Biocompatible Iron PhthalocyanineâAlbumin Assemblies as

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Biocompatible Iron Phthalocyanine-Albumin Assemblies as Photoacoustic and Thermal Theranostics in Living Mice Qingyan Jia, Jiechao Ge, Weimin Liu, Xiuli Zheng, Mengqi Wang, Hongyan Zhang, and Pengfei Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • Publication Date (Web): 07 Jun 2017 Downloaded from http://pubs.acs.org on June 8, 2017

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ACS Applied Materials & Interfaces

Biocompatible Iron Phthalocyanine-Albumin Assemblies as Photoacoustic and Thermal Theranostics in Living Mice Qingyan Jia,a,b Jiechao Ge,a,b* Weimin Liu,a,b Xiuli Zheng,a,b Mengqi Wang,a Hongyan Zhang,a Pengfei Wanga,b

a Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, People's Republic of China b School of future technology, University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China Keywords: iron phthalocyanine, human serum albumin, photoacoustic imaging, photothermal therapy, cancer Abstract Exploring novel and versatile nanomaterials for the construction of personalized multifunctional phototheranostics with significant potentials in bioimaging-guided tumor

phototherapies

has

attracted

considerable

attention.

Herein,

the

phototheranostic agent HSA-FePc nanoparticles (HSA-FePc NPs) were fabricated for photoacoustic (PA) imaging-guided photothermal therapy (PTT) of cancer in vivo. The prepared HSA-FePc NPs exhibited high stability, efficient NIR absorption, good capability and stability of photothermal behavior with a high photothermal conversion efficiency of ~44.4%, high contrast and spatial resolution of PA imaging, efficient cancer

therapy,

and

low

long-term

toxicity.

This

potent

multifunctional

phototheranostic is, therefore, very promising and favorable for effective, precise, and safe antitumor treatment in clinical application. 1. INTRODUCTION

ACS Paragon Plus Environment


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Photothermal therapy (PTT), which applies near-infrared (NIR) light-induced heating from hyperthermia to ablate cancer, has recently drawn considerable attention in cancer treatment with high specificity and minimal invasiveness on surrounding normal tissues.1-4 An ideal hyperthermia is generally characterized to possess the following: 1) strong NIR light absorption; 2) outstanding photothermal conversion efficiency; 3) excellent photostability, biocompatibility, and biodegradability; 4) high tumor-homing ability; and 5) easy functionalization.5-8 In the past decade, many advanced studies have been performed to widely explore various candidates, including gold, silver, and platinum nanostructures,9-11 carbon nanomaterials,12,

13

metal sulfide or metallic oxide nanoparticles,14-16 organic indocyanine green (ICG),17-19 black phosphorus nanoparticles,20 and organic polymers,21-23 for PTT of cancer. Many pre-clinical in vivo studies based on the explored hyperthermia have demonstrated the massive potential of PTT for clinical applications in the near future. Insufficient visualization of the delivery, distribution, metabolism, and digestion of hyperthermia, as well as insufficient precise and comprehensive evaluation of PTT outcome toward tumour tissues, significantly restrict the in-depth application of PTT.24,

25

Therefore, different modal imaging-guided PTT nanotheranostics that

encompass bioimaging [one or more of the following: magnetic resonance imaging (MRI), upconversion luminescence (UCL), ultrasound (US), photoacoustic (PA), computer tomography (CT), and positron emission tomography (PET)] and PTT on a single nanoplatform have been extensively exploited in the past decade to meet the requirements of the future precision nanomedicine.26-33 Compared with the traditional


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optical imaging methodologies, PA imaging could provide deeper tissue-imaging with higher spatial resolution due to the PA effect, which has been successfully used for in vivo imaging.34-37 Despite the significant achievements obtained, considerable efforts should be devoted to exploring novel and versatile materials for the construction of personalized multifunctional phototheranostics with significant potentials in bioimaging-guided tumor phototherapies. Phthalocyanine (Pc) are promising second generation photosensitizers for photodynamic therapy.38-40 As reported previously, iron (II) phthalocyanine (FePc) was widely used in a variety of catalytic transformations, preparation of esters and oximes, reduction, oxidation, and radical reactions.41, 42 However, significant research aimed at achieving the application of FePc as PS for cancer treatment in vivo has resulted in limited success due to the poor water solubility and incapable singlet oxygen generation. Moreover, FePc exhibits a strong NIR absorption and no fluorescence generation. Thus, FePc may be utilized as an efficient photothermal agent for PA imaging-guided PTT of cancer if we overcome the shortcomings about water dispersibility and nontargeted effect of FePc. Recently, human serum albumin (HSA), a major component of serum proteins, has been extensively utilized as a natural drug carrier to sequester inorganic oxide or organic molecules, such as bismuth selenide, IR825, and Ce6, for fabricating effective phototheranostics because of its inherent biocompatibility, reduced immunogenicity, prolonged circulatory half-life, low levels of mononuclear phagocyte system clearance, improved pharmacokinetic properties, and versatile roles in drug delivery.43-48 Furthermore,



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HSA-based NPs reportedly accumulate preferentially at tumor sites through intravenous (i.v) injection.49,

Therefore, preparing new cancer phototheranostic

50

based on FePc through albumin-based self-assembly is highly possible. In this work, we designed and fabricated the HSA-FePc nanoparticles (HSA-FePc

NPs)

as

new

multifunctional

phototheranostic

agent

for

PA

imaging-guided PTT of cancer in vivo. The HSA-FePc NPs exhibited high stability in diverse physical solutions over a long period, efficient NIR absorption, good capability and stability of photothermal behavior with a high photothermal conversion efficiency of ~44.4%, high contrast and spatial resolution of PA imaging, efficient cancer therapy, and low long-term toxicity. To the best of our knowledge, the use of FePc in PA imaging-guided PTT of cancer has never been reported. This potent multifunctional phototheranostic is, therefore, very promising and favorable for effective, precise, and safe antitumor treatment in clinical application. 2. EXPERIMENTAL SECTION 2.1. Chemicals and Materials HSA, triethylamine (TEA), calcein AM, propidium iodide (PI), and FePc were purchased from Sigma-Aldrich. Fetal bovine serum (FBS), dulbecco’s modified Eagle’s medium (DMEM), streptomycin (100 μg mL−1), and penicillin (100 μg mL−1) were purchased from Gibco. Ultrapure water was used in all experiments. 2.2. Synthesis of HSA-FePc NPs To prepare HSA-FePc NPs, 1 mg of FePc and 10 μL of Triethylamine (TEA) were dispersed in 1 mL of methanol, respectively. Then, 100 μL of FePc/methanol


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solution was mixed with 10 mL of HSA aqueous solution (1 mg/mL). After stirring for 1h, the HSA-FePc NPs were prepared by subsequent dialysis. 2.3. Synthesis of HSA-FePc-Cy7.5 NPs To prepare HSA-FePc-Cy7.5 NPs, 1 mg of FePc, 10 μL of TEA, and 0.1 mg of Cy7.5 were added into 1 mL of methanol in succession. Then, 100 μL of the resulting solution was added into 10 mL of HSA aqueous solution (1 mg/mL). After stirring for 1 h, the HSA-FePc-Cy7.5 NPs were prepared by subsequent dialysis using a dialysis bag (MWCO 3500 Da). 2.4. Photodynamic Therapy of HSA-FePc NPs in vitro 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium bromide (MTT) assay was firstly carried out to confirm the cytotoxicity and PTT efficacy of the HSA-FePc NPs against HeLa cells in vitro. HeLa cells were obtained from the Center of Cells at Peking Union Medical College, and were cultured in DMEM with 10% FBS and maintained at 37 °C with 5% CO2. Then, HeLa cells were seeded in a 96-well plate, and treated with different concentrations of HSA-FePc NPs (0, 2.5, 5, 10, 15, and 20 μM FePc) for 4 h. The cells were subsequently irradiated under 671 nm laser (0.5 W cm-2, 10 min). Then, 100 μL of fresh medium were substituted, and incubated for 24 h. Afterwards, 20 μL (5 mg mL-1) of MTT was added and incubated for another 4 h. After removing the culture medium, 80 μL of DMSO was subsequently added and the absorbance at 570 nm was collected to confirm the cell survival rate. To further confirm the photothermal effect of HSA-FePc NPs, HeLa cells were treated with HSA-FePc NPs (20 μM) and incubated for 4 h. Then, the cells were



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irradiated under 671 nm laser (0.5 W cm-2, 10 min). After co-stained with calcein AM and PI, the cells were imaged by laser scanning confocal microscope (Nikon C1si). HeLa cells without adding HSA-FePc NPs upon irradiation under same conditions were used as controls. 2.5. Photoacoustic imaging of HSA-FePc NPs in vitro The HSA-FePc NPs with different concentrations (0 - 20 µM FePc) were added into the agarose tube (37 °C), and the pure-water was used as the control. Then, the PA images and signals were obtained using MOST inVision 128 with excitation wavelength ranging from 680 nm to 850 nm. 2.6. Photoacoustic imaging of HSA-FePc NPs in vivo Animal experiments were approved by the China Committee for Research and Animal Ethics in compliance with the law on experimental animals. 2 × 106 4T1 cells in PBS (50 μL) was injected subcutaneously into the buttock of female nude mice (4 weeks old, 15 - 20 g). When tumor size reached 75 - 100 mm3, PA imaging was obtained after the i.v. injection of HSA-FePc NPs (0.2 M FePc, 100 μL) at different time periods with excitation wavelengths ranging from 680 nm to 850 nm. The PA images were reconstructed offline using data acquired from all 128 transducers at each view through a modified back-projection algorithm. 2.7. Photothermal therapy of HSA-FePc NPs in vivo The tumor-bearing nude mice were divided into four groups (n=5, each group), and treated with different administration: without any treatment (group I), irradiation of 671 nm laser (10 min, 0.5 W cm-2) only (group II), intravenous injection of


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HSA-FePc NPs (0.2 M FePc, 100 μL) only (group III), and intravenous injection of HSA-FePc NPs (0.2 M FePc, 100 μL) + 671 nm (10 min, 0.5 W cm-2) (group IV). Then, the data, such as tumor sizes and body weights, were collected every other day. The tumor volume (V) was calculated following the Eq. (1): ab 2 V 2

(1)

where a is the tumor length and b is the tumor width. Relative tumor volume was normalized to its initial size when the administration was initiated. 2.8. Histopathological Examination After different treatments, the tumors in each group were excised and fixed in 4% formalin solution for histopathological tests. In brief, tumor samples embedding in paraffin blocks were sectioned into 4 μm slices, and then mounted them onto glass slides for hematoxylin and eosin (H&E) staining, and observed their photos using an optical microscope. The histopathological tests for the tissues (heart, liver, spleen, lung, and kidneys) were carried out according to the similar procedures performed in tumor. 3. RESULTS AND DISCUSSION 3.1. Characterization of HSA-FePc NPs As shown in Figure 1a, the HSA-FePc NPs were prepared by mixing HSA with FePc and then dialyzing the solution against pure-water to remove free FePc.44 The FePc calibration curve at 660 nm was used to measured the loading efficiency of FePc in HSA-FePc NPs. As described in the following equation: Y = 0.038X + 0.002 (R2 = 0.993), and the loading efficiency of FePc in HSA-FePc NPs was calculated to be ~



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51.3 wt% (Figure S1). Transmission electron microscopy (TEM) image of HSA-FePc NPs is shown in Figure 1b. The image indicates that the HSA-FePc NPs had a spherical structure with the diameter of approximately 30 nm. Dynamic light scattering (DLS) analysis revealed that the diameters of HSA-FePc NPs were approximately 55 nm (Figure 1c), which are larger than that measured by TEM due to the hydrated diameter of the HSA-FePc NPs combined with the solvent coating layer.51, 52 The measured-Zeta potential of the HSA-FePc NPs is ca. -26.9 mV (Figure 1d). The suitable hydrated diameter of approximately 55 nm and the negatively charged surface of HSA-FePc NPs enable it to accumulate in the tumor sites through the enhanced permeability and retention (EPR) effect.53, 54 In addition, compared with the absorption of FePc at 660 nm, the obtained HSA-FePc NPs red-shifted to 664 nm, which may originate from the J-aggregates formed by the self-assembly of aromatic molecules (Figure 1e).55-57 Further, a high absorption band ranging from 650 nm to 680 nm was observed. Therefore, the laser of 671 nm (NIR-light) can be used as the illuminant for subsequent PTT cancer treatment in vitro and in vivo. For biological application, the stabilities of HSA-FePc NPs in ultrapure water, PBS, 10% FBS, and DMEM were also investigated (Figure 1f). The HSA-FePc NPs exhibited excellent dispersivity and stability in all mediums without significant macroscopic aggregates. Further DLS (Figure 1g), Zeta potential (Figure 1h) investigations, and the release of FePc experiments (Figure S2) indicated that the HSA-FePc NPs are stable under physiological conditions even lasting for seven days.


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Figure 1. (a) Schematic illustration of HSA-FePc NPs preparation. (b) TEM image of HSA-FePc NPs. (c) The DLS analysis of HSA-FePc NPs in aqueous solution. (d) The zeta potentials of HSA-FePc NPs in aqueous solution. (e) The absorption spectra of HSA-FePc NPs in water and FePc in MeOH. (f) The dispersion stability of HSA-FePc NPs in various solutions. (g) The DLS stability of HSA-FePc NPs in various solutions for seven days. (h) The Zeta Potential stability of HSA-FePc NPs in various solutions for seven days.

3.2. Photoproperties of HSA-FePc NPs

Figure 2. (a) The concentration-dependent temperature elevation of HSA-FePc NPs solutions under 671 nm laser irradiation. (b) The temperature IR images of HSA-FePc NPs solutions under irradiation of 671 nm laser for 10 min. (c) The temperature change of HSA-FePc NPs solution upon 671 nm laser irradiation. The laser was switched off at 15 min post-irradiation. (d) Plot of



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cooling time (10 min) versus the negative natural logarithm of the temperature driving force obtained from the cooling stage, as shown in Figure 3c. (e) The temperature variations of HSA-FePc NPs aqueous solution and free FePc in MeOH at the same concentration under 671 nm laser irradiation for 8 cycles (each cycle for 15 min).

To evaluate the photothermal properties of HSA-FePc NPs, the HSA-FePc NPs with various FePc concentrations (0 - 20 µM) were irradiated under 671 nm laser (0.5 W cm-2, 10 min). Figures 2a and 2b reveal obvious concentration-dependent temperature increases for HSA-FePc NPs. Upon irradiation for 10 min, the temperature of HSA-FePc NPs at the concentration of 20 µM of FePc increased by 25.3 °C, which is much higher than that of pure-water (4.1 °C), indicating that HSA-FePc NPs can rapidly and efficiently convert NIR light into thermal energy. To further study the photothermal effect of HSA-FePc NPs, the photothermal conversion efficiency (η) was calculated.58, 59 According to the obtained data (Figure 2c and 2d), the η can reach approximately 44.4%, which is higher than that of most previously reported nanostructures, such as Au nanorods (21%), Dpa-melanin CNSs (40%), Cu2-xSe (22%), Cu3BiS3 (27.4%), and black phosphorus (36.8%).20,

60-63

Next, we

assessed the photothermal stability of HSA-FePc NPs compared with free FePc molecules. The variation in the temperature of HSA-FePc NPs and free FePc solutions at the same concentration was monitored as the irradiation of the solutions with 671 nm laser for 15 min progressed and then followed by natural cooling to room temperature. As showed in Figure 2e, after eight cycles of irradiation, the photothermal heating efficiency of free FePc declined rapidly in marked contrast to HSA-FePc NPs, whose photothermal heating capability remained robust after eight


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cycles of laser exposure, demonstrating the excellent photostability of HSA-FePc NPs compared with free FePc molecule. The high photothermal performance and excellent photostability of HSA-FePc NPs make it an encouraging photothermal agent for PTT of cancer in vitro as well as in vivo. 3.3. In vitro photothermal therapy

Figure 3. (a) The relative viability of HeLa cells incubated with different concentrations of HSA-FePc NPs for 4 h and then irradiated with/without 671 nm laser (*P < 0.05). (b) The co-staining images of HeLa cells by Calcein AM and PI incubated with/without HSA-FePc NPs under irradiation of 671 nm laser. Scale bars: 100 μm.

To investigate the cellular interactions between HSA-FePc NPs and tumor cells (Figure S3a), the NIR dye (Cy7.5) was incorporated into HSA-FePc NPs. Then, the confocal images of HeLa cells cultured with HSA-FePc-Cy7.5 NPs for 4 h were clearly observed in Figure S3b. The overlay of fluorescence and bright field images of the staining HeLa cells reveals that the emission of the HSA-FePc-Cy7.5 comes from the cytoplasm rather than in the cell nucleus. Encouraged by the high photothermal performance, excellent photostability, and prominent biocompatibility of HSA-FePc NPs, the PTT efficacy of HSA-FePc NPs was evaluated using the standard MTT assay in vitro. As shown in Figure 3a, the HSA-FePc NPs without irradiation of 671 laser exhibit negligible toxicity to HeLa cells even at 20 µM concentration, indicating



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the low cytotoxicity and good biocompatibility of HSA-FePc NPs. However, with the increasing concentration of HSA-FePc NPs, the cell viabilities of the group incubated with HSA-FePc NPs and then irradiated with 671 nm laser gradually decreased. A mortality rate of ~ 100% is observed at 20 µM concentration, indicating the excellent PTT efficiency of HSA-FePc NPs in vitro under NIR-light irradiation. The PTT effect of HSA-FePc NPs in vitro was further verified by PI and Calcein AM co-staining assay.64,

65

No cell death occurred in the group treated with only laser irradiation

because all of the cells displayed green fluorescence (Figure 3b). However, in the PTT group, which was incubated with HSA-FePc NPs and then irradiated by 671 nm laser for 3 and 7 min, some cells died. When prolonged irradiation time to 10 min, all the cells exhibited homogeneous red fluorescence, indicating the complete cells death, which agreed well with the results of MTT assay. These results strongly demonstrate that the HSA-FePc NPs can be used as an efficient photothermal agent for PTT cancer treatment. 3.4. In vitro and in vivo photoacoustic imaging To investigate the feasibility of PA imaging, the in vitro PA imaging performance of HSA-FePc NPs in an agarose gel phantom was evaluated via a commercial MSOT invision 128 PA tomography system. Figure 4a shows the PA images of HSA-FePc NPs solutions, which correspond to the signal intensities at 680 nm (Figure S4a). With increasing HSA-FePc NPs concentration from 0 µM to 20 µM, the enhancement of the PA signal is linearly dependent on the concentration of HSA-FePc NPs (Figure S4b). Encouraged by the above excellent in vitro PA imaging


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result, we next investigated the in vivo PA imaging performance of HSA-FePc NPs after i.v. administration. As shown in Figure 4b, the PA images of 4T1 tumor-bearing mice injected with HSA-FePc NPs or free FePc molecules were collected at various time intervals. The result indicates that HSA-FePc NP is an excellent PA imaging agent, which can significantly show a clear tumor microstructure with higher contrast and spatial resolution compared with free FePc molecules. We calculated the average signal intensity of the region of interest (Figure 4c). The PA signals of the HSA-FePc NPs at tumor site reached maximum at 12 h. Accordingly, 12 h post-i.v. injection of HSA-FePc NPs was selected as the suitable time point for PTT of cancer. We then quantitatively measured Fe levels in the tumor and major organs at 12 h post-i.v. injection of HSA-FePc NPs using inductively coupled plasma atomic emission spectroscopy (ICP-AES) method. As shown in Figure S5, aside from higher HSA-FePc NPs accumulation in the liver and kidney, the tumor exhibited a higher intensity compared with the other organs (heart, spleen, and lung), indicating that i.v.-injected HSA-FePc NPs were localized at tumor sites through EPR effect. Therefore, the HSA-FePc NPs can be used as an excellent PA imaging agent to assess the accumulation of this phototheranostic at tumor sites for guiding PTT cancer treatment in vivo.



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Figure 4. (a) The PA imaging in vitro of HSA-FePc NPs with different concentrations. (b) The time-dependent in vivo PA imaging of tumor sites post-i.v. administration of free FePc or HSA-FePc NPs. (c) The time-dependent average signal intensities of tumor sites.

3.5. In vivo photothermal therapy To investigate the in vivo therapeutic effect of HSA-FePc NPs, the tumor-bearing mice with tumor volumes of 75 - 100 mm3 were divided into four groups randomly (five mice per group). Then, the four groups were treated with different administrations: without any treatment (group I), irradiation of 671 nm laser (10 min, 0.5 W cm-2) only (group II), intravenous injection of HSA-FePc NPs (0.2 M FePc, 100 μL) only (group III), and intravenous injection of HSA-FePc NPs (0.2 M FePc, 100 μL) + 671 nm (10 min, 0.5 W cm-2) (group IV). Among them, group IV was selected as PTT group, and the others were controls. We initially measured the intratumoral temperatures of mice in group IV in the progress of irradiation by 671 nm laser. As shown in Figure 5a and 5b, after irradiation of 671 nm laser for 10 min, the temperature of tumor rapidly increased to 55.4 °C, thereby causing irreversible damage to cancer cells.34,

66

By contrast, other control groups exhibited negligible

temperature increases after different treatments, indicating that the HSA-FePc NPs play a key role in heat generation.


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Figure 5. (a) The IR thermal imaging of the mice with different treatments. (b) The tumor temperature change curves of the mice. (c) The tumor growth curves of the mice (n = 5, *P < 0.05). (d) The representative photographs of the mice. (e) Tumor H&E stained slices of the mice.

Subsequently, tumor growth rates and mouse survival rates were monitored to verify the PTT efficacy of HSA-FePc NPs. As shown in Figure 5c, the tumor growth was completely inhibited in PTT group (group IV). However, the tumors of group II and III showed no apparent shrinkage of size compared with group I, suggesting that either light or HSA-FePc NPs alone cannot affect the tumor growth rate. The representative photographs of the four groups also demonstrate excellent PTT effect of HSA-FePc NPs. As shown in Figure 5d, the mice in group IV showed complete tumor ablation with the PTT. In control groups, the tumor continuously increased with the prolonged feeding time. Furthermore, tumor slices from H&E staining were subsequently investigated. As shown in Figure 5e, the tumor tissue of PTT group was completely destroyed, whereas no noticeable cell damage could be observed in other



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control groups. Compared with mice in the control groups, which showed average lifetimes of approximately 16 - 35 days, mice after PTT therapy (group IV) survived over 50 days without a single death (Figure S6). In addition, we also monitored the mouse weight to evaluate the HSA-FePc NPs toxicity. As shown in Figure S7, after treatments, the weights of all the mice did not show obviously abnormal changes, indicating that the HSA-FePc NPs have negligible toxicity in vivo. Overall, these results demonstrate that the highly effective PTT of HSA-FePc NPs after i.v. administration in vivo. 3.6. In vivo long-term toxicity of HSA-FePc NPs


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Figure 6. (a) H&E-stained images of the heart, liver, spleen, lung and kidney in mice on 3, 7, and 14 days post-i.v. injection of HSA-FePc NPs; serum biochemistry data including liver function markers of (b) ALT, (c) AST, (d) ALP; kidney function markers of blood urea nitrogen (BUN) levels (e), and A/G ratios (f); Complete blood counts. Blood levels of (g) WBC, (h) RBC, (i) HCT, (j) HGB, (k) MCV, (l) MCH, (m) MCHC, and (n) MPV. Healthy nude mice were sacrificed at 1, 7, and 30 days post-i.v. injection with HSA-FePc NPs (dose of HSA-FePc NPs = 10 mg kg-1) for blood collection. Untreated healthy mice were used as the control and Statistic was based on 5 mice per data point (*P < 0.05).

To assess the potential long-term in vivo toxicity of HSA-FePc NPs, we initially evaluated the major organ (heart, liver, spleen, lung, and kidney) slices of H&E



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staining for histology analysis at 1, 7, and 30 days after i.v. injection of HSA-FePc NPs (Figure 6a). Compared with the control group, neither significant inflammation nor damage was observed, which may ascribe to the low biotoxicity of the HSA-FePc NPs. To further understand the potential toxicology of HSA-FePc NPs in long term, the mice were subjected to serum biochemistry assay and complete blood count at 1, 7, and 30 days after i.v. injection of HSA-FePc NPs.67, 68 As shown in Figures 6b-f, the liver function markers [alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)] and kidney function markers [albumin/globin ratio (A/G) and urea nitrogen (BUN)] were all measured to be normal, thereby suggesting that no significant mice hepatic or kidney injury was induced by HSA-FePc NPs treatment. Furthermore, all important indexes of routine hematology studies, including white blood cells (WBC), hematocrit (HCT), red blood cells (RBC), mean corpuscular volume (MCV), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and mean platelet volume (MPV), were measured at regular levels. As shown in Figure 6g-n, compared with the control group, all parameters were normal and within the reference ranges for healthy mice. These results indicate that the HSA-FePc NPs are highly efficient NIR-light responsive PA imaging agent, suitable for imaging-guided PTT of cancer in vivo. 4. CONCLUSION In conclusion, the HSA-FePc NPs were successfully fabricated and explored their in vitro and in vivo PA imaging and PTT application. The introduction of HSA


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not only improved the dispersibility of FePc molecule in the physiological environment and stability of photothermal behavior but also facilitated the accumulation in tumors through EPR effect. In addition, the HSA-FePc NPs also showed highly contrast and spatial resolution of PA imaging, efficient cancer therapy, and low long-term toxicity in vivo. These collective properties support the HSA-FePc NPs to be utilized as a versatile, precise, highly efficient, and low long-term toxic phototheranostic agent for simultaneous PA imaging and PTT cancer treatment. Our work developed the biomedical applications of FePc and promises future explorations of this multifunctional phototheranostic agent in nanomedical and clinical applications. ■ ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/(( am-2017-04360h)) The UV-vis absorption spectra of FePc in different concentrations; The PA signals of HSA-FePc NPs at different concentrations; The investigation on the body weights and survival rates of mice at post-treatments (PDF). ■ AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing ﬁnancial interest. ■ ACKNOWLEDGE



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This work was supported by the NNSF of China (Grant Nos. 51572269 and 51472252) and the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB17030400). ■ REFERENCES [1] Dykman, L. A.; Khlebtsov, N. G., Multifunctional Gold-Based Nanocomposites for Theranostics. Biomaterials, 2016, 108, 13-34. [2] Shanmugam, V.; Selvakumar, S.; Yeh, C. S., Near-Infrared Light-Responsive Nanomaterials in Cancer Therapeutics. Chem. Soc. Rev., 2014, 43, 6254-6287. [3] Kim, J. W.; Galanzha, E. I.; Shashkov, E. V.; Moon, H. M.; Zharov, V. P., Golden Carbon Nanotubes as Multimodal Photoacoustic and Photothermal High-Contrast Molecular Agents. Nat. Nanotechnol., 2009, 4, 688-694. [4] Zhou, B.; Li, Y.; Niu, G.; Lan, M.; Jia, Q.; Liang, Q., Near-Infrared Organic Dye-Based Nanoagent for the Photothermal Therapy of Cancer. ACS Appl. Mater. Interfaces, 2016, 8, 29899-29905. [5] Yuwen, L.; Zhou, J.; Zhang, Y.; Zhang, Q.; Shan, J.; Luo, Z.; Weng, L.; Teng, Z.; Wang, L., Aqueous Phase Preparation of Ultrasmall MoSe2 Nanodots for Efficient Photothermal Therapy of Cancer Cells. Nanoscale, 2016, 8, 2720-2726. [6] Chen, Y. W.; Su, Y. L.; Hu, S. H.; Chen, S. Y., Functionalized Graphene Nanocomposites for Enhancing Photothermal Therapy in Tumor Treatment. Adv. Drug Delivery Rev., 2016, 105, 190-204. [7] Liu, B.; Li, C.; Cheng, Z.; Hou, Z.; Huang, S.; Lin, J., Functional Nanomaterials for Near-Infrared-Triggered Cancer Therapy. Biomater. Sci., 2016, 4, 890-909. [8] Cheng, L.; Wang, C.; Feng, L.; Yang, K.; Liu, Z., Functional Nanomaterials for Phototherapies of Cancer. Chem. Rev., 2014, 114, 10869-10939. [9] Gao, S.; Zhang, L.; Wang, G.; Yang, K.; Chen, M.; Tian, R.; Ma, Q.; Zhu, L., Hybrid Graphene/Au Activatable Theranostic Agent for Multimodalities Imaging Guided Enhanced Photothermal Therapy. Biomaterials, 2016, 79, 36-45. [10] Tang, S.; Chen, M.; Zheng, N., Multifunctional Ultrasmall Pd Nanosheets for Enhanced Near-Infrared Photothermal Therapy and Chemotherapy of Cancer. Nano Res., 2014, 8, 165-174. [11] Ma, N.; Jiang, Y. W.; Zhang, X.; Wu, H.; Myers, J. N.; Liu, P.; Jin H.; Gu, N.; He, N.; Wu, F. G.; Chen, Z., Enhanced Radiosensitization of Gold Nanospikes via Hyperthermia in Combined Cancer Radiation and Photothermal Therapy. ACS Appl. Mater. Interfaces, 2016, 8, 28480-28494. [12] Ge, J.; Jia, Q.; Liu, W.; Lan, M.; Zhou, B.; Guo, L.; Zhou, H.; Zhang, H.; Wang, Y.; Gu, Y.; Meng, X.; Wang, P., Carbon Dots with Intrinsic Theranostic Properties for Bioimaging, Red-Light-Triggered Photodynamic/Photothermal Simultaneous Therapy in Vitro and in Vivo. Adv. Healthcare Mater., 2016, 5, 665-675. [13] Singh, R.; Torti, S. V., Carbon Nanotubes in Hyperthermia Therapy. Adv. Drug Delivery Rev., 2013, 65, 2045-2060. [14] Cheng, L.; Liu, J.; Gu, X.; Gong, H.; Shi, X.; Liu, T.; Wang, C.; Wang, X.; Liu, G.; Xing, H.; Bu, W.; Sun, B.; Liu, Z., PEGylated WS(2) Nanosheets as a Multifunctional Theranostic Agent for in Vivo


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