Facile Synthesis of Uniform-Sized Bismuth Nanoparticles for CTVisualization of Gastrointestinal Tract in VivoBoxiong Wei,†,∥ Xuejun Zhang,†,∥ Cai Zhang,‡ Ying Jiang,† Yan-Yan Fu,† Chunshui Yu,‡ Shao-Kai Sun,*,†

and Xiu-Ping Yan§

†School of Medical Imaging, Tianjin Medical University, Tianjin 300203, China‡Department of Radiology, Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin300052, China§College of Chemistry, Research Center for Analytical Sciences, State Key Laboratory of Medicinal Chemical Biology (NankaiUniversity), Tianjin Key Laboratory of Molecular Recognition and Biosensing, and Collaborative Innovation Center of ChemicalScience and Engineering (Tianjin), Nankai University, 94 Weijin Road, Tianjin 300071, China

*S Supporting Information

ABSTRACT: High-performance and biocompatible contrast agents are the key toaccurate diagnosis of various diseases in vivo via CT imaging. Fabrication of pure Binanoparticles is the best way to maximize X-ray absorption efficiency due to theultrahigh X-ray attenuation ability of Bi and 100% content of Bi element. However,high-quality Bi nanoparticles prepared through a facile strategy are still lacking.Herein, we report a simple noninjection method to fabricate uniformly sized pure Binanoparticles using only two commercial reagents by simply heating the mixture ofraw materials in a short time. The obtained Bi nanoparticles owned highly uniformsize, excellent monodispersity, and impressive antioxidant capacity. After beingmodified with oligosaccharide, the “sweet” Bi nanoprobe with comfortable patientexperience and favorable biocompatibility was successfully used in CT visualization ofgastrointestinal tract in detail.

KEYWORDS: Bi nanoparticles, gastrointestinal tract imaging, uniform size, non hot-injection, CT imaging

1. INTRODUCTION

X-ray computed tomography (CT) is one of the most powerfuland efficient diagnostic imaging techniques in clinic.1,2

Nevertheless, clinical small molecular contrast agents sufferfrom short diagnostic time window and low sensitivity becauseof the poor X-ray attenuation ability.1,3 As X-ray absorptioncoefficient highly depends on atomic number, nanosized heavymetal-based CT contrast agents (Yb, Lu, W, Ta, Au, and Bi)have been developed to improve the diagnostic time windowand the sensitivity in the past decade.1−4 Especially, bismuthhas the biggest atomic number among “nonradioactiveelements”, thus bismuth-based nanomaterials hold greatattraction as novel CT contrast agents because of theirultrahigh X-ray attenuation coefficient.1−3 In addition, bismuthis one of the most biocompatible heavy metals5,6 and “bismuththerapy” based on Bi compounds, such as colloidal bismuthsubcitrate (CBS, De-Nol), ranitidine bismuth citrate (RBC,Pylorid, Tritec), bismuth subcitrate potassium (Pylera) andbismuth subsalicylate (Helidac), has been used for thetreatment of gastrointestinal diseases in clinic for more thanthree centuries.5,6 In addition, bismuth is the most cheapelement among the heavy metal elements used in CT contrastagents, which further makes Bi-based nanomaterials a favorablecandidate for constructing CT imaging agents with highsensitivity and excellent biocompatibility.1,7

To date, Bi2S3 and Bi2Se3 nanomaterials with various shapessuch as nanoparticles (NPs) and nanorods and sizes rangedfrom several nanometers to dozens of nanometers have beensynthesized for in vivo CT diagnosis.7−14 Although the contentof Bi element in Bi2S3 and Bi2Se3 nanoprobes can reach 81.3%and 63.8%, respectively, fabrication of pure Bi NPs is the onlyway to maximize the efficiency in absorbing X-ray due to the100% content of Bi element and solve the bottleneck problemsof CT imaging contrast agents in the aspects of sensitivity andbiocompatibility.15−17 Various methods such as reductionmethod, solvothermal method, metal−organic precursormethod and photochemical method have been developed forthe synthesis of Bi NPs.15−34 Reduction method andsolvothermal method are the most widely used strategies dueto their relatively simple procedures,15−30,34 while precursormethod and photochemical method can be used to preparehigh quality nanoparticles with good monodispersity.31−33

However, the available methods are still not convenient enoughto obtain high quality Bi NPs. On one hand, strong reductantsbased reduction method and solvothermal methods are hardlyto produce highly uniform-sized nanoparticles.16−30 To control

Received: March 25, 2016Accepted: May 4, 2016Published: May 4, 2016

Research Article

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© 2016 American Chemical Society 12720 DOI: 10.1021/acsami.6b03640ACS Appl. Mater. Interfaces 2016, 8, 12720−12726

the size of the nanoparticles, complicated and energyconsuming “hot injection” process and preparation of Biorganic precursor are required in reduction method and metal−organic precursor method, respectively.15,31,32,34 On the otherhand, most of the processes in above-mentioned methods needat least three kinds of reactants except several reports, whichproduce a wide size distribution of Bi NPs unfortunately.27,30

So, it is highly desired to develop a facile strategy to producehigh quality Bi NPs with minimum reagents.CT visualization of the gastrointestinal (GI) tract is often

predominant and mandatory in the diagnosis of digestivesystem diseases to ensure efficient treatment with minimumside effects.35−39 Currently, BaSO4 suspension and smalliodinated molecules such as meglumine diatrizoateare areroutine contrast agents for X-ray contrast enhancement of GItract in clinic. However, the former suffers from false-positiveresults due to intrinsic insolubility, while the latter may causeserious iodine hypersensitivity reaction and large dose is neededdue to their native poor X-ray absorbing efficiency.39−41

Furthermore, it is still difficult to get an accurate and conclusivedescription of GI tract associated disease status (especiallysmall intestine) using the above-mentioned two kinds ofcontrast agents due to the length, complex loops, andperistalsis.37,42 Recently, BaYbF5, Bi2S3 and W18O49 nanoma-terials have been fabricated for the visualization of the GI tractsuccessfully.37−39 Nevertheless, more high-performance con-trast agents are urgently needed to obtain complementary andaccurate information on GI tract.Herein, we report a novel noninjection method to synthesize

high quality dodecanethiol modified Bi NPs (DT-Bi NPs) withgood monodispersity via simply heating only two reagents(Scheme 1). A commercial reagent Bi(NO3)3 was used as the

Bi source, and dodecanethiol (DT) was used as the ligand,reductant and solvent at the same time. The uniformly sized BiNPs with favorable antioxidant ability were synthesized usingminimum two reagents in merely 30 min-heating process. Thehydrophobic DT-Bi NPs were further modified witholigosaccharide based on the self-polymerization of glucose togenerate a “sweet” water-soluble agent (OS-Bi NPs). The as-prepared OS-Bi NPs gave low cytotoxicity and in vivo toxicity,impressive chemical stability, and high X-ray absorbing ability.The “sweet” OS-Bi NPs with comfortable patient experiencewere successfully used in CT visualization of GI tract. Theproposed strategy is the most convenient and efficient methodto generate high-performance Bi NPs with uniform size as far as

we know. To the best of our knowledge, this is the first timethat Bi NPs were used as CT contrast agents for visualization ofthe GI tract in vivo.

2. EXPERIMENTAL SECTION2.1. Chemicals and Materials. All reagents were of analytical

grade and used without further purification. Bi(NO3)3·5H2O waspurchased from Alfa Aesar (Shanghai, China). 1-dodecanethiol (DT)and D-(+)-Glucose were purchased from Aladdin Reagent Co., Ltd.(Shanghai, China). BaSO4 was purchased from Qingdao DongfengChemical Co., Ltd. Chloroform, ethanol, and N,N-dimethylformamide(DMF) were obtained from Concord (Tianjin, China). Ultrapurewater was used throughout this work (Tianjin Wahaha Foods Co.,Ltd., Tianjin, China).

2.2. Synthesis of DT-Bi NPs. Bi(NO3)3·5H2O (970 mg) wasadded to 10 mL of 1-dodecanethiol under vigorous stirring in a three-neck flask. The light yellow mixture was purged with Ar for 10 min andthen heated to 178 °C with electric jacket. At about 172 °C, thesolution turned black from dark brown. The mixture was then kept at178 °C for 1 min. During the whole reaction process, it was necessaryto keep a flow of Ar through the three-neck flask in order to keep outof oxidation. After cooling to 40 °C, the nanoparticles were obtainedby centrifugation and washed with ethanol three times (12 000 rpm,10 min) to remove any possible remnants.

2.3. Preparation of OS-Bi NPs. Oligosaccharide was coated onthe hydrophobic DT-Bi NPs by in situ-polymerization. Briefly, the as-prepared DT-Bi NPs were dissolved in chloroform (10 mg/mL) as thestock solution. Then, 2 mL of DT-Bi NPs (10 mg/mL) stock solutionwas dissolve in 8 mL of chloroform under ultrasound. After that, theabove solution was added dropwise to 10 mL of DMF containing 20mg glucose. Then, the mixture was heated and kept at 120 °C for 2.5h. After cooling to room temperature, the OS-Bi NPs were obtained bycentrifugation and washed with ethanol and water four times (12 000rpm, 10 min). The final product was redispersed in ultrapure water forfurther characterization and application.

2.4. Characterization. The high-resolution transmission electronmicroscopy (HRTEM) images of DT-Bi and OS-Bi NPs wereobtained on a Philips Tecnai G2 F20 microscope (Philips, Eindhoven,Netherlands) with an accelerating voltage of 200 kV and HT7700transmission electron microscope (Hitachi, Tokyo, Japan) with anaccelerating voltage of 80 kV respectively. The X-ray diffraction(XRD) spectra were characterized on a Rigaku D/max-2500 X-raydiffractometer (Rigaku, Tokyo, Japan). Fourier transform infraredspectra (FT-IR) were obtained using a Nicolet IS 10 spectrometer(Thermo Scientific, Madison, WI). The determination of Bi elementwas performed on an X series inductively coupled plasma massspectrometer (ICP-MS, Thermo Elemental, U.K.). Dynamic lightscattering (DLS) analysis was performed at different time points afterdissolving OS-Bi NPs (0.1 mg/mL) in various media including water,PBS (pH 6.5 and 7.4), 10% of 1640 cell medium and serum-supplemented 1640 cell medium.

2.5. In Vitro CT Imaging. To assess CT contrast efficiency, theOS-Bi NPs and BaSO4 suspension were dispersed in 10 mM PBSsolution with different mass concentrations (0, 1, 2, 4, 6, 8 mg/mL).After that, the tubes were scanned in a GE HDCT750 imaging systemutilizing clinical voltages (80 kV and 120 kV). The CT values weremeasured using the AW volumeshare4 software.

2.6. Chemical Stability Assessment. DT-Bi NPs were exposedin air at room temperature, and the antioxidant ability of DT-Bi NPswas monitored by XRD patterns before and after 7 days. To evaluatethe resistance ability toward GI tract environment of DT-Bi NPs andOS-Bi NPs, different-pH buffer solutions (2.2 and 8.0) were preparedto mimic the environment of GI system. Then 12 mg of DT-Bi NPs(OS-Bi NPs) were immersed in 1 mL various buffer solutions for 3days. After that, the solution of DT-Bi NPs (OS-Bi NPs) werecentrifuged, washed with water, and then characterized by XRDpattern to assess the change of crystal structure of DT-Bi NPs (OS-BiNPs). To assess the leakage of Bi element, the supernatant was

Scheme 1. Schematic Illustration of the Synthesis Process ofDT-Bi and OS-Bi NPs for GI Tract CT Imaging

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ultrafiltrated with centrifuge filter tube (cut off Mw = 3 k Da), and thefiltrate was collected for ICP-MS analysis.2.7. In Vitro Cytotoxicity. HeLa cells were incubated in culture

medium containing 90% RPMI 1640, 10% calf serum and 1%penicillin−streptomycin at 37 °C in a humidified atmosphere of 5%CO2. The cytotoxicity was assessed by MTT assay. Briefly, HeLa cellswith the density of 105/mL were planted in a 96-well plate andincubated at the same atmosphere for 24 h to allow the cellattachment. Then, the medium was washed with PBS two times andreplaced with fresh medium containing different concentrations ofoligosaccharide coated OS-Bi NPs (0, 12, 25, 50, 100, 200, 300, 400mg/L). After being incubated for another 24 h, the cells were treatedwith 10 μL of MTT for 4 h to find the metabolically active cells. Then,the medium was removed, and 120 μL DMSO was added to each wellto dissolve the formazan crystals. Subsequently, 100 μL supernatantfrom each well was added to a new 96-well plate for avoiding the colorinfluence of the OS-Bi NPs. Finally, the new plate was read at 490 nmunder a Microplate Reader. Mean and standard deviation in the 6-foldwells in each group were calculated.2.8. Histological Analysis and Biochemical Assessment in

Vivo.Mice were sacrificed at 7 and 14 days after oral administration of400 μL of PBS or 400 μL of 14 mg/mL OS-Bi NPs resolved in PBS(pH = 7.4, 10 mM) (4 mice in each group). The main organs indigestive system (stomach, intestine and colon) were havested andstained with hematoxylin and eosin (H&E). After that, the slices wereexamined by a digital microscope. Meanwhile, the blood of eachmouse was extracted and all the blood biochemical paremeters weredeterminated in Tiajin Medical University General Hospital.2.9. In Vivo CT Imaging of GI Tract. In vivo CT imaging was

performed on GE HDCT750. Imaging parameters were as followed:field of view (80 × 80 mm), slice thickness 625 μm, tube current 210μA, tube voltage 80 kV. The 3D reconstruction was done by VolumeRender (VR) method. The CT images were analyzed using AWvolumeshare4. All the operations of animal experiments were approved

by the Tianjin Medical University Animal Care and Use Committee.The Kunming mice (4 mice in each group) were anesthetized byintraperitoneal injection of 4 wt % chloral hydrate prior to imagingfollowed by oral administrated of 400 μL OS-Bi NPs solution with aconcentration of 14 mg/mL. On the other hand, 600 μL OS-Bi NPssolution or BaSO4 suspension (14 mg/mL) was poured into theintestinal canal via anus of another group of Kunming mice (n = 4) toobtain lower digestive tract imaging. Thereafter, the GI tract imagingwas carried out by CT at different time intervals.

2.10. In Vivo Clearance of OS-Bi NPs. Kunming mice were orallyadministrated with 400 μL 14 mg/mL OS-Bi nanoparticles andsacrificed at different time points (2 h, 1 day, and 2 day; n = 4 in onegroup) to extract stomach and intestine. The organs including thecontents were dissolved in aqua regia and the contents of Bi elementin each organ at various time points were quantified by ICP-MS.

3. RESULTS AND DISCUSSION3.1. Synthesis of DT-Bi NPs. Uniform DT-Bi NPs were

synthesized via direct heating without precursor injection(Scheme 1). Briefly, Bi(NO3)3 was added to 1-dodecanethiolunder vigorous stirring. The light yellow mixture was purgedwith Ar for 10 min, heated to 178 °C and kept for 1 min toobtain DT-Bi NPs. During this synthesis, low-melting metalthiolates were generated first due to the strong interactionbetween Bi3+ and thiols,33,43,44 then the metal thiolate meltedand dispersed in solvent to form homogeneous bright yellowreaction system and to facilitate the generation of high qualitynanocrystals as temperature increased.44 Finally, high temper-ature triggered reduction-based burst nucleation process.33,43,44

At the same time, the abundant dodecanethiol acts as ligand torestrict nanoparticles from growing too big and uniform DT-BiNPs with excellent monodispersity were thus formed.33,43,44

Figure 1. HRTEM images of DT-Bi NPs with different scale bars (a) 200 nm and (b) 50 nm.

Figure 2. (a) XRD patterns of OS-Bi NPs and DT-Bi NPs (the vertical lines are the peaks of the standard rhombohedral Bi, JCPDS 85−1331); (b)FTIR spectra of DT, DT-Bi NPs and OS-Bi NPs.

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3.2. Characterization of DT-Bi NPs. The prepared DT-BiNPs were characterized by XRD, HRTEM and FT-IR. The as-prepared DT-Bi NPs show uniform size with the diameter of 22± 0.92 nm and excellent monodispersity (Figure 1) and arhombohedral Bi structure (Figure 2a) with a clear lattice fringe(Figure S1). The νCH2 and νCH3 stretches (3000−2800 cm−1)and bendings (∼1466 cm−1) of DT confirm the presence of DTligand modified on the surface of Bi NPs (Figure 2b). Thecompact decoration of DT provides a strong passivation effectto avoid the oxidation of DT-Bi NPs, as confirmed from theneglectable change in the XRD pattern after DT-Bi NPs wereexposed in air for 7 days (Figure S2).3.3. Synthesis and Characterization of OS-Bi NPs.

Next, we employed oligosaccharide to coat the Bi NPs.Oligosaccharide can not only enhance the water solubility andbiocompatibility of the nanoparticles, but also bring extraadvantage of “sweet” taste which can make it easy to be takenby patients. We prepare OS-Bi NPs via in situ polymerization ofglucose.45 We chose DMF as the solvent not only to provide analkaline condition but also to facilitate the reaction byabsorbing the water molecules generated during polymer-ization. The obtained “sweet” Bi NPs was characterized by ICP-MS, XRD, HRTEM, and FT-IR. The content of Bi in the OS-BiNPs was 83.6%, which is the highest value in available Bi-basedNPs as far as we know. Oligosaccharide modification produceda 5.4 nm thick oligosaccharide shell on the surface of DT-Bi

NPs (Figure S3) but did not affect the crystal structure of BiNPs (Figure 2a). The formation of oligosaccharides layer onthe surface of OS-Bi NPs was further confirmed from thecharacteristic bands of oligosaccharides in the 1000−1450 cm−1

region (C−O stretching vibrations) and at 3000−3700 cm−1

(O−H bending vibrations) in the FT-IR spectra (Figure2b).45,46 The successful modification of oligosaccharide madethe obtained “sweet” Bi NPs well dispersed in water. DLSanalysis in 24 h indicated OS-Bi NPs were stable in water,buffer solution (pH 6.5 and 7.4) and diluted 1640 cell medium,and stable aggregation of OS-Bi NPs could form in dilutedserum-supplemented 1640 cell medium (Figure S4). The OS-BiNPs even at high concentration (14 mg/mL) could be easilysuspended in water and form stable colloidal solution via simpleshaking, ensuring their practicability as a GI tract contrast agentthrough oral administration.

3.4. CT Imaging In Vitro. To evaluate the contrast efficacyof OS-Bi NPs, we compared the X-ray absorption of OS-Bi NPsand BaSO4 suspension in vitro (Figure 3a,b). The CT values(Hounsfield units, HU) increased linearly with the concen-tration of OS-Bi NPs. OS-Bi NPs gave much higher CT valueper unit mass concentration than BaSO4 regardless of theoperating voltage (1.4 and 1.5 times at 80 kV and 120 kVrespectively). We also found that OS-Bi NPs produced highercontrast than BaSO4 suspension because of the larger X-rayattenuation coefficient of Bi than Ba and the high content of Bi

Figure 3. (a) In vitro CT image of OS-Bi NPs and BaSO4 at different concentrations (0, 1, 2, 4, 6, and 8 mg/mL) and (b) CT values (HU) of OS-BiNPs and BaSO4 determined at clinical voltages (80 kV and 120 kV) as a function of mass concentrations of the agents. (c) Cytotoxicity of OS-BiNPs determined by the MTT assay.

Figure 4. (a) Histological changes of major digestive organs stomach, small intestine (SI) and large intestine (LI) at various time points (7 d, 14 d)after oral administration of 400 μL 14 mg/mL OS-Bi NPs. Mice administrated with the same amount of PBS were set as contrast. (b) Biochemicalmarkers of mice at various time points (1, 7, and 14 days) after oral administration of 400 μL 14 mg/mL OS-Bi NPs. The control group was treatedwith the same amount of PBS (n = 4).

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element in OS-Bi NPs (Figure 3a). The above results revealthat OS-Bi NPs can provide an equivalent contrast at a lowerdose relative to clinical BaSO4 suspension. The reduced dose inadministration is highly favorable as it significantly reduces theside effects in patients.3.5. Chemical Stability Assessment and Cytotoxicity

Assay. To assess the suitability for use as a contrast agent invivo, the pH stability and the cytotoxicity of OS-Bi NPs wereinvestigated. The XRD patterns of OS-Bi NPs and DT-Bi NPshad no change and the leaching of Bi3+ ions were neglectableafter 3 days incubation of the materials in simulated body fluidat pH 2.2 for stomach and pH 8.0 for small intestine (Figure S2and Table S1). MTT assay showed that the cell viabilityassociated with HeLa cells was not influenced by OS-Bi NPs upto a concentration of 200 mg/L. Even when the dose of OS-BiNPs reached up to 400 mg/L, the cell viability was over 80%(Figure 3c). These results demonstrate excellent stability inharsh GI tract conditions and low cytotoxicity of OS-Bi NPs.3.6. In Vivo Toxicity. The potential toxicity in vivo was

investigated in terms of Hematoxylin and Eosin (H&E)staining and blood chemical assessment prior to in vivoapplication. H&E staining of digestive organs includingstomach, small intestine, and large intestine (exposed directlyto the contrast agent) of mice with the administration of OS-BiNPs showed no obvious difference with that of the controlgroup (Figure 4a). The results indicate neglectable adverseeffect associated with the oral administration of OS-Bi NPs. Inaddition, blood chemistry assessment of mice with or withoutthe treatment of OS-Bi NPs showed that the liver functionbiomarkers including total protein (TP), albumin (ALB),aspartate alanine aminotransferase (ALT), and kidney functionbiomarkers including serum creatinine, urea nitrogen (BUN),and urea were all normal, indicating low hepatic and kidneytoxicity of OS-Bi NPs (Figure 4b). All the above results suggestOS-Bi NPs be a low-toxic contrast agent.3.7. In Vivo CT Imaging of GI Tract.We then assessed the

feasibility of OS-Bi NPs as a contrast agent to visualize theupper and lower GI tract. The 3D-renderings CT images of GItract show the process of OS-Bi NPs through the GI tract(Figure 5). The main organs of upper digestive systemincluding stomach, duodenum and a few loops of the smallintestine began to be bright obviously at 2 min after oraladministration of the contrast agent, and the CT value of thestomach increased remarkably (Figure 5a). After 20 min, thesmall intestine was lighted up due to the presence of muchmore OS-Bi NPs. The CT value of small intestine showed anobvious increasement, revealing the excellent contrast efficacyof the proposed NPs. More importantly, the arrangement andsequence of the small intestinal loops could be describedclearly, which facilitates the diagnosis of inflammatory,neoplastic intestinal lesions, and incidental extra-intestinalpathological changes (Figure 5c). In contrast, the perfuse effectof BaSO4 suspension to visualize stomach and intestine wasunsatisfactory due to its innate insolubility (Figure S5). At 180min after the administration of OS-Bi NPs, the small intestinalempting advanced significantly and large intestine began to befilled with the NPs. After 1 day, only a small amount of the NPswere in the sigmoid colon and rectus, and almost all the OS-BiNPs were excreted from body after 2 days, ensuring theneglectable side effect. However, BaSO4 still remained on thewall of stomach even after 2 days (Figure S5). To investigate invivo clearance of OS-Bi NPs quantitatively, the organs(stomach and intestine) including their contents of mice after

the treatment of OS-Bi NPs at different time points weredissolved in aqua regia and the contents of Bi element in eachorgan were quantified by ICP-MS. The results indicated thatthe contents of Bi element in different organs were consistentwith the signal intensity in CT imaging at different time points(Figure S6).The prepared OS-Bi NPs was also used to visualize the lower

GI tract via CT imaging by administrating the NPs throughanus (Figure 5b). The contrast enhancement effect of largeintestine could last 2 h. During this period of time, the anatomy

Figure 5. CT imaging of GI tract in vivo. (a) Upper GI tract imagingat different time intervals after oral administration of 400 μL 14 mg/mL OS-Bi NPs. (b) Lower GI tract imaging after administration of 600μL 14 mg/mL OS-Bi NPs through the anus. (c) Enlarged images of(left) upper GI tract 1 h post oral administration and (right) lower GItract 60 min post anus administration of OS-Bi NPs.

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and pathology of rectus and descending colon could be clearlyseen in detail (Figure 5c). The prolonged time window andcomprehensive CT imaging exhibit particular valuable impacton the diagnosis of lower GI tract associated diseases. At 1 dayafter administration, only a little OS-Bi NPs were left in therectus. All of the contrast agents were defecated 2 days later.The CT imaging of GI tract reveals that the OS-Bi NPs couldbe used to clearly visualize both upper and lower GI tract indetail due to the remarkable contrast efficacy and widediagnosis time window. Furthermore, the contrast agent canbe thoroughly drained from the GI tract in 2 days which coulddecrease the possibility of further organ toxicity. Therefore, theproposed high-performance OS-Bi NPs have great potential inthe application of visualization of the GI tract in clinic.

4. CONCLUSIONIn summary, we report a facile noninjection strategy toconstruct high-quality DT-Bi NPs using only two commercialreagents for the first time. The DT-Bi NPs were formed viasimple heating of the mixture of raw materials in a short time.The proposed DT-Bi NPs show uniform size, excellentmonodispersity and good antioxidant capacity. Furtheroligosaccharide modification of DT-Bi NPs made the materialhydrophilic, biocompatible and “sweet” for the application inCT imaging in vivo. The content of Bi element in OS-Bi NPscan reach 83.6%, ensuring the ultrahigh efficiency in absorbingX-ray. The low cytotoxicity and in vivo toxicity, favorablechemical stability in harsh environments of GI system, andultrahigh efficiency in absorbing X-ray enable OS-Bi NPs tosuccessfully visualize the upper and lower GI tract in detail. Inbrief, we not only design a novel strategy to synthesize high-quality Bi NPs but also demonstrate the promising potentialapplication of Bi NPs as a high performance CT GI tractcontrast agent.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acsami.6b03640.

HRTEM images of OS-Bi NPs with clear lattice fringe,HRTEM images of OS-Bi NPs, XRD pattern of DT-BiNPs exposed in air and DT-Bi, OS-Bi NPs afterimmersed in various buffer solution for 3 days, GI tractCT imaging of mouse after oral administration of BaSO4

suspension, and The leakage of Bi3+ in simulated bodyfluid. (PDF)

■ AUTHOR INFORMATIONCorresponding Author* E-mail: shaokaisun@163.com.

Author Contributions∥These authors contributed equally. The manuscript waswritten through contributions of all authors. All authors havegiven approval to the final version of the manuscript.

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis work was supported by the National Natural ScienceFoundation of China (Grants 21435001, 21405112, 21505099)

and the China Postdoctoral Science Foundation (Grants2014M550146, 2015M571270).

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ACS Applied Materials & Interfaces Research Article

DOI: 10.1021/acsami.6b03640ACS Appl. Mater. Interfaces 2016, 8, 12720−12726

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