Renal Clearable BiâBi2S3 Heterostructure Nanoparticles for Targeting

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Biological and Medical Applications of Materials and Interfaces

Renal Clearable Bi-Bi2S3 Heterostructure Nanoparticles for Targeting Cancer Theranostics Lile Dong, Peng Zhang, Xiangjian Liu, Ruiping Deng, Kaimin Du, Jing Feng, and Hongjie Zhang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b21280 • Publication Date (Web): 30 Jan 2019 Downloaded from http://pubs.acs.org on January 31, 2019

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ACS Applied Materials & Interfaces

Renal Clearable Bi-Bi2S3 Heterostructure Nanoparticles for Targeting Cancer Theranostics

Lile Dong,†,‡ Peng Zhang,§ Xiangjian Liu,‡ Ruiping Deng,† Kaimin Du,†,‡ Jing Feng,*,†,‡ and Hongjie Zhang*,†,‡

†State

Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied

Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, People’s Republic of China. ‡University

of Science and Technology of China, Hefei, Anhui 230026, People’s Republic

of China. §Department

of Radiology, The Second Hospital of Jilin University, Changchun, Changchun

130041, People’s Republic of China.

KEYWORDS: Bi-Bi2S3 heterostructure, renal clearable, targeting theranostic agent, CT imaging, photoacoustic imaging, photothermal therapy

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ABSTRACT: Recent development of precise nanomedicine has aroused overwhelming interest in integration of diagnosis and treatment for cancers. To design renal clearable and targeting nanoparticles (NPs) have specific cancer theranostics implications and it remains a challenging task. In this work, the ultrasmall folic acid and bovine serum albumin modified Bi-Bi2S3 heterostructure nanoparticles (Bi-Bi2S3/BSA&FA NPs) with excellent CT and photoacoustic imaging abilities and outstanding photothermal performance were synthesized in aqueous phase via a simple method. Bi-Bi2S3/BSA&FA NPs have the following criteria: (i) Bi-Bi2S3/BSA&FA NPs with heterostructure possess better stability than Bi NPs and higher Bi content than Bi2S3 NPs, which are conducive to the enhancement of CT imaging effect; (ii) Bi-Bi2S3/BSA&FA NPs with folic acid molecules on the surface could target the tumor site effectively; (iii) BiBi2S3/BSA&FA NPs could inhibit tumor growth effectively under 808-nm laser irradiation; (iv) Ultrasmall Bi-Bi2S3/BSA&FA NPs could be cleared through kidney and liver within a reasonable time, avoiding long-term retention/toxicity. Therefore, the renal clearable BiBi2S3/BSA&FA NPs are promising agent for targeting cancer theranostics.


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INTRODUCTION Cancer with extremely high morbidity and mortality has already placed a heavy burden on countless patients. Theranostic nanoparticles combinate with diagnostic and therapeutic functions can improve the cure rate of cancer because they can help doctors evaluate the therapeutic effect in real time and formulate appropriate therapeutic plans.1-5 X-ray computed tomography (CT) imaging and photoacoustic (PA) imaging guided photothermal therapy has been intensively studied due to the outstanding properties and advantages of the theranostic agents.6-11 Usually, to obtain comprehensive diagnostic information from CT images, a large dose of CT contrast agent is required due to lack of sensitivity for soft tissue, which may bring potential toxicity for visceral organ. While, for PA imaging, PA signal could be detected at a relative low dose of contrast agent, compared with CT imaging. To date, it is still a challenging task to synthesize renal clearable and targeting CT and PA imaging contrast agents through a facile method. Currently, various Bi-based nanomaterials have been extensively investigated for CT imaging and PA imaging guided photothermal therapy due to unique properties of bismuth.12-14 As well known, one can obtain comprehensive information from CT imaging by improving the content of Bi in the contrast agent, such as designing synthetic Bi nanoparticles. However, there are many limitations for Bi nanoparticles that need to be addressed, such as poor stability, large size, laborious postsynthetic surface modification, and poor targeting property.15-17 The stable Bi2S3 nanoparticles not only hold promise for CT imaging compared with Bi nanoparticles, but also could be served as theranostic agent for PA imaging and photothermal therapy. However, it remains challenge to obtain renal clearable Bi2S3 nanoparticles through simple aqueous route, because Bi3+ ions are readily to be hydrolyzed, resulting in the relative large size. In addition, in


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order to reduce the toxicity caused by the long-term retention of the nanoparticles and improve the therapeutic effect, the targeting nanoparticles with renal metabolism have been extensively studied.18-22 Multifunctional Bi-based nanoparticles combining the advantages of Bi and Bi2S3 nanoparticles are ideal theranostic agents for cancer.23,24 With this in mind, we design and synthesize novel folic acid (FA) and bovine serum albumin (BSA) modified Bi-Bi2S3 heterostructure nanoparticles (Bi-Bi2S3/BSA&FA NPs) for CT imaging and photoacoustic imaging guided photothermal therapy (Scheme 1). BSA molecule promotes the formation of Bi2S3 nanoparticles on the surface of the heterostructure, thus enhancing the stability of Bi nanoparticles in the central region and improving the content of Bi in the heterostructure nanoparticles. Meanwhile, folic acid as the targeting molecule can recognize the tumor cells. It is worth noting that Bi-Bi2S3/BSA&FA NPs contain 4.6 wt% folic acid by thermogravimetric analysis, which makes Bi-Bi2S3/BSA&FA NPs possess excellent targeting properties.25,26 As a comparison, bovine serum albumin modified Bi-Bi2S3 nanoparticles (Bi-Bi2S3/BSA NPs) with similar size and morphology was synthesized by the same method. Bi-Bi2S3/BSA&FA NPs show higher cell uptake compared with Bi-Bi2S3/BSA NPs in intracellular uptake experiment. The accumulated amount of Bi-Bi2S3/BSA&FA NPs in the tumor site is about three times higher than that of Bi-Bi2S3/BSA NPs by ICP-MS analysis, indicating Bi-Bi2S3/BSA&FA NPs could be used as targeting agent for cancer theranostics. Meanwhile, the photothermal conversion efficiency of Bi-Bi2S3/BSA&FA NPs (35.3%) is higher than that of Bi-Bi2S3/BSA NPs (31.8%). In addition, Bi-Bi2S3/BSA&FA NPs have excellent water solubility and stability due to the presence of BSA molecules on the surface of the nanoparticles.27,28 Bi-Bi2S3/BSA&FA NPs can be metabolized out of the body through kidney due to small hydrodynamic size,29-31 which can be confirmed by ICP-MS analysis and TEM


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image of urine. It can be also seen from the CT image that Bi-Bi2S3/BSA&FA NPs could be expelled from the body through the urine (Scheme 1). Importantly, Bi-Bi2S3/BSA&FA NPs possess good biocompatibility based on the results of the routine blood tests and histological examinations of major organs. Furthermore, the tumor growth is inhibited effectively after intravenous injection of Bi-Bi2S3/BSA&FA NPs under 808-nm laser irradiation due to excellent photothermal property. Therefore, Bi-Bi2S3/BSA&FA NPs could be applied as renal clearable and targeting nanotheranostic agent for cancer. RESULTS AND DISCUSSION Ultrasmall Bi-Bi2S3/BSA&FA NPs were prepared via a simple aqueous route. Briefly, bismuth nitrate pentahydrate is hydrolyzed in water to form bismuth hydroxide and BiONO3 compounds. BSA and FA molecules can be adsorbed on the surface of the above compounds. Then, the ultrafast reduction reaction could be triggered by sodium borohydride to form small Bi-Bi2S3/BSA&FA NPs. In this strategy, BSA not only acts as coating agent but also promotes the formation of ultrasmall heterostructures. We also synthesized BSA modified Bi-Bi2S3 nanoparticles (Bi-Bi2S3/BSA NPs, Figure S1, Supporting Information) by the same method as the control sample. Typically, as shown in transmission electron microscope (TEM) images (Figure 1A), Bi-Bi2S3/BSA&FA NPs are monodisperse with the diameter of ~9.2 nm. The heterostructure of Bi-Bi2S3/BSA&FA NPs is confirmed by the spherical aberration-corrected transmission electron microscope (AC-STEM) images, as shown in Figure 1B and C. The lattice distances at the edge region of the nanoparticles in Figure 1C (I and IV; III) were measured to be 0.282 nm and 0.305 nm, respectively, corresponding to the (1 2 2) and (0 2 3) planes of orthorhombic Bi2S3 (PDF#65-3884). The lattice distance in the central region of the nanoparticles (Figure 1C, II) is measured to be 0.235 nm, which consistent with the (1 0 4) plane


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of hexagonal Bi (PDF#01-0688). The heterostructure is also proved by powder X-ray diffraction (XRD) patterns (Figure 1D). From Figure 1E and F, it indicates that Bi-Bi2S3/BSA&FA NPs contain both Bi and S elements. The molar ratio of Bi to S is determined to be 1.07 by inductively coupled plasma-optical emission spectrometry (ICP-OES). It early demonstrates that the content of Bi in heterostructure nanoparticles is higher than that of Bi in Bi2S3 NPs (~0.67). Furthermore, the element valence states of Bi-Bi2S3/BSA&FA NPs were confirmed by X-ray photoelectron spectroscopy (XPS). As shown in Figure 1G, the Bi 4f peaks at 152.9 and 159.2 eV are assigned to metal Bi while the peaks at 158.6 and 164.1 eV are associated with Bi3+ ions.16 The peaks of S 2p1/2 and S 2p3/2 centered at 164.4 and 163.7 eV could be assigned to S-2 from Bi2S3.11 The successful modification of BSA molecule on the surface of Bi-Bi2S3/BSA&FA NPs was confirmed by Fourier transform infrared (FTIR) spectrum (Figure S2). As shown in Figure 1h, the mass percentages of BSA and FA molecules in Bi-Bi2S3/BSA&FA NPs are 62.9% and 4.6%, respectively, which agrees with the initial doping amount. As a result, BiBi2S3/BSA&FA NPs have good dispersibility and stability (Figure 1I and S3). In addition, as shown in Figure S3, Bi-Bi2S3/BSA&FA NPs were stable without obvious agglomeration after placing for 30 days. Meanwhile, the zeta potential of Bi-Bi2S3/BSA&FA NPs in aqueous solution was about -18 mV. The above result indicates Bi-Bi2S3/BSA&FA NPs could be used as water-dispersible and stable nanotheranostic agent. As exhibited in Figure 2A, Bi-Bi2S3/BSA&FA NPs have strong absorption in the NIR region. Furthermore, as shown in Figure 2B, Bi-Bi2S3/BSA&FA NPs possess good photothermal performance and the temperature increases following concentration-dependent manner. The photothermal conversion efficiency of Bi-Bi2S3/BSA&FA NPs (Figure S4) could be calculated as 35.3% with the reported method,1,2,32 which is similar to Bi2Se3 nanoplates (34.7%),9 and


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higher than Bi-Bi2S3/BSA NPs (31.8%), BSA-coated BiOI@Bi2S3 nanoparticles (28.5%),14 Bi2S3 nanorods (33.58%),33 PEGylated Bi nanocrystals (30.1%),13 poly(vinylpyrrolidone)protected bismuth nanodots (30%)16 and Au nanorods (21%).34 Bi-Bi2S3/BSA&FA NPs possess excellent NIR photostability (Figure 2C). As exhibited in Figure 2D, Bi-Bi2S3/BSA&FA NPs show good blood compatibility based on hemolysis of red blood cells. The cytotoxicity of nanoparticles on tumor cells were also investigated by the standard MTT assay. As shown in Figure 2E, both Bi-Bi2S3/BSA&FA and Bi-Bi2S3/BSA NPs have no toxicity towards the cells. To illustrate the targeting performance of Bi-Bi2S3/BSA&FA NPs, As presented in Figure 2F, compared with Bi-Bi2S3/BSA NPs, Bi-Bi2S3/BSA&FA NPs show higher cell uptake owing to the targeting agent folic acid, which allows Bi-Bi2S3/BSA&FA NPs to enter cells through folic acid receptors. Then, the in vitro photothermal performance of Bi-Bi2S3/BSA&FA NPs was investigated by MTT assay, and the temperature was monitored every 2 s with thermocouple microprobe. As dispalyed in Figure 2G, Bi-Bi2S3/BSA&FA and Bi-Bi2S3/BSA NPs have similar photothermal properties. In contrast, as shown in Figure 2H and I, compared with that of BiBi2S3/BSA NPs under the same condition, the 4T1 cell viability almost dead as the concentration of Bi-Bi2S3/BSA&FA increased, which may due to lots of Bi-Bi2S3/BSA&FA enter cells and kill the tumor cells under laser irradiation. To further investigate the biocompatibility and targeting characteristic of Bi-Bi2S3/BSA&FA, the biodistribution of nanoparticles in the tumor-bearing mice was measured by ICP-MS after intravenous injection of Bi-Bi2S3/BSA&FA NPs (100 μL, 4 mg Bi kg-1). As displayed in Figure 3A and B, the uptake of nanoparticles in the liver decreased with time. Meanwhile, the ultrasmall Bi-Bi2S3/BSA&FA NPs can be excreted through renal clearance. Furthermore, we characterized the urine of mice by TEM after 1 d post-injection. As shown in Figure 3C and S5, Bi-


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Bi2S3/BSA&FA NPs with good crystallinity were dispersed in urine, showing that the nanoparticles possess excellent stability in vivo. Importantly, we also evaluated the targeting property of Bi-Bi2S3/BSA&FA NPs by ICP-MS after intravenous injection of Bi-Bi2S3/BSA&FA or Bi-Bi2S3/BSA NPs (100 μL, 4 mg Bi kg-1) under the same condtion. As dispalyed in Figure 3D, the maximum accumulated amount of Bi-Bi2S3/BSA&FA NPs in the tumor site was about three times larger than that of Bi-Bi2S3/BSA NPs, indicating Bi-Bi2S3/BSA&FA NPs possess excellent targeting property. Then, we tested the long-term toxicity of Bi-Bi2S3/BSA&FA NPs on the health mice after intravenous injection of Bi-Bi2S3/BSA&FA NPs (100 μL, 4 mg Bi kg-1) by routine blood tests. As exhibited in Figure 3E, the change of blood cell number and its morphological distribution are within the normal reference range, indicating Bi-Bi2S3/BSA&FA NPs did not cause damage to cells. In addition, Bi-Bi2S3/BSA&FA NPs did not induce noticeable damage in the major organs by histological examinations, as presented in Figure 3F. As shown in Figure 4A, the CT imaging effect of Bi-Bi2S3/BSA&FA NPs progressively became brighter along with the increasing concentrations. Doctors can distinguish different tissues by using HU values in CT imaging. As displayed in Figure 4B, the X-ray absorption coefficient of Bi-Bi2S3/BSA&FA NPs (50.4 HU L g-1 or 10.6 HU mM-1) is higher than that of iohexol (24.1 HU L g-1), indicating that Bi-Bi2S3/BSA&FA NPs possess high CT performance. In addition, the heterostructure makes Bi-Bi2S3/BSA&FA NPs possess higher HU value compared with the other reported nanoparticles (such as Bi, Bi2S3, Bi2Se3, Au-, and lanthanidebased CT contrast agents; Table S1), indicating that the rich information could be obtained of from CT imaging by injecting low dose of Bi-Bi2S3/BSA&FA NPs. Then, as shown in Figure 4C, the tumor site can be clearly observed after 2 h injection, which agrees with the distribution recorded by ICP-MS. In addition, CT signals in the bladder were also significantly enhanced,


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indicating Bi-Bi2S3/BSA&FA NPs can be excreted through urine. Therefore, Bi-Bi2S3/BSA&FA NPs is safely and targeted nanotheranostic agents. Then, photoacoustic imaging of the tumorbearing mouse was performed to further realize the earlier diagnosis of cancer due to the good photothermal conversion efficiency of Bi-Bi2S3/BSA&FA NPs (35.3%). As shown in Figure S6, the significantly enhanced PA signal could be observed at tumor site after 2 h injection, which is agrees with the distribution recorded by ICP-MS and CT imaging. What’s more, the imaging guided photothermal therapy was also investigated at 2 h post intravenous injection of BiBi2S3/BSA&FA NPs (100 μL, 4 mg Bi kg-1). As exhibited in Figure 4D, the temperature of the tumor increases to 56.6 oC, indicating the tumor cells can be killed under this condition. Then, we applied photothermal therapy to the tumor-bearing mice after 2 h injection of BiBi2S3/BSA&FA NPs (100 μL, 4 mg Bi kg-1). The mice were divided into four groups: BiBi2S3/BSA&FA+NIR; NIR; Bi-Bi2S3/BSA&FA; and the control group. As shown in Figure 5AC, the tumor growth of Bi-Bi2S3/BSA&FA+NIR group was obviously inhibited after 18 d treatment. In contrast, the tumor growth of the other three groups (NIR; Bi-Bi2S3/BSA&FA; and the control group) showed exponential growth, indicating that it is difficult to control tumor growth with 808-nm laser irradiation or Bi-Bi2S3/BSA&FA NPs only, as presented in Figure 5D. Meanwhile, Bi-Bi2S3/BSA&FA NPs has good biocompatibility (Figure 5E). Furthermore, the tumor tissue of the four groups were also histological examinations with H&E staining after 18 d treatment. As dispalyed in Figure 5F, the tumor cells of Bi-Bi2S3/BSA&FA+NIR group were remarkably damaged, confirming Bi-Bi2S3/BSA&FA NPs is effective photothermal therapy agent. Meanwhile, the survival rate of the tumor-bearing mice in Bi-Bi2S3/BSA&FA+NIR group was significantly high compared with the other groups (Figure S7), implying that BiBi2S3/BSA&FA NPs exhibited excellent therapeutic effect under 808-nm laser irradiation.


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CONCLUSION In summary, novel heterostructure Bi-Bi2S3/BSA&FA NPs as effective nanotheranostic agent were successfully fabricated via a simple aqueous route. Bi-Bi2S3/BSA&FA NPs possess good CT and PA imaging features, excellent photothermal performance, favorable cancer cell-killing ability, as well as excellent biocompatibility and low cytotoxicity. Bi-Bi2S3/BSA&FA NPs could accumulate in the tumor site effectively due to the targeting ability of FA molecule and enhanced permeability and the retention effect. Bi-Bi2S3/BSA&FA NPs exhibit satisfactory tumor ablation efficiency triggered by 808-nm laser. More importantly, Bi-Bi2S3/BSA&FA NPs can be easily cleared through kidney and liver, avoiding the longterm toxicity. Therefore, Bi-Bi2S3/BSA&FA NPs are promising targeting nanotheranostic agent for cancer.

MATERIALS AND METHODS Chemicals. Analytical grade Bi(NO3)3·5H2O, bovine serum albumin (BSA), folic acid (FA) and NaBH4 were obtained from Aladdin. Synthesis of Bi-Bi2S3/BSA&FA NPs. Folic acid (22 mg) and bovine serum albumin (200 mg) were dissolved in 40 mL of water, and stirred for 10 min. Then, Bi(NO3)3·5H2O (121.3 mg) was added into the above solution, and stirred for 5 min. Subsequently, 1 mL of NaBH4 solution (50 mg mL-1) was quickly added to the above mixture and stirred for another 20 min. The black solution was centrifuged at high speed to remove the impurities. Bi-Bi2S3/BSA&FA NPs can be obtained by concentrating the supernatant.


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Characterization. The morphology, particle size, HAADF-STEM images, EDS mapping, and EDS analysis of the nanoparticles were obtained with HR-TEM operating with a field-emission gun at 200 kV. HR-TEM images were obtained with the spherical aberration-corrected transmission electron microscope (AC-STEM). XRD patterns were carried out on D8 ADVANCE X-ray diffractometer with Cu Kα radiation (λ = 1.5418 Å; voltage: 40 kV; current 40 mA). XPS was obtained on a VG ESCALAB MKII spectrometer. ICP-MS was obtained on an ELAN 9000/DRC. The visible-NIR absorption spectrum was recorded on Shimadzu UV-3600 spectrophotometer. Photothermal Ablation Property of Bi-Bi2S3/BSA&FA NPs. 4T1 murine breast tumor cells (4 × 104 cells) were incubated with Bi-Bi2S3/BSA&FA NPs dispersions (Bi concentrations: 0, 13, 25, 50, 100, 200, and 400 ppm) for 1 d and then irradiated under 808-nm laser irradiation for 10 min. The cell viability was analyzed using the standard 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay. Then, the cells were stained with calcein acetoxymethyl ester and propidium iodide and observed by Nikon Ti-S fluorescence microscope, the live cells exhibited green and dead ones showed red. Cellular Uptake Assay. The tumor cells (105 per well) were incubated with Bi-Bi2S3/BSA&FA or Bi-Bi2S3/BSA NPs dispersions (Bi concentrations: 50, 100, 200, and 400 ppm) for 24 h. Then cell suspensions were digested, and the intracellular Bi concentration used for ICP-MS. Animal Experiments. Female Kunming mice were provided by the Laboratory Animal Center of Jilin University (China). We conducted strict the National Regulation of China for the Care and Use of Laboratory Animals for all animal experiments. The tumor model was established by subcutaneous injection of H22 cells in the left axilla of each mouse.


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Biodistribution. The tumor-bearing mice were intravenous injection of Bi-Bi2S3/BSA&FA or Bi-Bi2S3/BSA NPs (100 μL, 4 mg Bi kg-1). At given time, the mice (n = 4) were euthanized. Then the major organ, tumor and feces dissolved in the HNO3 solution. The contents of Bi were quantified by ICP-MS. CT and PA Imaging. CT imaging was measured by Philips iCT 256 slice scanner operated at 120 kV and 300 mA. PA imaging was performed Then, we performed the CT and PA imaging on the tumor-bearing mice after intravenous injection same dose of Bi-Bi2S3/BSA&FA NPs (100 μL, 4 mg Bi kg-1) at given time points. Photothermal Therapy in Vivo. The tumor-bearing mice (tumor volume: 100 mm3) were divided into the following groups (n = 3): Bi-Bi2S3/BSA&FA+NIR group, mice treated with 808-nm laser irradiation after 2 h intravenous injection of Bi-Bi2S3/BSA&FA NPs (100 μL, 4 mg Bi kg-1); NIR group, mice treated with the 808-nm laser irradiation; Bi-Bi2S3/BSA&FA group, mice only injected with Bi-Bi2S3/BSA&FA NPs; and the control group, mice without any treatment. The tumor volume could be determined as V (mm3) = (width)2 × (length)/2. ASSOCIATED CONTENT Supporting Information. Additional characterization results: TEM, HRTEM, FTIR spectroscopy, DLS, photothermal conversion efficiency, survival rates. AUTHOR INFORMATION Corresponding Authors *E-mail (J. Feng): [email protected] *E-mail (H. Zhang): [email protected]


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Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS The authors are grateful for the financial aid from the National Natural Science Foundation of China (21871246, 21590794, 21210001, and 21521092), the Youth Innovation Promotion Association of Chinese Academy of Sciences (2015181), and Jilin Province Science and Technology Development Plan Project (20180101172JC). REFERENCES (1) Dong, L.; Ji, G.; Liu, Y.; Xu, X.; Lei, P.; Du, K.; Song, S.; Feng, J.; Zhang, H. Multifunctional Cu-Ag2S Nanoparticles with High Photothermal Conversion Efficiency for Photoacoustic Imaging-Guided Photothermal Therapy In Vivo. Nanoscale 2018, 10, 825-831. (2) Dong, L.; Zhang, P.; Xu, X.; Lei, P.; Du, K.; Zhang, M.; Wang, D.; Feng, J.; Li, W.; Zhang, H. Simple Construction of Cu2−xS:Pt Nanoparticles as Nanotheranostic Agent for ImagingGuided Chemo-Photothermal Synergistic Therapy of Cancer. Nanoscale 2018, 10, 10945-10951. (3) Song, X.; Wang, X.; Yu, S.; Cao, J.; Li, S.; Li, J.; Liu, G.; Yang, H.; Chen, X. Co9Se8 Nanoplates as a New Theranostic Platform for Photoacoustic/Magnetic Resonance Dual-ModalImaging-Guided Chemo-Photothermal Combination Therapy. Adv. Mater. 2015, 27, 3285-3291. (4) Ge, X.; Song, Z.; Sun, L.; Yang, Y.; Shi, L.; Si, R.; Ren, W.; Qiu, X.; Wang, H. Lanthanide (Gd3+ and Yb3+) Functionalized Gold Nanoparticles for In Vivo Imaging and Therapy. Biomaterials 2016, 108, 35-43. (5) Zhao, L.; Ge, X.; Yan, G.; Wang, X.; Hu, P.; Shi, L.; Wolfbeis, O.; Zhang, H.; Sun, L. Double-Mesoporous Core-Shell Nanosystems Based on Platinum Nanoparticles Functionalized


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Figure Captions Scheme 1. Renal clearable Bi-Bi2S3/BSA&FA NPs as targeting cancer theranostic agent.

Figure 1. (A) TEM image (inset: sizes distribution) of Bi-Bi2S3/BSA&FA NPs; (B) AC-STEM image of Bi-Bi2S3/BSA&FA NPs; (C) Lattice distances of Bi-Bi2S3/BSA&FA NPs based on ACSTEM images; (D) XRD patterns of Bi-Bi2S3/BSA&FA and Bi-Bi2S3/BSA NPs; (E) HAADFSTEM and EDS mapping images of Bi-Bi2S3/BSA&FA NPs; (F) EDS analysis of BiBi2S3/BSA&FA NPs; (G) XPS spectra of Bi 4f and S 2p in Bi-Bi2S3/BSA&FA NPs; (H) Thermogravimetric analysis of Bi-Bi2S3/BSA&FA and Bi-Bi2S3/BSA NPs; (I) Hydrodynamic size of Bi-Bi2S3/BSA&FA NPs.

Figure 2. (A) The visible-NIR absorption spectra of Bi-Bi2S3/BSA&FA NPs; (B) Photothermal characterization of Bi-Bi2S3/BSA&FA NPs; (C) Photothermal conversion cycling test of BiBi2S3/BSA&FA NPs; (D) Hemolytic percent of red blood cells incubated with BiBi2S3/BSA&FA NPs; Relative viability (E) and cellular uptake assay (F) of tumor cells after incubation with Bi-Bi2S3/BSA&FA or Bi-Bi2S3/BSA NPs for 24 h; (G) Temperature elevation of cells after adding Bi-Bi2S3/BSA&FA or Bi-Bi2S3/BSA NPs as a function of irradiation time (inset: infrared thermographs of the plate after irradiation); Relative viabilities (H) and fluorescence images (I) of 4T1 murine breast tumor cells after various treatments; All the scale bars are 10 μm.

Figure 3. (A) Distribution of Bi-Bi2S3/BSA&FA NPs in the major organs; (B) Distribution of Bi-Bi2S3/BSA&FA NPs in the feces and urine; (C) TEM image of Bi-Bi2S3/BSA&FA NPs in


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urine; (D) Distribution of Bi-Bi2S3/BSA&FA and Bi-Bi2S3/BSA NPs in the tumor; (E) Blood biochemistry tests of the mice from the control group and test group; (F) H&E staining images of the major organs from the control group, 15 d, and 30 d postinjection. All the scale bars are 500 μm.

Figure 4. CT images (A) and CT values (B) of Bi-Bi2S3/BSA&FA NPs and iohexol solution; (C) CT images of mice, the tumor sites were marked by green circles and bladder were marked by blue circles; (D) IR thermal images of the tumor sites.

Figure 5. (A) Photographs of tumor-bearing mice before and after 18 d different treatment, the tumor sites were marked by blue circles; Photographs (B) and weight (C) of tumor under different treatments; (D) Tumor growth curves of different groups; (E) Tumor mice weight in different groups; (F) H&E stain of tumor from different groups. All the scale bars are 50 μm.


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Scheme 1


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Figure 1


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Figure 2


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Figure 3


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Figure 4


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Figure 5


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Renal Clearable BiâBi2S3 Heterostructure Nanoparticles for Targeting

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