynamic treatment (PDT) agent to generate singlet oxygen.[8] In addition, both BP nanoparticles and BP quantum dots show broad absorptions across the entire visible light region, making them possess near-infrared (NIR) photothermal properties for photothermal treatment (PTT).[3a,9] For example, PEG modified BP nano-particles were used to treat breast tumor through PTT with photoacoustic imaging. These unique properties of BP make it very promising as new drug delivery system of multimodal therapy for cancer. Unfortunately, to date, rare work is about exploring BP nanosheets as multimodal therapy platform for cancer therapy.

Herein we present an interesting concept of BP nanosheet-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer. We found that BP can hold higher amounts of doxorubicin (DOX) on the sheet sur-face (950% in weight) than the reported 2D materials system. This drug delivery system not only possesses the improved drug loading efficiency, and pH-/photoresponsive drug release, but also is able to generate the 1O2 and photothermal activity to enhance the therapeutic effect of anticancer drugs. As expected, the drug-loaded BP nanosheet displays dramatically enhanced ability for tumor cell killing, benefiting from the synergistic combination of chemotherapy, photothermal and photo-dynamic therapies.

Figure 1a illustrates the schematic procedure for fabricating BP-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer. BP was prepared through a liquid exfoliation method.[8,9] Its morphology was examined by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The TEM image shows that the BP nanosheet is free standing with lateral size of about 200 nm (Figure 1b). The thickness of BP is determined to be about 5.5 nm by AFM (Figure S1a, Supporting Information). The size distribution determined by dynamic light scattering

The development of highly efficient anticancer medical strategy is urgent since cancer is still one of the most serious dis-eases for human beings. To date, the conventional sole-modal therapy still suffers from poor bioavailability, impaired target specificity, and systematic and organ toxicity. One of the most promising ways to address these issues is the combination therapy due to its high efficiency and low risk of recurrence.[1] Early combination therapy involves lipid- and polymer-based nano capsules with two or three drugs,[2] but their performance largely relies on the loading capacity of different drugs. To date, an increasing interest about novel medical applications of 2D nanomaterials with extraordinary physicochemical properties has led to a burst of research activities in the development of 2D nanocarrier for multimodal nanomedicine.[3] For example, graphene,[4] Bi2Se3,[5] MoOx,[6] WS2,[7] and MoS2[3c] have been utilized to construct combination therapy platforms, showing the outstanding performance in cancer therapy. However, to develop new strategies to produce multifunctional 2D nano-materials with higher loading capacity for synergistic combination therapy is still the main challenge.

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reveals that the average diameter of BP is 281 ± 9.5 nm with polydisperse index at 0.294 (Figure S1b, Supporting Informa-tion). The typical peaks at Raman spectrum of BP nanosheets are slightly redshifted compared with those of bulk BP, further verifying the structure of BP nanosheets (Figure S1c, Sup-porting Information).[8,9] The X-ray photoelectron spectroscopy of BP shows the characteristic 2p3/2 and 2p1/2 doublets at 129.1 and 129.9 eV (Figure S1d, Supporting Information). The sub-band at 132.5 eV is probably due to the existence of oxidized phosphorus (i.e., POx).[9]

Considering the absorbance of BP nanosheets across the whole NIR region, BP nanosheets may possess the photo-thermal effect. We found that the temperature was increased from 23 °C to 45 °C for BP solution under 808 nm laser irra-diation for 3 min. By contrast, it was only increased by 3.8 °C for BP-free solution under the same conditions (Figure 1c). It proves that BP nanosheets can convert NIR light to heat. Furthermore, the photostability of BP was investigated. From Figure 1d, BP can keep stable photothermal effect even after six cycles. Also, there are no significant changes of UV–vis absorption spectrum for BP nanosheets after 808 nm laser irradiation (Figure S2, Supporting Information), verifying the high photostability of BP nanosheets. We compared the

photostability of BP with that of indocyanine green (ICG), an organic photothermal molecule has been approved by the U.S. Food and Drug Administration for clinical use on patients. The experimental result shows that the photothermal effect of ICG decreased significantly after irradiation for 3 min, and gradually weakened within six cycles. The UV–Vis absorption spectrum also shows that ICG was easily photobleached under 808 nm irradiation for 5 min (Figure S2, Supporting Information), sug-gesting that BP nanosheets exhibit better photostability than organic photothermal molecules.

Considering its high surface area, we supposed BP could be used as a superior drug nanocarrier. The loading and release behavior of BP-drug nanocomposites were studied. As BP is negatively charged in water with the interlay distance around 5.24 Å.[10] Small molecule drugs with positive charge have the possibility to be encapsulated within the interlayer spaces through electrostatic interaction. Thus, DOX, a normally used chemotherapy drug in clinic, was chosen as the model drug and loaded onto the BP nanosheets. We found that BP-DOX nanosheets with the characteristic color of DOX were well dispersed in water without any noticeable agglomeration (Figure S3, Supporting Information). UV–vis spectra were used to characterize the drug loading, as shown in Figure 1e.

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Figure 1. a) Schematic illustration of BP-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer. b) TEM image of BP nanosheets. c) Photothermal effect and d) photostability of BP and BP-DOX in water under 808 nm irradiation (1 W cm−2), DOX or ICG was used as control. e) UV–vis absorption spectra of DOX, BP, and BP-DOX. f) Fluorescence spectra of DOX, BP mixed with DOX for 10 s, and BP-DOX.

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The loaded DOX shows a slight red shift (from 488 nm to 503 nm) in the absorption compared with the free DOX. The redshift is similar to DOX loaded onto graphene,[11] verifying there is the interaction between the DOX and BP nanosheets. The Fourier transform infrared spectrum of BP-DOX also con-firmed the successful DOX loading on BP (Figure S4, Sup-porting Information). Furthermore, the fluorescence of DOX was quenched after DOX loading on BP (Figure 1f). However, little fluorescence quenching was observed for DOX mixed with BP (Figure 1f), excluding the possibility of inner filter effect. Thus, the fluorescence quenching of DOX is mainly through fluorescence resonance energy transfer mechanism, which can be ascribed to the short distance between BP and DOX after DOX loading. We also measured the DOX loading capacities with increasing DOX concentrations (Figure 2a). The loading capacity was as high as 950% when DOX concentra-tion was 1 mg mL−1, much higher than the reported 2D drug

delivery systems so far (Table S1, Supporting Information). The zeta potential test also shows that the surface potential of BP nanosheets was increased from −21 to +1.5 mV after DOX loading (Figure 2b), due to the positively charged DOX mole-cules immobilized onto the negatively charged BP nanosheets. Thus, both the large surface area of BP[12] and the electrostatic interaction between BP and DOX endow the BP nanosheets with a high DOX loading capacity of 950% in weight. The release of DOX from BP was then studied at pH 5.0 and 7.4, respectively (Figure 2c). The release rate is increased by six times at pH 5.0 compared with that at pH 7.4, ascribed to the accelerated solubility of DOX at pH 5.0.[3d] The electrostatic interaction between BP and DOX facilitates the drug release at lower pH environment. The pH-dependent release of DOX from BP-DOX benefits the application for the intratumoral drug delivery because of the acidic tumor microenvironments. The photothermal effect of BP-DOX was also measured under the same conditions, revealing that the DOX loading has little change on the photothermal effect of BP (Figure 1c). The photo responsible drug release behavior was also investigated. As illustrated in Figure 2c, over 90% DOX was released when irradiated with 808 nm laser for 20 min, indicating that the DOX release behavior could be further promoted under irradiation due to the photothermal effect of BP.

Moreover, the photodynamic activity of BP nanosheets was tested using 1,3-diphenylisobenzofuran (DPBF) as a probe for reactive oxygen species (ROS).[13] The ROS produced by BP can react with DPBF, and further generate colorless ortho-dibenzoylbenzene, accompanied with the decay of the absorp-tion at 410 nm. To prevent the photobleaching of DPBF under 660 nm laser irradiation at high power density (data not shown), the measurement was performed at low power density (0.015 W cm−2). As shown in Figure 2d and Figure S5 (Sup-porting Information), when water was irradiated under 660 nm laser, little changes of the absorption were observed because few ROS were generated. In contrast, when BP was irradiated for 10 min, the absorption was decreased by ≈20%, demon-strating the photodynamic activity of BP. Furthermore, we com-pared the photodynamic activity of BP with BP-DOX. The result shows that the DOX loading has very little influence on the photodyanmic activity of BP. Also, we carried out an experiment to test the photostability of BP-DOX under 660 nm laser irra-diation, where a widely used organic photosensitizer methylene blue (MB) was used as control. As shown in Figure S2 (Sup-porting Information), MB is almost completely photobleached under 660 nm laser irradiation (0.5 W cm−2) for 5 min. As a comparison, no significant photobleaching was observed for BP and BP-DOX, suggesting the high photo stability of BP and BP-DOX.

We also investigated the biocompatibility of BP through hemolysis assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5-di-phenyl-2-H-tetrazolium bromide (MTT) cytotoxicity assay. As shown in Figure 2e, there is no significant hemolysis (

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blood biochemistry including RBCs, white blood cells, platelets as well as hemoglobin were within normal ranges (Figure S8, Supporting Information). The liver and kidney function markers including alanine aminotransferase, aspartate amino-transferase, blood urea nitrogen, and creatinine were meas-ured and compared with untreated healthy rats. No significant change of liver and kidney functions was detected after injec-tion of BP for 7 d (Figure S8, Supporting Information).

Considering the superior properties of the BP-DOX, we explored its cellular uptake process and in vitro therapeutic effects. First, the endocytosis process of BP-DOX was studied. Generally, external nanomaterials can interact with cell mem-brane and enter into cells mainly through three types of endocy-tosis processes: (a) caveolae-mediated endocytosis, (b) clathrin-mediated endocytosis, and (c) macropinocytosis.[14] As revealed in Figure 3i and Figure S6 (Supporting Information), the inter-nalization is almost inhibited when the cells were kept at 4 °C, indicating the internalization is energy dependent endocytic process.[15] The cellular uptakes of BP-DOX nanosheets were further evaluated in the presence of three endocytosis inhibi-tors, including methyl-β-cyclodextrin, sucrose and amiloride, corresponding to the caveolae-mediated endocytosis, clathrin-mediated endocytosis, and macropinocytosis, respectively. The intracellular fluorescent intensity was significantly decreased when the cells were treated with amiloride (Figure 3i and Figure S6, Supporting Information), suggesting that the endo-cytosis process of BP-DOX was through macropinocytosis.

Then, we tested the intracellular drug release behavior by incubating the BP-DOX with murine breast cancer 4T1 cells. The weak red fluorescent signal came from the endocytosis of the BP-DOX nanocomposites. After the irradiation under 808 nm laser for 5 min, the fluorescence of DOX was signifi-cantly increased (Figure 3a,b). Flow cytometer results also con-firmed that after irradiated with 808 nm laser, the intracellular fluorescence intensity of DOX was increased by four times com-pared with BP-DOX in the dark (Figure 3c). Clearly, the photode-pendent DOX intracellular release could be facilitated by the photothermal effect of BP. As is known, propidium iodide (PI) is a cell membrane impermeable dye, and can bind with the nuclear DNA of dead or apoptosis cell with strong red fluores-cence emission. In the cytoplasm of the living cells, the calcein-AM is able to be hydrolyzed by endogenous esterases to generate green fluorescent emission to verify the cell viability. To fur-ther confirm the above results, the PI delivery was also carried out using the BP as the carrier.[16] As illustrated in Figure 3d, only cytoplasm was stained by calcein-AM, and little red fluo-rescence from PI was observed in the nuclear area. This could be because that PI is cell membrane impermeable, and little PI was released into the cytoplasm. However, when cells were irradiated under 808 nm laser for 5 min, both the cytoplasma and nuclear were stained by calcein-AM and PI, respectively (Figure 3e,f). The results indicate that the photothermal effect efficiently increases the permeability of the cell membrane even to cell impermeable molecules such as PI. Considering the intrinsic photodynamic activity of BP, the intracellular pho-todynamic activity of BP-DOX nanosheets were then studied with 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFH-DA) as the ROS probe, generating green fluorescence in the pres-ence of ROS.[17] When the cells were cultured with only 660 nm

laser or BP-DOX (Figure 3g), there were little changes of the intracellular ROS content. In contrast, when cells were cultured with BP-DOX and irradiated with 660 nm laser for 10 min, the intracellular fluorescence intensity of H2DCFH was increased by eight times (Figure 3g,h). Thus, BP-DOX can produce ROS inside the cells during the irradiation with 660 nm laser.

The combination therapies with BP-DOX were then investi-gated. 4T1 cells were incubated with free DOX, BP, or BP-DOX with or without light irradiation (660 nm, 10 min, 0.5 W cm−2; 808 nm, 5 min, 1 W cm−2). The MTT assay together with live/dead assay was performed to evaluate the therapeutic efficacy of BP-DOX in vitro (Figure 3j and Figure S9, Supporting Informa-tion). For the cells treated with BP alone or 808/660 nm laser irradiation, more than 95% cells were survived, indicating that BP possesses good biocompatibility. Compared to the chemo-therapy alone with DOX in dark, PDT with BP-DOX under 660 nm laser exposure, or PTT with BP-DOX under 808 nm laser irradiation, the combined tri-treatment by BP-DOX offers the most effective cancer cell killing, demonstrating the effi-cacy of synergistic photothermal/ photodynamic/chemotherapy (Figure 3j and Figure S9, Supporting Information). For the cells treated with BP-DOX, 35% cells were killed, a little lower than that of free DOX. The cytotoxicity of BP-DOX further increases under the irradiation of 660 or 808 nm laser. However, there were still more than 30% cells survived. When BP-DOX nanosheets were combined with both 660 and 808 nm laser, nearly all of the cells were killed.

Inspired by the exciting results in our triple modal combi-nation therapy in vitro, we further carried out the combination therapy in vivo using BP-DOX on mice bearing 4T1 tumors. The mice were divided into eight groups: (a) saline as the con-trol group, (b) BP nanosheets, (c) 660 and 808 nm laser irra-diations, (d) free DOX, (e) BP-DOX, (f) BP-DOX with 660 nm laser irradiation, (g) BP-DOX with 808 nm laser irradiation, and (h) BP-DOX with both 660 and 808 nm laser irradiations. To demonstrate the photothermal activity of BP inside the tumor, the temperature of the tumor under irradiation was moni-tored using thermal camera. For BP or BP-DOX treated group, the temperature of the tumor was increased from ≈36.2 to ≈53.7 °C after irradiated for 5 min. In contrast, the temperature of the tumor in the control group was only increased to 41.2 °C (Figure 4a).

After conducting different treatments, the tumor volumes were measured by a caliper for 14 d and normalized against their initial sizes (0 day). The BP alone or laser irradiation alone exhibited little therapeutic effect on tumor (Figure 4b). As expected, the chemotherapy using free-DOX or BP-DOX without laser irradiation could partially inhibit the tumor growth, with tumor growth inhibition (TGI) rates at 43.6% and 47.4%, respectively. While the PDT/chemotherapy using BP-DOX with 660 nm irradiation showed the moderated growth inhibition effect with TGI at 56.2%, and the PTT/chemo-therapy using BP-DOX with 808 nm irradiation exhibited the improved growth inhibition effect with TGI at 84.8%. Impor-tantly, the inhibition of tumor growth in mice after the com-bined tri-therapy using BP-DOX plus 660 nm and 808 nm laser irradiation (TGI at 95.5%) is significant, showing remarkably enhanced therapeutic effect compared to other control groups. The digital photos of excised tumors from representative mice

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(Figure 4c) visually displayed that the tumor sizes treated with BP-DOX under 660 and 808 nm laser irradiations were smaller than the other groups. Histological analysis further proves that after treated with BP-DOX under 660 and 808 nm laser irra-diations, most of tumor tissue cells were destroyed and became

necrotic, while cells partially or largely retain their normal mor-phology in the other groups (Figure 4d).

The reason for the outstanding synergistic antitumor effi-ciency probably benefits from the following aspects. First, the local hyperthermia accelerates the DOX release from BP-DOX,

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Figure 3. a) Fluorescence images of 4T1 cells incubated with BP-DOX without or b) with 808 nm laser irradiation (0.8 W cm−2). c) The intracellular fluorescence was analyzed through flow cytometer. d) Fluorescence images of 4T1 cells treated with BP-PI without or e) with 808 nm irradiation (0.8 W cm−2). f) The intracellular fluorescence was quantified using CellSens software. g) The intracellular ROS production under different treat-ments, (1) PBS, (2) 660 nm irradiation, (3) BP-DOX, (4) BP-DOX with 660 nm irradiation, using H2DCFH-DA as probe. h) Normalized intracellular fluorescence in (g). i) Inhibition of endocytosis under different inhibitors and low temperature. j) MTT assay of 4T1 cells under different treatments. (Scale bar = 50 µm.)

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resulting in the rapid intratumoral DOX release and enhancing the efficacy of chemotherapy[18] (Figure 2c). Second, since the binding site of DOX is nucleus[19] and PDT of BP is mainly through the oxidation damage to organelles such as mito-chondria.[20] The local hyperthermia increases the permeability of cell membrane and the chance of interaction with corre-sponding organelles (Figure 3d,e). Third, the photothermal/photodynamic/chemotherapy can replenish mutually, improve the antitumor efficiency and reduce the risk of recurrence (Figures 3j and 4b).

Notably, during the treatment, mice did not lose body weight, and no obvious differences among each group were observed (Figure 4e). Furthermore, the histological analysis of the typical heart, liver, spleen, lung, and kidney of the mice (Figure S10, Supporting Information) also shows no significant off-target damage to normal tissues. Therefore, our newly developed BP-drug treatment can be a safe multimodal therapeutic system.

In summary, we reported a new class of multimodal thera-peutic system based on BP nanosheets. Using DOX as a modal drug, BP possessed extremely higher drug loading capacity for DOX than the other 2D nanomaterials such as graphene and MoS2. The BP drug delivery system displayed pH-/photo-responsive release properties, in which the drug release was accelerated under the acidic tumor microenvironments, and further promoted by irradiation with 808 nm laser due to the photothermal effect of BP nanosheets. Importantly, the intrinsic properties of BP nanosheets allowed them to simultaneously serve as both efficient PDT and PTT agents. The outstanding in vivo antitumor therapeutic outcome was realized after the syn-ergistic photodynamic/photothermal/chemotherapy with the BP-based drug delivery system. The BP-nanosheet-based drug delivery system was photostable and biocompatible, and had substantial potential for future clinical application. Moreover, this system should be applicable to deliver other drugs, DNA,

Figure 4. The in vivo antitumor study of BP-DOX. a) In vivo photothermal effect of BP and BP-DOX with 808 nm laser irradiation as control. b) Tumor growth curves of tumor-bearing mice after different treatments. The tumor volumes were normalized to their initial sizes (n = 5, mean ± SD). Asterisks indicate statistical significance (P < 0.05). c) Digital photo of representative tumor in mice with different treatments. d) Histological microscopy images of the tumor tissues stained with H&E after the treatments (on day 14). Scale bar = 50 µm. e). The body weights of mice were measured every other day.

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siRNA, proteins, etc., and opens up new perspectives in the design of multifunctional nanomedicine platform.

Supporting InformationSupporting Information is available from the Wiley Online Library or from the author.

AcknowledgementsW.C. and J.O. contributed equally to this work. This work was supported by the National Natural Science Foundation of China (No. 21476266, 21276285, 21574147, and 21374133), and the start-up funding from Peking University and Young Thousand Talented Program.

Received: July 21, 2016Revised: September 14, 2016

Published online: November 24, 2016

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