Design and Synthesis of a Lead Sulfide Based Nanotheranostic Agent

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Design and Synthesis of Lead Sulfide-Based Nanotheranostic Agent for Computer Tomography/Magnetic Resonance Dual-Mode Bioimaging Guided Photothermal Therapy Yibiao Zou, Honglin Jin, Fei Sun, Xiaomeng Dai, Zushun Xu, Shengli Yang, and Guangfu Liao ACS Appl. Nano Mater., Just Accepted Manuscript • DOI: 10.1021/acsanm.8b00359 • Publication Date (Web): 17 Apr 2018 Downloaded from http://pubs.acs.org on April 17, 2018

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ACS Applied Nano Materials

Design and Synthesis of Lead Sulfide-Based Nanotheranostic Agent for Computer Tomography/Magnetic Resonance Dual-Mode Bioimaging Guided Photothermal Therapy Yibiao Zou,†,┴ Honglin Jin,‡,┴ Fei Sun,§ Xiaomeng Dai,‡ Zushun Xu*,† Shengli Yang,*,‡ Guangfu Liao,*,†,║ †

Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials; Ministry of Education

Key Laboratory for The Green Preparation and Application of Functional Material, Hubei University, Wuhan, Hubei 430062, China ‡

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and

Technology, Wuhan 430022, China §

Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science

and Technology, Wuhan 430077, China ║

School of Materials Science and Engineering, PCFM Lab, Sun Yat-sen University, Guangzhou 510275,

China ABSTRACT: The dual-modality imaging guided photothermal therapy (PTT) exhibits great potential in the field of diagnosis and treatment. Herein, we report a controllable method (Atom Transfer Radical Polymerization (ATRP)) for the preparation of gadolinium (III) complexes-grafted-lead sulfide (GCGLS) nanoparticles. A series of characterizations (such as TEM, HR-TEM, EDX, XRD, FTIR, etc.) proves that GCGLS nanoparticles have been successfully prepared. The GCGLS nanoparticles with ultrasmall sizes (ca. 11 nm) have quite strong photoabsorption intensity in near-infrared (NIR) regio due to a low S vacancy concentration of lead sulfide (PbS). As the addition amount of gadolinium (III) complexes increases, the sizes o f GCGLS nanoparticles have no evident change. The temperature of GCGLS nanoparticles solutions can quickly elevate to 57.5 °C in 10 min after near-infrared laser irradiation (1.5 W/cm2) at 808 nm, this result reveals it possesses high photothermal conversion efficiency (~ 31 %). When GCGLS nanoparticles are injected into the mice, the tumor site is clearly observed efficient accumulation. Moreover, the GCGLS nanoparticles also show excellent a prominent X-ray computer tomography (CT) and T1-weight magnetic resonance (T1-MR) imagings in vitro/vivo. By combination of GCGLS and near-infrared laser irradiation, the effective tumor treatment experiment is conducted achieving in mice. ACS Paragon Plus Environment

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Therefore, the prepared GCGLS nanoparticles with dual-modality imaging guided PTT can be used as a potential diagnosis and treatment reagents for clinical applications. KEYWORDS: dual-modality imaging, photothermal therapy, ATRP, near-infrared, diagnosis and treatment 1. INTRODUCTION As a non-invasive method for antitumor treatment, photothermal therapy (PTT) has attached much attention in the past decade and showed advantages of controllable and high specificity.1-6 Through using near-infrared (NIR, λ = 700 − 1350 nm) to irradiate the tumor site, the photothermal agents could effectively kill the tumor cells by generating heat.7-9 However, the single photothermal agents are unable to reveal whether the agents could have an effective treat at pathology location. For example, Li et al.10 prepared a new material based on conjugated polymer dots but its only function is used for cancer PTT, which severely limited its usage for clinical treatment. To further improve the therapeutic efficiency of PTT, nanotheranostic reagents with imaging-guided are highly worth considering. Over the past decade, lead sulfide (PbS) has received increasing attention in the field of photodetectors due to its unique electronic properties.11 Until very recently, PbS was investigated in biomedical research for use as CT and fluorescence contrast agent because of the features of high atomic number,12,

13

admirable X-ray absorption,11 and excellent NIR absorption.14 For

example, Liu et al.15 prepared PbS nanodots by using L-glutathione reduced as stabilizing agent. The nanodots exhibited much significant X-ray/CT imaging contrast in gastrointestinal. But such reagents will quickly be eliminated and not suitable for imaging at tumor site. Antonio et al.16 presented a platform for high-resolution fluorescence imaging in vivo applications based on the excellent properties of PbS/CdS/ZnS quantum dots (QDs). The QDs can be used as an effective platform for deep tissue imaging probe and nanothermometer.17 Deficiently, the strong NIR absorption has no further researched, and the photothermal property of PbS nanodots in the biomedical field has been ignored. Theoretically, nanoagents with good NIR absorption usually accompanied a photothermal effect.10,

18-23

For example, various photothermal therapy reagents have been prepared such as

containing polymer (Mn2+-coordinated PDA),24 transition metal sulfide semiconductors25 and carbon nanotubes,26 etc. These agents have a strong absorption band within the “first biological ACS Paragon Plus Environment

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window” (700 − 950 nm). As one of the semiconductor materials, PbS has exhibited obvious optical band gaps and higher charge carriers, which leading a strongly contribute to semiconductor absorption in the NIR region.16 Thus, the nanoagents based on PbS could used as an novel agent for PTT in NIR-I windows. Insufficiently, the lowly sensitivity of CT imaging could not provided powerful information in the visual representations for clinicians.27-30 In recent years, gadolinium contrast agent, based on magnetic resonance (MR) and CT imaging coexistence, is expected to be the most powerful imaging technologies.31-34 However, the imaging efficiency and long-term toxicity remain the major challenges.35-37 For example, Hou et al.38 reported a monodisperse, regular and stable nanoclusters via electrostatic interactions between negatively-charged carboxylic groups and trivalent cations of gadolinium. Unfortunately, the high toxicity and low adsorption rates severely limited its application in organisms. Yang et al.39 synthesized a deep tissue penetration and low toxicity biocompatible Gd-integrated CuS nanotheranostic agent, which suffer from lots of restrict such as low imaging efficiency and short imaging time. Furthermore, the low photothermal conversion efficiency is not conducive to effective tumor treatment. Therefore, it is necessary to find an excellent reagent, which possessed a series of advatanges such as low toxicity,40 high load rate, high spatial resolution and excellent photothermal effect .41-44 Our groups have recently developed a novel agent for brain tumor (glioma) MR imaging, which could be used as an good MRI contrast agent with high relaxation rate MRI.45 This agent can be used as a functional monomer to participate in polymer polymerization. The nanoagents combining T1-MR imaging and PbS can be successfully prepared by surface-initiated atom transfer radical polymerization (ATRP).46, 47

ATRP is a promising ‘‘grafting from’’ technique which possesses many advantages such as good control

over molecular weight and monodispersity, and thickness of the polymer shell. Another advantage is that the end-functionalized polymers or block copolymers grafted onto the nanoparticles surface can offer a variety of active sites for further multi-biofunctionalization and specific targeting. As a hopeful “grafting from” means, this method can offer various of active sites to graft the end-functionalized polymers onto the nanoparticles, is one of the most effective technologies in vivo diagnosis and treat.48 On this basis, we design and fabricate a simple and controllable approach for the preparation of gadolinium (III) complexes-grafted-lead sulfide (GCGLS) nanoparticles by ATRP to achieve a theranostic agent for combined CT and T1-MR imagings guided photothermal ablation (Scheme 1). The GCGLS nanoparticles ACS Paragon Plus Environment


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with ultrasmall sizes (~ 11 nm) display strong NIR absorbance and higher efficient photothermal conversion of 31 % due to its high surface ratios and low S vacancy concentration, which can be served as the excellent photothermal reagents in tumor cells. The GCGLS nanoparticles not only provide much better CT imaging effect than clinical iodine reagent, but the molecular weight and MR imaging effects (r1=13.65 mM−1s−1) can be regulated by changing the addition amount of Gd(AA)3Phen. In addition, the biocompatibility, cellular viability assay and tumor CT and MR dual-modality imaging performance are demonstrated in both ex vivo and in vitro.

Scheme 1. Schematic illustration of the preparation processes of GCGLS nanoparticles and used as dual-modality CT/MR imaging guided photothermal ablation.

2. EXPERIMENTAL 2.1. Materials. Lead acetate (Pb(CH3COO)2·3H2O), sodium sulfide (Na2S), copper(I) chloride, 2-Mercaptoethanol, 3-chloropropionic acid (CPA), 2,2'-bipyridine (Bpy) and poly(ethyleneglycol) monomethacrylate macromonomer (Mn ~ 300) were obtained from Aladdin Reagent Co. Ltd. Gadolinium oxide (Gd2O3, 99.99 %) and acrylicacid (AA, 98 %) were obtained from Shanghai Yuelong Nonferrous Metals and stored at 5 °C. Ammonium hydroxide (NH3·H2O, 25 % ~ 28 %), tetrahydrofuran (THF) and 1, 10-phenanthroline (Phen) were obtained from Sinopharm Chemical Reagent Co. Ltd. (China). All the reagents were AR and used without further purification. 2.2. Synthesis of CPA-modified PbS nanoparticles. The CPA-modified PbS (CPA-PbS) nanoparticles were ACS Paragon Plus Environment

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synthesized according to a facile method. Briefly, lead acetate (0.379 g) and 2-Mercaptoethanol (0.468 g) were dissolved in 190 mL aqueous solutions and then added to a three necked flask under nitrogen atmosphere. The temperature was adjusted to 50 °C for 1 h. Na2S (0.12 g) was dissolved in 10 mL aqueous solutions and then added slowly to result in production with dark color. One hour later, 3-chloropropionic acid (1.14 g) was added. The obtained product was separated through centrifugation and collected after washing with deionized water. Finally, the product was stored at 0 ~ 4 °C. 2.3. No-solvent atom transfer radical polymerization. The preparation of Gd(AA)3Phen are prepare via a method described in our previous paper.45 The CPA-PbS (45.0 mg) and Gd(AA)3Phen (5.1 mg) were dispersed in PEGMA monomer (5 mL) to form a black solution with a magnetic stir. The mixture was purged under nitrogen atmosphere for 1 h. Then CuCl (2.6 mg) and Bpy (12 mg) were added. After continuously stirring another 24 h under room temperature, the mixture was dissolved in THF. The product was collected under 2000 rpm centrifugation for 3 min in order to remove the Cu(II) impurity which formed in the ATRP process. Finally, the mixture was collected after 10000 rpm centrifugation. Before further characterization, the gadolinium (III) complexes-grafted-lead sulfide (GCGLS) nanoparticles were washed carefully with ultrapure water. 2.4. Characterization. The X-ray diffraction (XRD, Philips Corp. Nederland) were used to characterize CPA-PbS nanoparticles and GCGLS nanoparticles, and the Cu Kα radiation scanning rate was set as 10°/min from 20°~ 80°. The surface composition of GCGLS nanoparticles were determined by a Philips XL30 SEM with an energy dispersive X-ray spectroscopy (EDS). The size and the morphology of CPA-PbS nanoparticles and GCGLS nanoparticles were evaluated by FEI Tecnai G20 transmission electron microscopy (TEM, U.S.A.) and high resolution TEM (HR-TEM). The hydrodynamic size of the CPA-PbS and GCGLS were characterized from an Autosize Loc-Fc-963 dynamic light scattering (DLS, Malvern Instrument). The fourier transform infrared spectroscopy was carried out by a Perkin Elmer Spectrum one Transform Infrared spectrometer. The chemical composition of CPA-PbS and GCGLS nanoparticles were determined from X-ray photoelectron spectroscopy (XPS, AXIS His, Kratos Analytical Ltd.). UV-vis-NIR spectra were tested by UV3600 spectrophotometer (Shimadzu, Japan). For the CT images, the samples were tested besed on a mass concentration (0 ~ 16 mg/mL) and the following parameters were adopted: field of vision (FOV) = 90 mm × 140 mm, Rot. Time 1.0 s, D-FOV 220.3 s. A 3.0 T whole-body MR scanner (MAGNETOM Trio, A Tim System 3T, Siemens, Munich, Germany) was used to detect in vitro/vivo MRI, which performed at 25 °C and combine with an 8-channel wrist joint coil. For in vitro/vivo MR imaging experiment, the following parameters were employed: field of vision (FOV), 120 mm; imaging matrix, 384 × 384; slice thickness, 1.5 mm; repetition time (TR), 2000 ms; scanned time, 13 ~ 14 min, and flip angle was 120°. ACS Paragon Plus Environment


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2.5. Photothermal effect of GCGLS nanoparticles. A series of GCGLS nanoparticles aqueous solutions (total 0.5 mL) from different mass concentrations (0, 37.5, 75, 150, 300 µg/mL) were injected into 1 mL sample tube and then irradiated by a near-infrared laser for 10 min (808 nm, 1.5 W/cm2). Through a digital thermometer, the change of temperature was measured every 10 s. The ultrapure water was used as the control group. 2.6. Cell culture. In this study, B16 cells were chosen as modal cells. Dulbecco's modified Eagle's medium (DMEM) solution with 10% fetal bovine serum was used to incubate B16 cells under a humidified atmosphere of 37 °C and 5% CO2. 2.7. Cytotoxicity and hemolysis analysis. In vitro photothermal ablation, the cytotoxicity of GCGLS nanoparticles upon NIR light exposure was measured by MTT. B16 cells were first fostered in 6-well plates (5.0 × 105 cells/well) after 24 h. And then washed via PBS (10 mM, pH: 7.4), GCGLS nanoparticles (150 µg/mL) were added in and incubated for another 4 h. Then cells were irradiated for10 min by an NIR laser (1.5 W/cm2, 808 nm). 2 h later, the B16 cells were used to stain through Calcein (AM) and propidium iodide (PI) and the inverted fluorescence microscope (Olympus, Japan) were used to directly observe the fluorescence images of the cell viabilities. The MTT assay of GCGLS nanoparticles was also measured to reflect photo-induced cytotoxicity. Briefly, the 96-well plates were injected B16 cells (1.0 × 104 cells/well) to incubate 24 h. Then, GCGLS nanoparticles were added at difference Pb concentrations and incubation another 24 h. After washing with PBS and irradiation by NIR light (1.5 W/cm2, 808 nm) at different times (0, 10 min), then incubated for 24 h, the cells viability of the samples were also detected by the MTT assay. For hemolysis assay, the supernatant of fresh blood was removed via 10 min centrifuge at 1000 rpm. Then, to acquire the red blood cells (HRBCs), the blood was washed 5 times with PBS. HRCBCs suspension (0.1 mL) was diluted into 0.9 mL PBS (negative control group), 0.9 ml water (positive control group), or 0.9 mL GCGLS nanoparticles PBS solution at different Pb concentrations (35 ~ 560 µM), respectively. The mixtures were gentle shaked before reacted at room temperature for 2 h and then centrifuged 1 min at 10000 rpm. The hemolysis of GCGLS nanoparticles was recorded to measure with the absorbance of supernatants at 541 nm and the photos of the mixtures. The hemolysis percentages = (OD541 nm of the experiment group ‒ OD541 nm of the negative control group)/(OD541 nm of the positive control ‒ OD541 nm of the negative control group) × 100%. 2.8. In vitro dual-modality imaging. For the CT imaging, the ultrapure water was added control group (Clinical use of iodixanol) and GCGLS nanoparticles (mass concentration at 0 ~ 16 mg/mL), and then the samples were enclosed in 500 µL sample tube. The samples were tested besed on an Aquilion ONE 640 CT scanner (Japan). To obtain the relaxivity, the control group and GCGLS nanoparticles were dispersed into ultrapure water including gadolinium concentrations in the gradient of 0.00625 ~ 0.4 mM. An array of 500 µL sample tube were injected the samples and tested through MR ACS Paragon Plus Environment

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scanner, the samples were detected based on a series of MR sequences. The in-house software was used to compute the T1 relaxation time of the suspension and the relaxation time and Gd concentration (mM) curve were fitted to calculate the r1 relaxivity values. 2.9. In vivo dual-modality imaging. On the right side of black mice, 3 × 106 B16 cells/mouse was subcutaneously injected to build B16 tumor model. After the tumors volume was reach ~ 200 mm3, taking a test of CT and MR imaging. When time reaches to preset points, GCGLS nanoparticles ([Pb] = 14 mM, 150 µL) were injected into the mice to test CT images, by using a High resolution In-vivo X-ray microtomograph system (SkyScan 1176, Broker, Belgium). The SD mice (weight of approximately 21 g) were performed to test in vivo MRI studies. The trichloroacetaldehyde hydrate (10 %) was used to anaesthetize mice by using a dose of 45 mg/kg. The mice were scanned after inject 150 µL GCGLS nanoparticles under a dose of 6 mg (Gd)/kg via intravenously injected at preset time points. The MR scanner was used to obtain T1-weighted coronal MR images. The signal intensity (SI) was tested under each time point and plotted the relative SI changes. The relative signal enhancement values (RSEs) before (SIpre) and after (SIpost) injection of samples were calculated based on the following formula: [(SIpost - SIpre)/SIpre] × 100%. 2.10. In vivo photothermal tumor ablation. The female mice were subcutaneously injected ~3×106 B16 cells in PBS to establish the tumor model. When the tumors volume grew to ~ 200 mm3, mice were divided into two groups (n = 4). The GCGLS nanoparticles (150 µL, [Pb] = 14 mM) were injected into mice and then irradiated by an NIR light (808 nm, 1.5 W/cm2) for 10 min. With light irradiate, the temperature change of the tumor site was tested through electrical temperature detector. The tumor size was measured by caliper, and formula (V = (L × W2)π/6) was used to calculate out the volume of tumor, the L and W of formula stand for longer and shorter diameters of tumor, respectively. 21 days later, collected the tumor and fixed it in 10% buffered formalin solution, then use the light-field microscopy to observe the H&E stained specimens. 2.11. In vivo biodistribution of GCGLS nanoparticles. For biodistribution studies, GCGLS nanoparticles ([Pb] = 14 mM, 150 µL) were injected into B16 tumor model mice. After 0.5 h, 1 h, 5 h and 48 h intravenously injected, the main organs (heart, liver, spleen, lung, and kidney), bloods (50 µL) and tumors were extracted and weighed, respectively. The lead and gadolinium elements content in organs, blood and tumors were tested by ICP-AES, the extracted samples after digesting in aqua regia solution overnight. 2.12. In vivo security evaluation. For body weight measurement, four groups of mice were used to measurements body weight (n = 12). Two groups of mice intravenously injected with GCGLS nanoparticles ([Pb] = 14 mM, 150 µL) were denoted as test groups (GCGLS and GCGLS + Laser) and another intravenously injected with PBS solution (150 µL) as control groups (PBS and PBS + Laser). Four groups body weight were noted for 21 days. ACS Paragon Plus Environment


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For histochemical analysis, the organs (heart, liver, spleen, lung, and kidney) and tumors of control groups (PBS and PBS + Laser) and test groups (GCGLS and GCGLS + Laser) were harvested after 21 days of tail intravenous injection. The change in morphological features of each organ was performed to test after hematoxylin and eosin (H&E) staining assay.

3. RESULTS AND DISCUSSION 3.1. Characterization of GCGLS nanoparticles. The GCGLS nanoparticles with dual-modal imaging guided photothermal therapy were prepared by atom transfer radical polymerization (ATRP) (Scheme 1). Briefly, the PEGMA and Gd(AA)3Phen were grafted to CPA-PbS nanoparticles by ATRP. The images of CPA-PbS and GCGLS nanoparticles have tesed by TEM and HR-TEM (Figure 1A-B and Figure S1). The diameter of GCGLS nanoparticles was about 11 nm. The hydrodynamic diameter (Dh) was tested by DLS49-52 (Figure S2), and the result showed the hydrodynamic diameter of GCGLS nanoparticles were about 300 nm, 195 nm, 236 nm, and 238 nm by using deionized water, phosphate buffered solution (PBS), PBS with PH = 5.5 and dulbecco's modified eagle medium (DEME) as solvent, respectively (Figure S2C-E). EDX and mapping EDX were applied to achieve a chemical composition and atomic distribution. The Pb, S, C, N, Gd, Cl and O element signals were well observed in the EDX spectrum (Figure 1C and Figure S3) of GCGLS nanoparticles. In Figure 1C, we have tested the EDX spectrum of the GCGLS nanoparticles on the silicon chip. Since the peak area of the silicon element is large, and the content of the GCGLS nanoparticles is relatively few, which lead to the peak of other elements are shorter than silicon element. So, the peaks for the major elements of Pb and S were weak. The chemical information of the CPA-PbS and the GCGLS nanoparticles were measured by XPS analysis (Figure S4), the N 1s and Gd 4d (Gd 4d5/2 at 143.3 eV) signal peaks were clear. C 1s, O 1s, Cl 2p, S 2p (S 2p3/2 at 161.9 eV) and Pb 4f (Pb 4f7/2 at 137.8 eV) were almost as same as those of reported previously. Moreover, XRD result indicated that the prepared GCGLS nanoparticles were crystalline particles and formed a crystalline face-centered cubic CPA-PbS (Figure 1D). In detail, it exhibited the sharp peaks at 2θ angles of 25.9°, 29.9°, 43.0°, 50.9°, 53.3°, 62.6°, 68.9°, 71.1° and 79.1° for black line, corresponding to (111), (200), (220), (311), (222), (400), (331), (420), and (422) crystal planes of PbS. The sharp peaks at 2θ angles of 23.3° for red line, which corresponding to crystal planes of Gd(AA)3Phen.45 As can be seen from the Figure 1D, the peak of GCGLS is obviously lower than CPA-PbS. This reason is that the surface polymerization of GCGLS nanoparticles has a large number of organic monomers, which affect the detection of XRD. But this does not affect the inner crystal of GCGLS nanoparticles because we are “grafting from” on the surface. Thus, ACS Paragon Plus Environment

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the XRD results in Figure 1D were different widely. All the peak positions and related intensity are no significant differences with the PbS reference (JCPDS. NO 05-0592). For the FT-IR spectrum, the various absorption peak of CPA, PEGMA and Gd(AA)3Phen molecules could be identified between 400 and 2000 cm-1. Compared with 2-Mercaptoethanol, the absorption peak of S‒H around 2525 cm-1 in CPA-PbS was disappeared totally, which the interaction effect between 2-Mercaptoethanol and PbS were further demonstrated which mainly depended on the deprotonation and coordination of these thiol groups. The CPA on the surface of CPA-PbS was successful grafted by observed the carboxyl group absorption band at 1551 cm-1, as well as a broader CH2 stretch band at 2920 cm-1 and a stronger C=C absorption stretch band at 1624 cm-1. The spectrum of GCGLS nanoparticles modified with PEGMA and Gd(AA)3Phen showed a stronger C‒O‒C absorption stretch band (1110 cm-1), as well as an obvious Gd‒N (567 cm-1) and Gd‒O (418 cm-1) stretch bands,45 and a broader C=O (1718 cm-1) stretch band (Figure 1E). There also displayed a broader CH2 stretch band at 2920 cm-1. The characteristic band for C=C stretching vibration of the Gd(AA)3Phen, which provided a stronger absorption band at 1624 cm-1.

Figure 1. (A) TEM image of GCGLS. (B) HR-TEM image of GCGLS. (C) EDX spectrum analysis of the content of the Pb and Gd elements of the typical assembly. (D) XRD pattern of GCGLS with a face-centered-cubic phase. (E) FTIR spectra analysis of CPA-PbS and GCGLS. (F) UV-vis-NIR spectroscopy of the aqueous dispersion of GCGLS.

For the UV-vis-NIR, absorption spectrum was tested to confirm the excitation spectrum of GCGLS nanoparticles (150 µg/mL, 4 mL) in water. The GCGLS nanoparticles showed an obvious absorption at 808nm (Figure 1F). Comparing GCGLS (before light) and GCGLS + Laser (after light), the absorption ACS Paragon Plus Environment


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spectrum at 808 nm has no obvious change (Figure S5). This indicated that the GCGLS has a good photothermal conversion stability after multiple irradiated. It was proved that GCGLS nanoparticles had a favorable NIR absorption, and we have used it to photothermal therapy test. The infrared thermal images revealed that GCGLS nanoparticles had an excellent thermal effect after 808 nm NIR light irradiation (1.5 W/cm2). The control group (ultrapure water) showed a little change, and the experimental group showed an obvious concentration-dependence with temperature increases (Figure 2A and Fig. S6A). The critical temperature that induced the death of cancer cells was 43.0 °C. The experimental group (75 µg/mL) which irradiated less than 10 min would reach to this temperature, while ultrapure water increased only ~ 5.4 °C under the same irradiation. Besides, the experimental group showed an obvious power-dependence by using different power (0.5 W/cm2, 1 W/cm2, 1.5 W/cm2, 2 W/cm2) irradiated 10 min at 808 nm (Figure S6B). Another vital factor to evaluate photothermal agents was conversion stability. With the strong chemical bonds and recurrence of charge transfer, the temperature elevation was perfectly maintained upon multiple irradiate and the photothermal conversion efficiency of GCGLS was reached to ~ 31 % (Figure 2B and Figure S7A-C). Compared with other nanomaterials (such as FeS2 nanoparticles53 and gold nanorods54 etc), the temperature of GCGLS nanoparticles solutions can quickly elevate to 57.5 °C in 10 min after near-infrared laser irradiation (1.5 W/cm2) at 808 nm, this result reveals it possesses high photothermal conversion efficiency. Such strong photothermal conversion properties also provided high contrast for IR thermal imaging, with the imaging intensity relying on the concentration and irradiation time (Figure 2C). Thus, GCGLS nanoparticles had a great potential of using as an effective agent for PTT.

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Figure 2. (A) The temperature change of ultrapure water and GCGLS nanoparticles solutions under different concentrations after laser irradiate 10 min (808 nm, 1.5 W/cm2). (B) Temperature elevation of GCGLS nanoparticles (150 µg/mL) after 5 irradiation cycles. (C) IR thermal images of the GCGLS nanoparticles solutions after different concentrations upon near-infrared irradiation.

3.2. The cytotoxicity, hemolysis and cell internalization analysis of GCGLS nanoparticles. As a new diagnosis and treatment reagent, the biocompatibility test was very necessary for farther application. MTT assay was used to detect the potential cytotoxicity of GCGLS nanoparticles. The B16 cells viabilities were tested under different mass concentrations after 24 h and 48 h incubation with GCGLS nanoparticles. These results showed that the cell viability was up to 80 %, when the mass concentrations reached to 0.64 mg/mL (Figure 3A). After incubation with GCGLS nanoparticles for 48 h, the GCGLS nanoparticles begun to display slightly cytotoxicity when Pb concentrations higher than 0.08 mg/mL. The nanoparticles were proved has negligible adverse effect under the tested high concentrations. The MTT assay was executed to further test photothermal cytotoxicity with GCGLS nanoparticles in vitro. The GCGLS nanoparticles was added in B16 cells to incubate 24h at different concentration, and then used the 808 nm NIR light (1.5 W/cm2) to irradiate samples for 10 min, record the result of concentration- dependent photothermal effect, it was showed that approximately 80 % of B16 cells were killed at 0.04 mg/mL (Figure 3B). In contrast, GCGLS nanoparticles showed negligible toxicity to B16 ACS Paragon Plus Environment


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cells without near-infrared light irradiation. The live and dead cells were distinguished by Calcein-AM and propidium iodide (PI) staining. In Figure 3C-E, control group, laser irradiation alone and GCGLS nanoparticles alone group could not cause cell dead because there have not heat produced to kill the cells. So, the images displayed the survival of cells by green fluorescence. In Figure 3F, it was showed obvious cell killing effect after GCGLS + laser treated. Thus, the images displayed the death of cells by red fluorescence, it is not represent cell apoptosis. In contrast, it was showed obvious cell killing effect after GCGLS + laser treated, this result was similar to the MTT analysis, showed the GCGLS nanoparticles had a great potential of using as an effective agent for PTT. Hemocompatibility is another factor for the assessment of nanoparticles used in blood-contacting applications. The hemocompatibility of GCGLS nanoparticles were examined by hemolysis assays before their use as diagnosis and treatment reagent for tumor, in vivo (Figure 3G-H). The hemolysis percentages of GCGLS nanoparticles were quantified by UV-vis spectra at different Pb concentrations (0 ~ 560 mM) and the absorbance characteristic peaks at 542 nm of the supernatant. The GCGLS nanoparticles had no obvious hemolytic effects on red blood cell compare to positive control. The results showed that hemolysis percentage reaching to 3.1 % and threshold value was less than 5 % at the Pb concentration of 560 mM. This indicated that GCGLS nanoparticles can be used as a potential treatment reagent for clinical applications.


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Figure 3. (A) B16 cell viability after incubate for 24 h and 48 h. (B) B16 cell viability after treatment at different GCGLS concentrations. Photothermal killing effect (Calcein-AM and PI staining): (C) Cells alone; (D) Laser irradiation only; (E) 0.04 mg/mL GCGLS only; (F) 0.04 mg/mL GCGLS and 808 nm near-infrared laser irradiation 10 min (1.5 W/cm2). (G) Hemolytic activity of GCGLS under different Pb concentrations. (H) The enlarged UV-vis absorption of the supernatant after the blood incubation with water, PBS and GCGLS+PBS solution at different Pb concentrations for 2 h, respectively.

For cell internalization, we have provided electron microscopy images of B16 cells containing GCGLS nanoparticles (150 µg/mL) for 24 h and 48 h. The result showed that the GCGLS exhibited good solubility and have no aggregate in the medium (Figure S8). After the cells incubated with GCGLS for another 48 h, the GCGLS nanoparticles were internalized by the B16 cells may attributed to sostenuto endocytose, which resulted in cell membrane disruption and cytoskeleton disorganization. The cells number increased and retained a similar morphology. 3.3. Dual-modal imaging. The dual-modal imagings of GCGLS nanoparticles at various concentrations in water were studied. The X-ray absorption efficiency of Pb element could make the GCGLS nanoparticles possess intrinsic advantages for CT imaging. As is known to all, the attenuation coefficient enhancement progressively was increasing with atomic number and electron density. Therefore, the GCGLS nanoparticles were expected to have good imaging ability for CT. The X-ray attenuation potency was examined under various concentrations of Pb and the iodixanol were used as control group. It is clearly seen the CT signal of GCGLS nanoparticles increases in a concentration dependent manner (Figure 4A-B). At the same concentration, the GCGLS nanoparticles revealed higher X-ray attenuation potency than iodixanol. As previously reported, the smaller GCGLS nanoparticles exhibited more distinct X-ray attenuating ability than the larger one, this phenomenon was mainly attributed to the higher surface volume ratio.15, 38 Moreover, the different Gd concentrations of GCGLS nanoparticles were used to assess the contrast ability of T1-weight MR imaging. The T1-MRI relaxation rates (r1) of proton signals were measured in order to calculate the relaxation efficiencies of GCGLS nanoparticles. The GCGLS nanoparticles showed a high r1 value about 13.65 mM−1s−1 (Figure 5A). Although there are other nanomaterials based on Gd were researched for biomedical imaging, the prepared GCGLS nanoparticles exhibited high r1 relaxivity value for T1-weighted MRI. The GCGLS nanoparticles with different Gd ion concentrations were used as experimental group and the gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) as control group (Figure 5B). The signal enhancement progressively increased with the increasing of GCGLS nanoparticles concentrations, which revealed the potential of GCGLS nanoparticles ACS Paragon Plus Environment


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as powerful multifunctional diagnosis agent for T1-weighted MRI. To detect the possibility of GCGLS nanoparticles as a clinical cancer diagnosis agent, the CT and MR imaging techniques were used to assess the potential performance of GCGLS nanoparticles for dual-modality imaging by mouse models with B16 xenografted tumors. For T1-weighted MRI, the lightness of the tumor districts remarkably heightened post-injection of GCGLS nanoparticles (Figure 5C-D). The signal to noise ratio (SNR) was used to quantificat T1-weighted MRI signal intensity, and after 300 min post-injection the MRI signal reached to maximum (Figure 5E). These observations suggested that the blood circulation can effectively promote the GCGLS nanoparticles accumulate in the tumor area. Thus, the application of GCGLS nanoparticles had no remarkable influence for dual-modality cancer diagnosis, even if the GCGLS nanoparticles were lowly selected by cancer cells. Meanwhile, the tumor area exhibited a remarkable contrast enhancement by observed the CT imaging as well as T1-weighted MRI results after injected GCGLS nanoparticles, and the nanoparticles diffusion in tumor was attributed to blood circulation (Figure 4C and Figure S9A). Moreover, the kidney area of CT value also reached a maximum after intravenous injection 60 min. And the B16 cells were multiply faster than others, which lead to the tumor very large. The result proved that the GCGLS nanoparticles possessed a better CT imaging ability in vivo.

Figure 4. In vitro/vivo CT imagings of GCGLS nanoparticles. (A) CT values of the GCGLS nanoparticles and the ACS Paragon Plus Environment

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iodixanol aqueous solutions at the gradient concentrations as indicated (unit: mg·mL-1). (B) CT imagings and (C) in vivo CT imagings of mice before (Pre) and after i.v. injection of GCGLS nanoparticles ([Pb] = 14 mM, 150 µL;30 min, 1 h, 2 h and 5 h after injected, respectively). The kidneys are indicated by white arrow.

3.4. In vivo photothermal therapy. To assess in vivo therapy of GCGLS nanoparticles, the mice were chosen as bearing B16 tumors when initial volume at ~ 200 mm3. For the cytotoxicity analysis, the result showed that the cell viability was up to 80 % after 24 h incubation with GCGLS nanoparticles. The blood content of GCGLS nanoparticles was remained steady at a relatively low level after 24 h of circulation. It means that the content of the tumor site is the highest at 24 h. So, the mice (C57) were intravenously injected the samples for the PBS + laser and GCGLS + laser (14 mM Pb, 150 µL) after 24 h. The best therapy window was selected after the time of 24 h inject, the mice tumors of the laser groups were exposed to 10 min by 808 nm NIR light (1.5 W/cm2). The critical temperature that induced the death of cancer cells was 43.0 °C. The GCGLS + laser group of the tumor temperature was quickly enhanced from ~ 28.8 °C to ~ 52 °C in the time point 2 min, and steadily increased in the remaining 8 min (Figure 6A-B), the result proved that GCGLS nanoparticles can effective destroy tumor cells in vivo and suppressed the tumor growth. In contrast, the PBS + laser group exhibited slightly change of temperature after near-infrared light irradiation, it was showed that the photothermal effect was induced by the combination of GCGLS nanoparticles and NIR laser. The histological examination of the tumor slices were immediately tested after laser irradiate, and the tumor structure had no damage after NIR laser irradiation, but the GCGLS nanoparticles injected group were observed severe damage after laser irradiation (Figure 6D).



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Figure 5. In vitro/vivo T1 MR relaxometry of the GCGLS nanoparticles. (A) The linear fitting of inverse T1 of Gd-DTPA and GCGLS nanoparticles. (B) T1-MR images of Gd-DTPA and GCGLS nanoparticles. (C) and (D) In vivo T1-weight MR imagings of B16 tumor-bearing mice post injected GCGLS nanoparticles under different time points (0 min, 30 min, 1 h, 2 h and 5 h after the injection, respectively). (E) T1 signal to noise ratio around the tumors. B16 cells were multiply faster than others, which lead to the tumor are very large.

The therapeutic effectiveness of mice in different groups were evaluated by measured the tumor sizes (Figure 6C), the control groups of the tumors were similar increase rates over time. For the PBS , PBS + laser and GCGLS only groups, the volume of tumor increased rapidly to 1300 mm3 and ~ 810 mm3 at 21 days after treatment, nearly 8.7 and 5.4 times compared with origin volume (~ 150 mm3), the result showed the GCGLS nanoparticles and near-infrared light irradiation alone could not inhibit tumor increase. In marked contrast, the GCGLS + laser group could be clearly observed the significantly tumor restraint, the volume of the tumor clearly restraining to approximate 200 mm3 after 21 day PTT. For the cytotoxicity analysis, we have taken the related tested. The nanoparticles were proved has negligible adverse effect under the tested high concentrations. For in vivo security evaluation, the control group organs (heart, liver, spleen, lung, and kidney) and tumor were detected no noticeable abnormality or lesion by H&E stained slices. Thus, the GCGLS nanoparticles were proven safe. All these results revealed that the combination of GCGLS with NIR laser exposure could showed efficient photothermal ablation, and the light irradiated site could be controlled to facilitating selected therapy. In marked contrast, the control groups tumor was grew quickly, and the GCGLS + laser group could clearly found the black scars from tumor sites (Figure ACS Paragon Plus Environment

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S9B-C), which no longer growth at approximate day 15, the GCGLS nanoparticles were showed excellent effectiveness for tumors photothermal ablation in vivo.

Figure 6. In vivo PTT. (A) Thermal imagings of B16 tumor-bearing mice after injected PBS or GCGLS followed by a 808 nm laser irradiation for 10 min. (B) The temperature change curves of tumor sites. (C) Tumor growth curves after PTT. (D) H&E detected of tumor tissues after PTT.

3.5. In vivo biodistribution of GCGLS nanoparticles. The lead and gadolinium elements content in organs, blood and tumors were tested by ICP-MS. The GCGLS nanoparticles were show up a significantly accumulated in the kidney after injection at 48 h (Figure 7A and Figure S10A), the elements content in blood were showed a declining trend, and the lead and gadolinium elements content in tumors were presented an increasing trend (Figure S10B). Moreover, the heart, liver, spleen and lung were remained bits of Pb and Gd after injection, because of the GCGLS nanoparticles were suggested a low uptake by Reticulo-Endothelial System (RES) tissues and the lung was not significantly retained of GCGLS nanoparticles. The GCGLS nanoparticles were testified to be safe in vivo biomedical imagings applications.



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Figure 7. (A) Biodistribution of elemental Pb in the main organs ( heart, liver, spleen, lung and kidney), blood and the tumors of mice at 0.5 h, 1 h, 5 h and 48 h post intravenous injection of GCGLS (150 µL, [Pb] = 14 mM) (mean ± SD, n = 8). (B) Mice Body weights analisis. (C) Histology staining (heart, liver, spleen, lung and kidney) at day 21 after treatment.

3.6. In vivo security evaluation. The in vivo security evaluation of diagnostic reagents was necessary for their use in clinical disease diagnosis and treatment. In this study, the GCGLS nanoparticles were assessed safety as diagnosis and treatment reagent for body weight change, H&E-stained histology in vivo. After the PBS and GCGLS nanoparticles were intravenously injected 21 days, two groups (PBS + Laser and GCGLS + Laser) of the main organs (heart, liver, spleen, lung, and kidney) and tumor were detected no noticeable abnormality or lesion by H&E stained slices (Figure 7C). The other main indicator of organism intoxication was weight change. The whole time period of the experiment, there mice was no obvious body weight loss and death after GCGLS nanoparticles treated (Figure 7B and Figure S11). All of the data demonstrated that the GCGLS nanoparticles had large potential applied in clinic cancer diagnosis and treatment reagent. For in vivo pharmacokinetics and metabolism of GCGLS nanoparticles, mice were injected with GCGLS nanoparticles (150 µL, [Pb] = 14 mM), followed by collecting blood samples and excrement ACS Paragon Plus Environment

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(urine and feces) at eight time points in order to measure the amount of Pb or Gd by ICP-MS. The half-life of GCGLS was determined to be approximately 4.27 h (Figure S12A). The blood content of GCGLS nanoparticles was remained steady at a relatively low level after 24 h of circulation. Moreover, the ionic concentration of GCGLS nanoparticles in the excrement showed a trend of increase at 5 h and then decrease at 48 h (Figure S12B). Corresponding, the organs of liver and kidney presented a similar trend. 4. CONCLUSIONS In summary, we have successfully prepared a new type of PbS-based theranostic agents GCGLS nanoparticles, and these results show that GCGLS nanoparticles could be used as CT and MR dual-modality imaging guided photothermal agents. In this study, only one wavelength was used for excitation the efficiencies of the nanoagents: 808 nm for initiating GCGLS nanoparticles mediated PTT with good photothermal conversion efficiency (~ 31 %). The encapsulated PbS acted as a good CT contrast agent and the Gd(AA)3Phen provided a MR imaging. Compared with Gd-DTPA (4.98 mM−1s−1) and iodixanol, the prepared GCGLS nanoparticles exhibited high r1 relaxivity value for T1-weighted MRI (13.65 mM−1s−1) and excellent CT imaging. The dispersibility of GCGLS nanoparticles would depend on the amount of Gd(AA)3Phen. With the increasing of Gd(AA)3Phen, the stability of GCGLS nanoparticles reduced. Furthermore, GCGLS nanoparticles could effectively cause cancer cell ablation after near-infrared light irradiation. The mice tumor information could be obtained by dual-modality CT and MR imaging, such as site and size. The tumor was significantly ablated after the GCGLS + Laser treated. In addition, the resultant GCGLS nanoparticles exhibited high stability, safety, and biocompatibility in vitro/vivo. Compared to previously reported, our fabrication process is more feasible. Therefore, the GCGLS nanoparticles with dual-modality imaging guided photothermal therapy could have great potential for cancer theranostics.

■ ASSOCIATED CONTTENT Supporting Information The Supporting Information is available free of charge via the Internet at http://pubs.acsami.org. The calculate of photothermal conversion efficiency (η), TEM and HR-TEM imagings, hydrodynamic diameter analysis, EDX mapping analysis, survey XPS spectra, UV-vis-NIR absorption spectrum, temperature change of pure water, CPA-PbS and GCGLS nanoparticles solutions, photothermal response and linear time data versus obtained from the cooling period, electron microscopy images, representative photos after photothermal therapy, biodistribution, weight evaluation of main organs, in vivo ACS Paragon Plus Environment


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pharmacokinetics and metabolism.

■ AUTHOR INFORMATION Corresponding Authors * E-mail: [email protected]. * E-mail: [email protected]. * E-mail: [email protected]. Author Contributions ⊥

These authors contributed equally to this work.

Notes The authors declare no competing financial interest.

■ ACKNOWLEDGEMENTS This paper was supported by the National Natural Science Foundation of China (Grant No. 51573039).

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Design and Synthesis of a Lead Sulfide Based Nanotheranostic Agent

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