Coordination Nanosheets of Phthalocyanine as Multifunctional

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Biological and Medical Applications of Materials and Interfaces

Coordination Nanosheets of Phthalocyanine as Multifunctional Platform for Imaging-Guided Synergistic Therapy of Cancer Ke Zeng, Qunfang Xu, Jiang Ouyang, Yajing Han, Jianping Sheng, Mei Wen, Wansong Chen, and You-Nian Liu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b22008 • Publication Date (Web): 29 Jan 2019 Downloaded from http://pubs.acs.org on January 30, 2019

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ACS Applied Materials & Interfaces

Coordination Nanosheets of Phthalocyanine as Multifunctional Platform for ImagingGuided Synergistic Therapy of Cancer

Ke Zeng† ⊥ , Qunfang Xu† ⊥ , Jiang Ouyang†, Yajing Han†, Jianping Sheng†, Mei Wen†, Wansong Chen†,§,*, You-Nian Liu†,§, 

†

College of Chemistry and Chemical Engineering, Central South University, Changsha,

Hunan 410083, P. R. China

§ State

Key Laboratory of Powder Metallurgy, Central South University, Changsha, Hunan

410083, P. R. China

Corresponding

authors. Phone: +86-731-8887-9616

E-mail addresses: [email protected] (W. Chen); [email protected] (Y.-N. Liu).

ACS Paragon Plus Environment

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ABSTRACT: “All-in-one” nanodrugs integrating various functionalities into one nanosystem are highly desired for cancer treatment. Coordination nanosheets as one type of two dimensional (2D) nanomaterials offer great opportunities, but lack of enough candidates. Here, a new kind of coordination nanosheets based on phthalocyanine are constructed. Manganese phthalocyanine (MnPc) tetracarboxylic acid is employed as photoactive ligand to form MnPc nanosheets; meanwhile, hyaluronic acid (HA) is coated on their surface. The obtained MnPc@HA nanosheets exhibit superior near infrared (NIR) photothermal effect with photothermal conversion efficiency of 72.3%, much higher than previously reported photothermal agents. Due to their 2D nanostructures, MnPc@HA nanosheets possess superhigh drug loading capacity for chemotherapy drug curcumin. With HA as a targeting group, the nanosheets selectively accumulated in CD-44 overexpressed tumors, followed by drug release under the control of NIR light. Moreover, MnPc@HA nanosheets with intrinsic paramagnetism can serve as T1 contrast agent for magnetic resonance imaging. The synergistic effect of phototherapy and chemotherapy endows curcumin loaded MnPc@HA nanosheets with superior tumor-eradicating efficacy. Besides, MnPc@HA nanosheets are biocompatible and safe for biomedical


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applications. This work provides novel insight for developing new multifunctional platforms based on 2D coordination nanosheets to synergistically combat cancer.

KEYWORDS: 2D nanomaterials, photothermal therapy, drug delivery, theranostics, cancer therapy


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1. INTRODUCTION

In the fight against cancer, multifunctional nanodrugs integrating various functionalities into one nanosystem have exhibited obvious advantages. Such multifunctional nanodrugs can be selectively delivered to tumors through either the enhanced permeability and retention (EPR) effect or active targeting.1–3 Upon external stimuli, drug release could be remotely controlled in a spatially and temporally precise manner.4–6 Furthermore, nanodrugs could combine chemotherapy with other therapeutic modalities to achieve synergistically enhanced antitumor efficacy.7, 8 Especially, by virtue of labeling techniques, it is facile to monitor the accumulation of nanodrugs in tumors to further optimize the treatment under imaging guidance.9–11 In spite of the aforementioned advantages, constructing such “all-in-one” nanodrugs still suffers from several challenges, such as tedious fabrication, poor stability, low drug loading capacity and unsatisfied biocompatibility.

Two dimensional (2D) nanomaterials have sparked enormous research interests due to their specific flat nanostructures and physicochemical properties.12–15 To date, various


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2D nanomaterials have been reported, such as graphene,16 black phosphorus,17 g-C3N418 and Mxenes.19 Among them, coordination nanosheets have emerged as a new class of 2D materials, which are composed by organic ligands and metal ions through coordination interactions.20–23 Compared with other 2D nanomaterials, the chemical and physical structures of coordination nanosheets are easily tuned, due to the various combinations between organic ligands and metal ions.24 More intriguingly, photoactive molecules can be employed as ligands, producing photoactive coordination nanosheets. Their intrinsic photoactivity and nanosheet structure enable them to rapidly respond to light irradiation with superior phototherapeutic performance.25 Importantly, photoactive nanosheets with high surface area can serve as outstanding nanocarriers for chemotherapy drugs with high loading capacity.26 In most cases, photoactive molecules are utilized as imaging agents for theranostics through either fluorescence imaging or magnetic resonance (MR) imaging.27,

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For example, Yin and coworkers have well

demonstrated the great potential of photoactive coordination nanomaterials for fluorescence or MR imaging guided tumor therapy.29,

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All these characters make

photoactive coordination nanosheets more appealing to cancer therapy. Porphyrin is one


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of the most popular photoactive molecule for constructing 2D photoactive coordination nanosheets.22, 25, 31 Porphyrin nanosheets have been successfully prepared using either “bottom-up” or “top-down” strategies.22, 32 However, their photoactivity relies on the visible light irradiation, which is restricted by the poor tissue penetration.32 Comparatively, phthalocyanine compounds are excited by near infrared (NIR) light, which possesses deep tissue penetrating permeability.33 Besides, their safety has been approved by the US Food and Drug Administration (FDA) for clinical usage. Unfortunately, phthalocyanine based 2D photoactive coordination nanomaterials have rarely been explored.

Herein, we constructed phthalocyanine based coordination nanosheets as multifunctional nanodrugs for cancer treatment (Scheme 1). We found that manganese phthalocyanine (MnPc) tetracarboxylic acid as organic ligand coordinates with Zr(IV) based metal nodes to form MnPc nanosheets. Moreover, the surface of MnPc nanosheets was modified with hyaluronic acid (HA) to improve the dispersion stability as well as the tumor targeting ability of the nanosheets. With MnPc@HA nanosheets as carrier, curcumin was loaded with loading capacity as high as 89 wt%. The curcumin release from


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MnPc@HA nanosheets was responsive to both overexpressed hyaluronidase (HAase) in tumor microenvironment and NIR light irradiation. Especially, MnPc@HA nanosheets with high T1 relaxivity value (up to 11.04 mM–1 s–1) selectively accumulated in tumor for MR imaging guided tumor therapy. The in vitro and in vivo studies demonstrate that MnPc@HA nanosheets combining photothermal/chemotherapy efficiently ablate tumors with barely noticeable side effects. Therefore, MnPc@HA nanosheets featured with tumor targeting ability, high drug loading capacity, T1-weighted MR imaging function, NIR photothermal effect and synergistic antitumor activity, are an ideal multifunctional nanoplatform for cancer treatment.


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Scheme 1. Illustration of Cur-MnPc@HA nanosheets for tumor targeting delivery and MR imaging guided synergistic photothermal/chemotherapy.


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2. MATERIALS AND METHODS

2.1. Synthesis of MnPc nanosheets. MnPc tetracarboxylic acid (0.05 g) was dissolved in 50 mL of DMSO/DMF mixture solution (1:4, v/v). Then zirconyl chloride octahydrate (0.15 g) and benzdoic acid (1.4 g) were added, and the mixture solution was stirred at 90 oC for 12 h in the dark. After centrifugation at 13000 rpm for 10 min, the precipitation was washed with DMF for three times. MnPc nanosheets were obtained and stored in ethanol for further usage.

2.2. Drug loading on MnPc nanosheets. To load curcumin to MnPc nanosheets, 900 μL of MnPc nanosheets aqueous solution (0.1 mg mL–1) was mixed with 100 μL of curcumin solution (0.4, 0.8, 1.6 mg mL–1) in ethanol. The mixture was sonicated for 2 min and then stirred in the dark for 6 h. Afterwards, Cur-MnPc nanosheets were centrifuged and washed with ethanol to remove free curcumin. The content of free curcumin (C1) was quantified using UV-vis spectrometer. To prepare Cur-MnPc@HA nanosheets, Cur-MnPc nanosheets were re-dispersed in 0.5 mL of water, and then added into 0.5 mL of HA aqueous solution (10 mg mL–1). The mixture solution was sonicated at room temperature


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for 1 h and then stirred in the dark for another 6 h. The excess HA was removed by centrifugation (13300 rpm, 30 min) and washed with water for three times. The curcumin content in the supernatant (C2) was measured using UV-vis spectrometer. Curcumin loading capacity (LC) was calculated according to equation (1):

LC(%) =

𝐶𝑇 ― 𝐶1 ― 𝐶2 𝐶𝑇

× 100%

(1)

where, CT is the total content of curcumin for drug loading.

To HA aqueous solution (0.5 mL, 10 mg mL–1), MnPc nanosheets (0.5 mL, 0.1 mg mL–1) in water were added. The mixture solution was sonicated in water bath for 1 h and then stirred at room temperature for another 6 h. The excess HA was removed by centrifugation (13300 rpm, 30 min) and washed with water to obtain MnPc@HA nanosheets.

2.3. Photothermal effect. MnPc@HA nanosheets in water (5, 10, or 20 μg mL–1, 1 mL) were irradiated by a 730 nm LED light (Kiwilight Co., Ltd., China) at a power density of 0.9 W cm–2 for 5 min. The solution temperature was monitored by a thermal imaging camera (FLIR C2, USA). To study the photothermal stability, MnPc@HA nanosheets (10


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μg mL–1) or ICG (15 μg mL–1) aqueous solution were irradiated under 730 nm NIR light (0.9 W cm–2) for 5 cycles. The UV-vis spectra before and after NIR light irradiation were recorded by UV-vis spectrometer (UV-2450, Shimadzu, Japan). The photothermal effect and photostability of Cur-MnPc@HA nanosheets and MnPc@PAA nanosheets were measured following the similar procedures.

2.4. Drug release from Cur-MnPc@HA nanosheets. One milliliter of Cur-MnPc@HA (94.5 μg mL–1, with curcumin loading capacity of 89 wt%) was mixed with 1 mL of 10% FBS in phosphate-buffered saline (PBS). For group (1), the mixed solution was kept in the dark. For group (2), the solution was irradiation under 730 nm light (0.9 W cm–2). For group (3), 60 UN HAase was added into the solution and incubation in the dark. For group (4), 60 UN HAase was added into the solution and incubation for 1 h at 37 oC, then the solution was irradiation under 730 nm light (0.9 W cm–2). For group (1), (2) and (4), 0.2 mL of solution was taken out at predetermined time points. For group (1) and (3), the drug release was monitored for up to 24 h. To determine curcumin release, all samples were


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centrifuged at 13300 rpm for 15 min, and curcumin contents in the supernatants were quantified by a fluorescence spectrometer (λex = 420 nm).

2.5. CD44 expression on 4T1 cells. The expression of CD44 on 4T1 cells was studied through immunostaining. Briefly, 2 × 105 4T1 cells were incubated with FITC labeled antimouse CD44 for 1 h at 4 oC. Then cells were washed with cold PBS, and the nuclei were stained by Hoest33342. All the cells were fixed with 4% parafomaldehyde and imaged on a confocal laser scanning microscope (TI-E+A1 SI, NIKON, Japan).

2.6. Tumor targeting ability of Cur-MnPc@HA nanosheets. 4T1 and NIH/3T3 cells were treated with Cur-MnPc@HA (37.8 μg mL–1, with curcumin loading capacity of 89 wt%) for 4 h. Afterwards, cells were washed with PBS for three times and lysed with 1% SDS in PBS. The contents of Mn were measured by atomic absorption spectrometer (TAS-990, Persee, China).

2.7. Intracellular drug release. 4T1 cells were planted into 6 well plates at the density of 1 × 106 per well. Then cells were treated with Cur-MnPc@HA (94.5 μg mL–1, with curcumin loading capacity of 89 wt%) in cell culture medium for 4 h. The plates were


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irradiation by NIR light (0.9 W cm–2) for 5 min. After 30 min, cells were washed with PBS and detected under a fluorescence microscope. Cells were collected and the intracellular fluorescence intensity was quantified by flow cytometer (FACS-Calibur, Becton Dicknson, USA).

2.8. In vitro antitumor studies. 4T1 cells were cultured with MnPc@HA nanosheets (20 μg mL–1) or Cur-MnPc@HA nanosheets (37.8 μg mL–1, with curcumin loading capacity of 89 wt%) in DMEM medium for 12 h. Then cells were irradiated under 730 nm light (0.9 W cm–2) for 5 min. After 24 h, the cell viability was measured using CCK-8 kit. Meanwhile, the antitumor efficacy was further studied through live/dead staining. Cells were stained by calcein-AM (5 g mL–1) and PI (10 g mL–1) for 20 min. Then fluorescence images were taken under a fluorescence microscope (IX 83, Olympus, Japan).

2.9. JC-1 staining. 4T1 cells were cultured with MnPc@HA nanosheets (20 μg mL–1) or Cur-MnPc@HA nanosheets (37.8 μg mL–1, with curcumin loading capacity of 89 wt%) in cell culture medium for 4 h. Then the cell was irradiated under 730 nm NIR light (0.9 W


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cm–2) for 5 min. Subsequently, cells were stained by JC-1 staining kit and imaged on a fluorescence microscope.

2.10. Magnetic resonance imaging. The T1 relaxation time was measured on a 0.5 T NMR analyzer (PQ001-20, Niumag, China). Relaxivity (r1) was calculated according to the slopes of T1 relaxation time verse Mn concentration. T1-weighted images of different concentration of MnPc@HA nanosheets were captured by a 3.0T MR scanner (Skyra, Siemens Healthcare, Germany). The in vivo mice MR imaging at varied time points (0, 8, 12 and 24 h) after intravenous injection was performed on the 3.0T MR scanner. The parameters for T1-weighted MR imaging were as follows: repetition time (TR) = 2000 ms, echo time (TE) = 18 ms, slice thickness = 2 mm.

2.11. In vivo antitumor effect. Mice were divided into the following six groups: (1) blank control, (2) NIR light, (3) MnPc@HA nanosheets, (4) Cur-MnPc@HA nanosheets, (5) MnPc@HA + NIR light, and (6) Cur-MnPc@HA + NIR light. To fabricate tumor-bearing mice, 4T1 tumor cells were subcutaneously injected into the back of BALB/c mice (n = 5). When the tumor volume reached 100 mm3, MnPc@HA or Cur-MnPc@HA nanosheets


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were intravenously injected into mice (8 mg kg–1). After 12 h, mice were irradiated under 730 nm NIR light (0.9 W cm–2) for 5 min. Tumor size and body weight of mice were recorded for up to 15 days. On day 15, all the mice were sacrificed, and tumors were harvested for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Meanwhile, the main organs, including liver, heart, spleen, lung and kidney, were also examined by H&E staining.

3. RESULTS AND DISCUSSION

3.1. Synthesis and Characterization. It is well known that Zr(IV) with high valence is readily to coordinate with carboxylate ligands to form coordination nanomaterials.34,

35

Here, MnPc nanosheets were prepared from MnPc tetracarboxylic acid and zirconyl chloride via solvothermal reaction at 90 oC for 12 h. Transmission electron microscopy (TEM) clearly displays the free standing 2D structure of MnPc nanosheets (Figure 1a). The element mapping results show the distribution of Mn and Zr throughout the nanosheets (Figure S1). According to atomic force microscopy (AFM) analysis, the thickness of MnPc nanosheets is ~4.0 nm (Figure 1b). The average size determined by


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dynamic light scattering is around 100 nm with polydispersity index (PDI) of 0.19 (Figure 1c). In the X-ray photoelectron spectroscopy (XPS) spectra, the binding energies of C 1s, N 1s, O 1s, Mn 2p and Zr 3d were observed (Figure S2). The high-resolution XPS spectra of MnPc nanosheets show characteristic binding energy peaks of Mn 2p1/2 and Mn 2p3/2 at 652.8 and 641.8 eV (Figure 1d). The binding energy peaks at 182.2 and 184.6 eV are assigned to Zr 3d5/2 and Zr 3d3/2, respectively (Figure 1e). Besides, the UV-vis spectrum of MnPc nanosheets displays characteristic absorption bands of Pc compounds (Figure S3). Compared with MnPc tetracarboxylic acid, a slightly red shift from 725 nm to 730 nm was observed after the formation of nanosheets, which could be attributed to the Jaggregation of MnPc.36

To increase tumor targeting ability, the surface of MnPc nanosheets was modified with HA to obtain MnPc@HA nanosheets.37 The FTIR spectrum of MnPc@HA nanosheets shows characteristic bands of HA at 3395 (υO–H), 1610 (υC=O), 1405 (δC–N) and 1038 (δO–H) cm–1 (Figure 1f). According to the TEM image, HA decoration has little influence on the morphology of MnPc nanosheets (Figure S4). It is noteworthy that the


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surface charge was changed from 33.7 ± 2.6 mV to -8.0 ± 1.3 mV after HA modification (Figure S5), because of the abundant carboxylic acids in HA. Due to the steric hindrance of HA, MnPc@HA nanosheets exhibit extraordinary dispersion stability in physiological solution without any noticeable aggregates (Figure S6).

Figure 1. a) TEM and b) AFM images of MnPc nanosheets. c) Size distribution of MnPc nanosheets in water was analyzed by dynamic light scattering. d-e) XPS spectra of Mn and Zr of MnPc nanosheets. f) FTIR spectra of HA, MnPc nanosheets and MnPc@HA nanosheets. Scale bars are 100 nm.

3.2 Photothermal Activity of MnPc@HA Nanosheets. To evaluate the photothermal activity of MnPc@HA nanosheets, the solution was exposed to NIR light irradiation (λ=


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730 nm, 0.9 W cm–2) for 5 min, and the temperature elevation was recorded using thermal imaging camera (Figure 2a). In the presence of 20 μg mL–1 MnPc@HA nanosheets, the solution temperature was gradually increased by 48.3 oC under NIR light irradiation (Figure 2b). By contrast, the temperature of pure water was only increased by 3.2 oC under the same condition, validating the high photothermal activity of MnPc@HA nanosheets. In general, the photothermal activity is determined by two parameters, i.e., extinction coefficient and photothermal conversion efficiency. Based on the Lambert-Beer law, the extinction coefficient of MnPc@HA nanosheets at 730 nm was up to 49.7 Lg–1 cm–1 (Figure 2c). The photothermal conversion efficiency of MnPc@HA nanosheets was calculated to be 72.3%, much higher than conventional PTT agents, such as prussian blue nanoparticle (41.4%),9 black phosphorus quantum dots (28.4%),38 Au nanorods (21%)39 and Ta4C3 nanosheets (44.7%).40

For the majority of organic photothermal agents, their photostability is poor due to photobleaching effect. Herein, the photostability of MnPc@HA nanosheets was investigated. Meanwhile, indocyanine green (ICG), an FDA approved photothermal


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agent, was taken for comparison. The results show that the photothermal activity of ICG was substantially decreased after NIR light irradiation (Figure 2d). Comparatively, MnPc@HA nanosheets kept stable photothermal activity even after five irradiation cycles. Furthermore, UV-vis spectra of MnPc@HA nanosheets before and after light irradiation were almost the same (Figure S7); whereas, over 94% of ICG were photobleached under the same condition. The superior photostability of MnPc@HA nanosheets could be ascribed to the low photobleaching quantum yields of MnPc compounds (< 10–7).41 Taking together, all these data demonstrate the superior photothermal activity of MnPc@HA nanosheets, which would be a promising PTT agent for biomedical applications.


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Figure 2. a) Photothermal imaging of MnPc@HA nanosheets (0, 5 and 10 μg mL–1) under 730 nm NIR light irradiation (0.9 W cm–2). b) Temperature elevation of MnPc@HA nanosheets in water during NIR light irradiation. c) Temperature profile of MnPc@HA nanosheets in water with NIR light irradiation (black line), and time constant (τ) for heat transfer from the nanosheets (blue line). d) Photothermal stability of MnPc@HA nanosheets. ICG was taken for comparison. e) Curcumin loading capacity of MnPc@HA nanosheets. f) UV-vis absorption spectra of Cur-MnPc@HA, MnPc@HA and curcumin in water.


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3.3 Drug Loading and Release. To investigate the potential of MnPc@HA nanosheets for drug delivery, curcumin as model drug was loaded into the nanosheets. UV-vis spectrum of Cur-MnPc@HA nanosheets displays a broadened absorption band from 400 to 500 nm (Figure 2f). The FT-IR spectra of the Cur-MnPc@HA nanosheets clearly shows the characteristic bands of curcumin (νC=O 1510 cm–1, νAr-O 1280 cm–1), HA (νC=O 3392 cm–1, νC=O 1605 cm–1) and MnPc (σC-H 730 cm–1) (Figure S8). The above results indicated the successful loading of curcumin. The loading capacity of MnPc@HA nanosheets for curcumin is up to 89 wt% (Figure 2e), much higher than traditional nanocarriers (Table S1). The extremely high drug loading capacity could be ascribed to the following two aspects: (1) the 2D structure endows MnPc@HA nanosheets with high surface area for drug loading; (2) MnPc@HA nanosheets abundant with metal clusters and carboxylic acids could interact with curcumin through hydrogen bonds or coordinative interactions. The as-prepared Cur-MnPc@HA nanosheets exhibits high dispersibility in saline, PBS and cell culture medium (Figure S9).


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Next, the release profile of curcumin from the nanosheets was studied. As shown in Figure 3a, over 55% curcumin was released with 25 min under NIR light irradiation. The photoresponsive drug release was attributed to the photothermal effect of Cur-MnPc@HA nanosheets (Figure S10), which could promote the diffusion of curcumin from the nanosheets. In addition, HAase is overexpressed in a variety of tumor cells, such as breast tumors, colon carcinoma, human melanoma and glioblastoma cell lines. In the presence of HAase, the surface HA on MnPc@HA nanosheets can be gradually degraded into low-molecular-weight saccharides.42 As a result, curcumin release is further increase to 72% in the presence of both HAase and NIR light irradiation (Figure 3a). Accordingly, MnPc@HA nanosheets efficiently release curcumin in response to both external NIR light irradiation and endogenous HAase in tumor microenvironment. Such drug release profile facilitates the burst drug release at tumor sites to improve the final antitumor efficacy. It is noteworthy that the premature leakage of curcumin without NIR light irradiation is very slow. Only no more than 15% curcumin is leaked within 24 h (Figure S11), which is beneficial to reducing the side effects of chemotherapy.


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Figure 3. a) Curcumin release from the nanosheets in the presence of HAase under NIR light irradiation. b) The cellular uptake of Cur-MnPc@HA nanosheets by 4T1 and NIH/3T3 cells in the absence or presence of free HA. c) Intracellular curcumin release under NIR light irradiation, and d) the fluorescence intensity was analyzed through flow cytometry. Scale bar is 25 μm.

3.4 Tumor Targeting and Intracellular Drug Release. As HA selectively binds to CD44 on tumor cells, Cur-MnPc@HA nanosheets were expected to accumulate within tumors through their specific binding to CD44 receptors.43 The overexpression of CD44 on 4T1 cells was investigated through immunofluorescence staining with FITC labled anti-CD44. NIH/3T3 fibroblasts as representative normal cells were taken for comparison. The results


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reveal that negligible fluorescence was observed on NIH/3T3 cells (Figure S12). By contrast, obvious green fluorescence appeared clearly on the cell membrane of 4T1 cells, indicating the overexpression of CD44. Next, the cellular uptake of Cur-MnPc@HA nanosheets was measured to evaluate their targeting ability. Both 4T1 breast cancer cells and NIH/3T3 fibroblast cells were treated with Cur-MnPc@HA nanosheets for 4 h. Then the intracellular Cur-MnPc@HA nanosheets were measured by atomic absorption spectrometer. As expected, the content of Cur-MnPc@HA nanosheets in 4T1 cells is 2.6 times higher than that of NIH/3T3 cells (Figure 3b). To further confirm the binding specificity of Cur-MnPc@HA nanosheets, we carried out competitive binding experiment using free HA to block CD44 binding sites. We found that the addition of free HA significantly suppressed the internalization of Cur-MnPc@HA nanosheets. Based on these results, it can be concluded that HA mediates the cell uptake of Cur-MnPc@HA nanosheets in CD-44 postive tumor cells.

Then, we investigated NIR light-triggered curcumin release from Cur-MnPc@HA nanosheets in tumor cells. In Cur-MnPc@HA nanosheets, the fluorescence of curcumin


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is significantly quenched by MnPc@HA nanosheets via fluorescence resonance energy transfer (FRET) effect, and only recovered after curcumin release (Figure S13). Thus, the intracellular fluorescence intensity reflects the content of curcumin released from the nanosheets. For cells treated with Cur-MnPc@HA nanosheets in the dark, little fluorescence was observed (Figure 3c & 3d). However, upon NIR light irradiation, tumor cells exhibit bright green fluorescence in the cytoplasm. The photo-promoted curcumin release within tumor cells is ascribed to the photothermal effect of Cur-MnPc@HA nanosheets, which accelerates the diffusion of curcumin from the nanosheets.

3.5 Biocompatibility studies. The biocompatibility of the MnPc@HA nanosheets was evaluated through hemolysis and cytotoxicity assays. Barely noticeable hemolysis was found when red blood cells were incubated with MnPc@HA nanosheets for 8 h (Figure 4a). Cytotoxicity of MnPc@HA nanosheets was studied on three different cell lines (HeLa, L929 and 4T1 cells). All of the cells kept over 90% cell viability when the concentration of MnPc@HA nanosheets was up to 100 μg mL–1 (Figure 4b). To evaluate the in vivo biocompatibility, MnPc@HA nanosheets were intravenously injected into mice. The time


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dependent biodistribution of MnPc@HA nanoseets in the main organs during 72 h postinjection was explored (Figure S14). The Mn contents of in all main organs decline sharply after 12 h post-injection which might be due to the metabolism of mouse, indicating that MnPc@HA nanosheets could be cleared from the body. The blood biochemistry analysis reveals that all the blood cell numbers are in the normal ranges (Figure 4c–4e). The biochemistry parameters of liver/kidney functions are almost the same as those of healthy mice, suggesting the good biocompatibility of MnPc@HA nanosheets (Figure 4f–4i).


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Figure 4. Biosafety and biocompatibility studies. a) Hemolysis rates of red blood cells in the presence of MnPc@HA nanosheets. b) Cytotoxicity of the nanosheets against HeLa, L929 and 4T1 cells. c-i) Hematological indexes of BALB/c mice after intravenous injection of the nanosheets: red blood cell (RBC), white blood cell (WBC), platelet (PLT), blood urea nitrogen (BUN), total bilirubin (T-Bil), creatinine (Cr), and glutamic oxaloacetic transaminase (AST). The yellow areas indicate the normal ranges.

3.6 In Vitro Antitumor Activity. The in vitro antitumor activity of Cur-MnPc@HA nanosheets was measured via cytotoxicity assay. As shown in Figure 5a, neither NIR light irradiation nor MnPc@HA nanosheets show significant antitumor activity. For cells treated by curcumin or PTT with MnPc@HA nanosheets, the cell viability was only decreased by 32% and 63%, respectively (Figure 5a). By sharply contrast, after treating with CurMnPc@HA nanosheets under NIR light irradiation, over 92% tumor cells were killed. Besides, living and dead cells were stained by calcein-AM and PI with green and red fluorescence, respectively. Consistent with the cell viability results, large number of cells present green fluorescence when treated by Cur-MnPc@HA nanosheets in the dark (Figure 5b). Comparatively, almost all cells were dead and stained with red fluorescence


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after photothermal/chemo-therapy with Cur-MnPc@HA nanosheets. All these data validate the high synergistic effects of Cur-MnPc@HA nanosheets against tumor.

Figure 5. a) Cell viability and b) live/dead staining of 4T1 cells after different groups: (1) blank, (2) MnPc@HA nanosheets, (3) NIR light irradiation, (4) curcumin (Cur), (5) MnPc@HA nanosheets with NIR light irradiation, (6) Cur-MnPc@HA nanosheets with NIR light irradiation (0.9 W cm–2). c) Mitochondria integrity was checked by JC-1 staining. Cellular nuclei were stained by Hoest 33342. All scale bars are 100 μm.


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It is well known that mitochondria play a critical role in cell apoptosis. To further explore the antitumor mechanism of Cur-MnPc@HA nanosheets at subcellular level, we utilized JC-1 to assess the mitochondria integrity. JC-1 is readily to aggregate in normal mitochondria and display red fluorescence. Once mitochondrial membrane is disrupted, JC-1 would stay in cytoplasma as monomer with green fluorescence. The green/red fluorescence intensity ratio (G/R) reflects the mitochondria integrity. According to the fluorescent images in Figure 5c, the average G/R value of normal cells is 0.01. After PTT with MnPc@HA nanosheets, the G/R value is sharply increased to 0.83, much higher than those of other groups. Similar result was also observed in cells treated with CurMnPc@HA nanosheets under NIR light irradiation. Besides, the antitumor activity of curcumin is well demonstrated to be induced by cell cycle arresting.44 Therefore, during the antitumor process of Cur-MnPc@HA nanosheets, mitochondrial dysfunction and cell cycle arresting are simultaneously involved, achieving synergistically enhanced antitumor effect.


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Figure 6. a) Inversed relaxation time (1/T1) as a function of Mn concentration. Inset: T1weighted imaging of MnPc@HA nanosheets at different Mn concentrations (from left to right: 0, 0.01, 0.02, 0.15, 0.25 and 0.5 mM). b) In vivo T1-weighted MR imaging at 8, 12 and 24 h post intravenous injection of MnPc@HA nanosheets. Tumors were marked with red circles. c) The intensity of MR signal at tumors was quantified. d) Biodistributions of MnPc@HA and MnPc@PAA nanosheets at 12 h post injection.

3.7 In Vivo MR Imaging Guided Antitumor Therapy. Due to the paramagnetism, manganese based nanomaterials, such as MnO2 and Mn-based layered double hydroxide,45,

46

have been widely used for T1-weighted MR imaging.47 To study the

potential of MnPc@HA nanosheets as contrast agent, the T1-weighted MR images of


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MnPc@HA nanosheets at different concentrations were captured. As displayed in Figure 6a, T1-weighted MR signal of MnPc@HA nanosheets is linearly dependent on their concentration. The longitudinal relaxivity (r1) of MnPc@HA nanosheets was measured to be 11.04 mM–1 s–1, higher than many previous reported manganese-based nanomaterials.27, 45, 48, 49 Next, MnPc@HA nanosheets were intravenously injected into 4T1 tumor bearing mice, then T1 MR images of mice were taken on a 3 T clinical MR scanner. From Figure 6b and 6c, the T1 MR signal at tumor site gradually increased and reached a plateau at 12 h post-injection, which is 2.1 times as high as that that of preinjection. These results confirm that MnPc@HA nanosheets are a promising T1-weighted MR imaging agent in vivo.

The distributions of MnPc@HA nanosheets in the main organs were further quantified using ICP-MS. Due to the similar size distributions and surface charge to MnPc@HA nanosheets (see Figure S15&S16), polyacrylic acid (PAA) coated MnPc nanosheets (MnPc@PAA) were taken for comparison. The results show that over 9.8% of MnPc@HA nanosheets were accumulated in tumors (Figure 6d), much higher than


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that of MnPc@PAA nanosheets. Consequently, HA as tumor targeting group promotes the accumulation of MnPc@HA nanosheets at tumor sites.

For in vivo antitumor studies, all the mice were divided into four groups: (1) blank control, (2) NIR light, (3) MnPc@HA nanosheets, (4) Cur-MnPc@HA nanosheets, (5) MnPc@HA + NIR light, and (6) Cur-MnPc@HA + NIR light. MnPc@HA or Cur-MnPc@HA nanosheets were intravenously injected into mice. At 12 h post injection, mice were irradiated under 730 nm light (0.9 W cm–2) for 5 min, and the local temperature of tumors was monitored using infrared thermal camera. As shown in Figure 7a, for mice treated with Cur-MnPc@HA nanosheets, the local temperature reached as high as 56 oC after 5 min of irradiation. By constrast, the temperature in the control group was only increased to 3.5 oC, demonstrating that Cur-MnPc@HA nanosheets as photothermal agents efficiently convert NIR light energy into local hyperthermia. The tumor size and body weight of each mouse were recorded for two weeks. It can be observed that the tumor growth was remarkably inhibited by Cur-MnPc@HA nanosheets under NIR light irradiation (Figure 7b and 7c). Meanwhile, tumors were still in growth in other groups.


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Pathological changes of tumors were examined through TUNEL staining. The results reveal that most of the tumor cells were apoptotic and necrotic after the combination therapy of Cur-MnPc@HA nanosheets (Figure 7d). Comparatively, for tumors in other groups, amounts of tumor cells with normal morphology can still be observed. Notably, all the mice behaved normally and did not lose body weight during the treatments (Figure 7e). The main organs (liver, heart, spleen, lung and kidney) were harvested and checked through histological staining (Figure S17). No obvious off-target damages were found after the combination therapy with Cur-MnPc@HA nanosheets.

The outstanding antitumor performance of Cur-MnPc@HA nanosheets is attributed to the following three aspects: (1) the surface coating of HA promotes the accumulation of Cur-MnPc@HA nanosheets within tumor cells (Figure 3b and S12); (2) the extraordinary photothermal effect of Cur-MnPc@HA nanosheets accelerates the drug release at tumor microenvironment under NIR light irradiation (Figure 3c and 3d); and (3) the combination of photothermal therapy and chemotherapy eradicates tumor cells via


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two different pathways (Figure 5 and 7), achieving improved therapeutic efficacy and low risk of tumor recurrence.

Figure 7. a) In vivo photothermal effect of Cur-MnPc@HA nanosheets under NIR light irradiation (0.9 W cm–2) for 5 min. b) Tumor growth curves and c) digital photos after different treatments. d) TUNEL staining of tumor slices after the treatments. e) Changes of body weight during the treatments. Scale bar is 50 μm.

4. CONCLUSIONS


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In summary, we reported a new kind of coordination nanosheets (MnPc@HA nanosheets) as an “all-in-one” platform for imaging guided therapy of cancer. The nanosheets were constructed with photoactive and paramagnetic MnPc as building blocks, and decorated by tumor targeting HA on the surface. MnPc@HA nanosheets exhibit a superior NIR photothermal performance over most existing photothermal agents. As a 2D drug carrier, curcumin was efficiently loaded into MnPc@HA nanosheets, and released upon exposure to NIR light irradiation and HAase-rich tumor microenvironment. Moreover, under T1weighted MR imaging guidance, Cur-MnPc@HA nanosheets efficiently ablate tumors through combining photothermal/chemo-therapy. Besides, MnPc@HA nanosheets are biocompatible and safe for biomedical applications. Therefore, MnPc@HA nanosheets exhibit multiple merits for cancer treatment, including tumor targeting, high drug loading capacity, controllable drug release behavior, synergistic antitumor therapy, MR imaging property and excellent biocompatibility. All these features make MnPc@HA nanosheets a powerful platform for future synergistic therapy of cancer.


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ASSOCIATED CONTENT

Supporting Information.

The Supporting Information is available for free of charge on the ACS Publications website at DOI: XXX XXX.

Synthesis and characterization of MnPc tetracarboxylic acid, Experimental procedures. HAADF-STEM and element mapping of MnPc nanosheets, Figure S1. XPS spectrum of MnPc nanosheets, Figure S2. UV-vis spectra of MnPc tetracarboxylic acid and MnPc nanosheets in DMF, Figure S3. TEM image of MnPc@HA nanosheets, Figure S4. Size distributions and zeta potential analysis of MnPc nanosheets, MnPc@HA nanosheets and Cur-MnPc@HA nanosheets, Figure S5. Digital photo of MnPc and MnPc@HA nanosheets dispersed in different solution, Figure S6. UV-vis spectra of MnPc@HA nanosheets and ICG before and after NIR light irradiation, Figure S7. FTIR spectra of HA, Curcumin, MnPc nanosheets and Cur-MnPc@HA nanosheets, Figure S8. Digital photo of Cur-MnPc@HA nanosheets dispersed in water, PBS, saline and DMEM cell culture medium, Figure S9. Photothermal properties of Cur-MnPc@HA nanosheets in water


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during NIR light irradiation, Figure S10. Curcumin release from Cur-MnPc@HA nanosheets for 24 h, Figure S11. The expression of CD44 on 4T1 tumor cells and NIH/3T3 fibroblast cells via immunofluorescence staining, Figure S12. Fluorescence spectra of curcumin (Cur), Cur-MnPc@HA nanosheets, and MnPc@HA nanosheets mixed with curcumin, Figure S13. The biodistribution in major organs and tumor of MnPc@HA at different time after injection, Figure S14. Size distributions and surface charge of MnPc@HA and MnPc@PAA nanosheets in PBS, Figure S15. Photothermal properties of MnPc@PAA nanosheets in water during NIR light irradiation, Figure S16. H&E staining main organs (liver, heart, spleen, lung and kidney) after intravenous injection of MnPc@HA nanosheets, Figure S17. Loading capacities (LC) of traditional nanocarriers for curcumin, Table S1.

AUTHOR INFORMATION

Corresponding Authors *E-mail: [email protected] (W. Chen);

*E-mail: [email protected] (Y.-N. Liu).


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Author Contributions Ke Zeng⊥ and Qunfang Xu⊥ contributed equally to this work. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Funding Sources

This work was supported by the National Natural Science Foundation of China (No. 21636010, and 21807117), and Hunan Provincial Natural Science Foundation of China (No. 2018JJ3631), China Postdoctoral Science Foundation (No. 2017M620357), and the State Key Laboratory of Powder Metallurgy, Central South University, Changsha, China.

Notes The authors declare no competing financial interest.


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Coordination Nanosheets of Phthalocyanine as Multifunctional

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