CN111228489A - 一种四氧化三铁硫化铋纳米复合材料及其制备和应用 - Google Patents

一种四氧化三铁硫化铋纳米复合材料及其制备和应用 Download PDF

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CN111228489A
CN111228489A CN202010087311.1A CN202010087311A CN111228489A CN 111228489 A CN111228489 A CN 111228489A CN 202010087311 A CN202010087311 A CN 202010087311A CN 111228489 A CN111228489 A CN 111228489A
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ferroferric oxide
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王世革
罗科义
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University of Shanghai for Science and Technology
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Abstract

本发明公开了一种四氧化三铁/硫化铋纳米复合材料及其制备和在什么……中的应用。制备方法为：将Fe3O4和多巴胺分散至Tris‑HCl缓冲溶液中，得到Fe3O4@PDA纳米颗粒；将铋源分散于溶剂中，然后滴加到牛血清蛋白溶液中，得到BSA‑Bi2S3颗粒；将Fe3O4@PDA纳米颗粒分散到Na2HPO4‑NaH2PO4缓冲溶液中，加入BSA‑Bi2S3颗粒，得到Fe3O4@PDA@BSA‑Bi2S3纳米颗粒。本发明所得产物容易制备且无毒，并在细胞及动物水平具有良好的生物相容性、胶体稳定性及MRI&CT造影效果。

Description

一种四氧化三铁硫化铋纳米复合材料及其制备和应用
技术领域
本发明涉及一种可造影的四氧化三铁硫化铋纳米复合材料及其制备和应用，属于生物纳米材料技术领域。
背景技术
癌症(恶性肿瘤)是以细胞异常增殖及转移为特点的一大类疾病，已经成为影响人类健康与生存的主要威胁。目前临床上治疗癌症的方法：手术切除、化疗和物理放射治疗。其主要特征为手术治疗在通常情况下不能完全清除人体全部癌症细胞，易复发等特点；化疗使用药物杀死癌细胞，但在治疗的过程中易产生抗药性；而物理放射疗法会对患者产生极大的危害和副作用。因此，对于癌症的早期筛查与诊断，有助于合理制定治疗方案，及时地抑制恶性肿瘤细胞的扩散与迁移，从而提高患者生存率和康复治疗。基于以上面临的问题，寻求一种高效且毒害作用小的肿瘤治疗方法，显得尤为重要，被受广大科研工作者的密切关注。
在纳米技术和生物医学领域中，同时具有辅助治疗和诊断功能于一体的复合治疗药物，一直受到人们的长期关注。肿瘤的光热治疗技术，因其微创、高效方便、对正常组织损伤小的等特点，受到了人们的广泛关注。光热疗法的基本原理是运用近红外光吸收剂和对于人体组织穿透力较强的近红外光，利用光热转换产生出较高热量，使肿瘤组织局部升温，选择性地杀死肿瘤细胞。相对于传统的治疗方法，光热治疗具有良好的生物组织穿透性，对正常组织细胞毒副作用小以及对病变组织的精准治疗。随着纳米医学的不断发展，越来越多的光热纳米材料被开发应用。其中硫化铋(Bi2S3)是一种带隙N型半导体，具有高近红外吸收且具有良好的光热稳定性和优异的生物相容性。此外，铋元素具有较高的X射线衰减系数，已被广泛应用作为X射线响应的CT造影剂。目前，已经报道了许多在光热治疗应用方面的不同形态取向的材料，例如Bi2S3纳米棒、Bi2S3纳米球和Bi2S3片状等。但单一的光热疗法一般需要较高的激光功率密度或是提高材料的浓度，来达到消融肿瘤的目的，因此通常将光热疗法与其他治疗方法结合实现肿瘤的协同治疗。
化学动力学治疗(CDT)是利用具有细胞毒性的活性氧(ROS)进行肿瘤治疗的一种新技术疗法。其产生具有细胞毒性的活性氧源于内源性的化学反应，近而引发癌细胞的氧化损伤，引起细胞凋亡。在肿瘤微环境中具有独特的特征：酸性，还原性和过量生成的H2O2，是开发多功能治疗肿瘤的关键。譬如利用铁基的Fenton反应通过将肿瘤细胞过表达内源的H2O2转化为·OH来诱导肿瘤细胞凋亡。
发明内容
本发明所要解决的技术问题是：现有光热材料在肿瘤内部缺少影像信息，细胞相容性差且利用效率低的问题。
为了解决上述技术问题，本发明提供了一种四氧化三铁/硫化铋纳米复合材料，其特征在于，所述纳米复合材料为由Fe3O4@PDA与BSA-Bi2S3同步反应及表面修饰，制得的Fe3O4@PDA@BSA-Bi2S3纳米颗粒。
本发明还提供了上述四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，包括以下步骤：
步骤1)：将铁源、分散剂依次加入到二乙二醇中，超声使其分散均匀，然后加入乙酸钠，搅拌混合均匀后，并转移至对位聚苯内衬的不锈钢反应釜中密封反应；接着依次经离心分离、洗涤、真空干燥，得到Fe3O4；将Fe3O4和多巴胺(DA)均匀分散至Tris-HCl缓冲溶液中反应，依次离心分离、洗涤、冷冻干燥后，得到Fe3O4@PDA纳米颗粒；
步骤2)：将铋源分散于溶剂中，然后滴加到牛血清蛋白溶液(BSA)中，搅拌使之充分溶解、混合均匀，加入氢氧化钠调节pH值至12，反应后透析，得到BSA-Bi2S3颗粒；
步骤3)：将Fe3O4@PDA纳米颗粒分散到Na2HPO4-NaH2PO4缓冲溶液中，超声分散后加入BSA-Bi2S3颗粒，采用细胞超声粉碎机将BSA-Bi2S3修饰到Fe3O4@PDA纳米颗粒表面，反应结束后离心分离、洗涤，得到Fe3O4@PDA@BSA-Bi2S3纳米颗粒。
优选地，所述步骤1)中的铁源为六水合氯化铁或无水氯化铁，其在二乙二醇中的浓度为10-30mg/mL；分散剂为柠檬酸钠、聚乙烯吡咯烷酮(PVP)和聚苯乙烯磺酸钠-马来酸共聚物(PSSMA)中的任意一种，其在二乙二醇中的浓度为15-20mg/mL；铁源与分散剂的质量比为1：(5-10)。
优选地，所述步骤1)中的超声时间为5-20min，搅拌时间为10-60min，密封反应的温度为200-220℃，反应时间为7-10h。
优选地，所述步骤1)、步骤3)中离心分离的转速为8000-12000r/min，洗涤采用蒸馏水洗涤3-5次。
优选地，所述步骤2)中的溶剂为pH<5的酸性溶液；铋源为五水硝酸铋或氯化铋，其浓度为3-5mg/mL；反应的时间为12-15h。
更优选地，所述酸性溶液为硝酸或盐酸。
优选地，所述步骤3)中超声分散的时间为10-60min；细胞超声粉碎机的功率比为50-80％，超声开关时间分别为3s和5s，细胞超声粉碎机的处理时长为3-5h。
优选地，所述步骤3)中的洗涤使用蒸馏水，清洗次数为3-5次。
本发明还提供了上述四氧化三铁/硫化铋纳米复合材料作为药物分子在造影剂中的应用。Fe3O4不仅作为模拟过氧化物酶来引发肿瘤内的芬顿反应，并产生具有高细胞毒性的羟基自由基(·OH)诱导肿瘤细胞凋亡，还可以作为MRI造影剂可提供精确的癌症诊断。与此同时，Bi2S3具有较好的光热转化、CT造影的性能。因此该复合材料可用于由MRI/CT介导的光热/化学动力学治疗的有效药物。
本发明所得产物容易制备且无毒，并在细胞及动物水平具有良好的生物相容性、胶体稳定性及MRI&CT造影效果。通过本发明的方法制备得到的Fe3O4@PDA@BSA-Bi2S3纳米颗粒具有优异的光热转化效率，Fe3O4能引发内源性的芬顿反应，产生具有细胞毒性的羟基自由基，有望应用于肿瘤的光热和化学动力学联合治疗领域。
附图说明
图1a为Fe3O4@PDA@BSA-Bi2S3纳米颗粒分散于蒸馏水中水合动力学直径分布及丁达尔现象；
图1b为Fe3O4@PDA@BSA-Bi2S3纳米颗粒分散于PBS中的水合动力学直径分布及丁达尔现象；
图1c为Fe3O4@PDA@BSA-Bi2S3纳米颗粒分散于1640培养基中的水合动力学直径分布及丁达尔现象；
图2a、2b为Fe3O4@PDA@BSA-Bi2S3纳米颗粒不同比例的TEM图；
图3a为Fe3O4@PDA、BSA-Bi2S3、Fe3O4@PDA@BSA-Bi2S3的傅里叶红外变换光谱图；
图3b为Fe3O4、Fe3O4@PDA、BSA-Bi2S3、Fe3O4@PDA@BSA-Bi2S3的热重分析图谱；
图4a为Fe3O4@PDA@BSA-Bi2S3纳米颗粒的XRD图；
图4b为Fe3O4、Fe3O4@PDA、Fe3O4@PDA@BSA-Bi2S3的磁滞回线图谱；
图5a为Bi的XPS图谱；
图5b为Fe的XPS图谱；
图6a为用808nm(1W/cm2)激光照射蒸馏水和不同浓度Fe3O4@PDA@BSA-Bi2S3溶液的升温曲线；
图6b为用808nm(1W/cm2)激光照射蒸馏水和不同浓度Fe3O4@PDA@BSA-Bi2S3溶液的热成像图；
图6c为用不同功率密度的808nm激光照射浓度为200μg/mL的蒸馏水中的Fe3O4@PDA@BSA-Bi2S3溶液的升温曲线；
图6d为用不同功率密度的808nm激光照射浓度为200μg/mL的蒸馏水中的Fe3O4@PDA@BSA-Bi2S3溶液的热成像图；
图6e为Fe3O4@PDA@BSA-Bi2S3纳米颗粒在10次连续循环照射808nm，0.8W/cm2激光下的升温和自然冷却曲线；
图6f为Fe3O4@PDA@BSA-Bi2S3线性拟合冷却时间对热驱动常熟的自然对数的负值得曲线；
图6g为Fe3O4@PDA@BSA-Bi2S3颗粒光热转换效率；
图7a为在含或不含H2O2的Fe3O4@PDA@BSA-Bi2S3颗粒/TMB溶液的紫外-可见光谱和照相图像；
图7b为Fe3O4@PDA@BSA-Bi2S3颗粒/TMB/H2O2溶液的培育时间与H2O2浓度紫外-可见吸收光谱图；
图7c为Fe3O4@PDA@BSA-Bi2S3颗粒/TMB/H2O2溶液的培育时间与pH紫外-可见吸收光谱图(652nm)；
图7d为Fe3O4@PDA@BSA-Bi2S3颗粒的Michaelis-Menten动力学研究结果；
图7e为以H2O2为底物的Fe3O4@PDA@BSA-Bi2S3颗粒的Lineweaver-Burk图；其中，吸光度的初始斜率与时间的关系图用于计算稳态催化速率(v)；
图7f为Fe3O4@PDA@BSA-Bi2S3溶液不同浓度的紫外-可见吸收光谱图；
图8a为用不同浓度Fe3O4@PDA@BSA-Bi2S3溶液处理1h后的溶血率情况；
图8b为用蒸馏水，PBS和Fe3O4@PDA@BSA-Bi2S3颗粒处理离心后的mRBC的照片；
图8c为用不同浓度Fe3O4@PDA@BSA-Bi2S3溶液处理24h后的细胞存活率；
图8d为用不同浓度Fe3O4@PDA@BSA-Bi2S3溶液处理24h后L929细胞的活细胞/死细胞双染色剂染色结果的对比图；
图9a为不同Fe浓度的Fe3O4@PDA@BSA-Bi2S3颗粒的T2的MRI图像；
图9b为不同Bi浓度的Fe3O4@PDA@BSA-Bi2S3的CT图像；
图9c为不同Fe浓度的Fe3O4@PDA@BSA-Bi2S3的T2信号强度；
图9d为不同Bi浓度的Fe3O4@PDA@BSA-Bi2S3的HU强度；
图10为PBS作为对照的昆明尾静脉注射后在1天、7天、14天的血常规测试结果；
图11为昆明尾静脉注射200μL浓度为1mg/mL Fe3O4@PDA@BSA-Bi2S3的纳米材料1天、14天后的组织病理切片H&E染色结果；其中，PBS为对照组。
具体实施方式
为使本发明更明显易懂，兹以优选实施例，并配合附图作详细说明如下。
实施例1
将0.32g无水FeCl3和0.3g PSSMA溶解在20mL二乙二醇中，在60℃条件下搅拌30min，然后将0.5g CH3COONa加入到混合物中。溶解30min后，转移至100mL对位聚苯内衬的不锈钢反应釜中密封。将反应釜置入高温烘箱中200℃热处理7h，待自然冷却至室温后，离心分离反应混合物(8500rpm，5min)，用蒸馏水、乙醇各洗涤三次，得产物Fe3O4颗粒。最终将样品真空干燥以进一步使用。
将0.2g多巴胺溶解在40mL Tris-HCl缓冲溶液(pH＝8.5)中，然后添加80mg Fe3O4颗粒。在超声的条件下完全分散，置于振荡器上反应4h后，离心分离反应混合物(8500rpm，5min)，产物用水、乙醇各洗涤三次。最后所得产物为Fe3O4@PDA颗粒。
将250mg BSA均匀分散于蒸馏水(8.0mL)中，然后添加25mg Bi(NO3)3·5H2O预先溶于1.0mL HNO3溶液(2M)，并在室温下搅拌30min，用NaOH(2M)调节溶液pH至12，并在室温下反应12h，在此过程中溶液从无色变为深黑色，所得混合物在蒸馏水中透析3天，最后得到产物BSA-Bi2S3颗粒。
将上述制备的Fe3O4@PDA颗粒和BSA-Bi2S3颗粒添加到20mL磷酸盐缓冲液(Na2HPO4-NaH2PO4，pH＝8.0)中，通过细胞粉碎机超声，两者通过共价键形式键合，将产物常规离心(13000rpm，30min)，并用蒸馏水冲洗3次。最后得到产物Fe3O4@PDA@BSA-Bi2S3颗粒。
实施例2
取少许实施例1中制备的Fe3O4@PDA@BSA-Bi2S3颗粒，分散在蒸馏水中，PBS中，1640培养基中，图1a-c表明材料在放置5天后水合动力学直径无明显变化，在三种体系中的丁达尔现象明显，均具有良好的胶体稳定性。通过TEM观察材料的形貌和微观结构。将适量纳米片超声均匀分散于无水乙醇后，将镀有碳膜的铜网浸入上述无水乙醇中。待样品自然干燥后，通过TEM观察、拍照(TEM操作电压为200kV)。由图2a、2b可以看出，实施例1中所得材料结构超小纳米颗粒。
实施例3
使用TGA(TGA-50热重分析仪)测试和计算实施例1中制备的Fe3O4@PDA@BSA-Bi2S3颗粒中各成分的百分含量，分别取一定质量的Fe3O4，Fe3O4@PDA，BSA-Bi2S，Fe3O4@PDA@BSA-Bi2S3颗粒加入到热重分析仪的铂金坩埚中，读取所加入的样品的质量后设置实验参数进行TGA测试，测试条件是在空气气氛下以15℃/min从室温升至800℃。使用FTIR(NicoletNexus 670红外光谱仪)测试和分析实施例1中制备的Fe3O4@PDA@BSA-Bi2S3的组成和结构，取少许Fe3O4@PDA，BSA-Bi2S3，Fe3O4@PDA@BSA-Bi2S3颗粒分别与一定量的溴化钾(KBr)粉末混合，在红外灯下研磨以便保证样品的干燥，待研磨均匀并压片后，置于Nicolet Nexus 670红外光谱仪样品架上，测试4000-400cm-1范围的FTIR谱图。
TGA结果表明，当样品从室温升至800℃时，产品表现出两个阶段的失重，从室温至100℃时，第一阶段的失重归因于结合水的蒸发，而在100至550℃时，处于第二阶段的失重归因于表面涂层的PDA和BSA的分解。由图3a可知，Fe3O4，Fe3O4@PDA，Bi2S3-BSA和Fe3O4@PDA@BSA-Bi2S3颗粒的失重率分别为42.48％，63.26％，90.85％和49.89％。Fe3O4的重量损失归因于Fe3O4表面上存在PSSMA。根据Bi2S3-BSA的重量损失，BSA的表面涂层量为9.15％，因此，根据Fe3O4和Fe3O4@PDA的重量损失，可计算出PDA的表面涂层量为20.78％。
分析图3b可知，BSA在1640cm-1和1500cm-1处的吸附峰分别是酰胺I(-NH2)和酰胺II(-NH-)的弯曲振动峰。PDA和BSA酰胺基团的-NH-拉伸振动位于3400cm-1、3300cm-1，并且还检测到PDA的-C＝C-拉伸振动位于1500cm-1，清楚地表明PDA和BSA已成功地修饰在复合材料的表面上。
实施例4
分别取实施例1中制备的Fe3O4@PDA@BSA-Bi2S3纳米材料，分析其组成及结构。使用XRD(Rigaku D/max-2200PC，日本)研究纳米片的XRD衍射图谱的晶体结构。以Cu2Kα射线为光源，操作电压为40kV，电流为200mA，扫描角度(2θ)范围为3°-70°。该材料的磁特性通过振动样品磁力计(VSM，MPMS SQUID)计算。系统磁场强度：纵向磁体：±9T，扫描速度：1-200Gauss/s，磁场分辨率：0.02mT，温度控制范围：1.9-400K，温度扫描速度：0.01-12K/min，温度稳定性：温度小于10K时为±0.2％；温度大于10K时为±0.02％。用ThermalScientific公司的ESCAlab250型X射线光电子能谱仪(XPS)表征纳米片中Fe和Bi元素的化合价。激发源为单色器Al KαX射线(λ＝0.8339nm)，能量为1486eV，线宽为0.9eV，功率为150W。结合能用C的1s峰(284.8eV)校正。
如图4a进一步用XRD以确定物质的结构性质。衍射峰与Fe3O4(JCPDS card No.26-1136)和Bi2S3(JCPDS card No.79-2384)标准衍射峰一致，而且峰型尖锐且强度较高，几乎没有杂峰的出现，进而表明该材料具有优异的晶体特性和纯度，通过室温VSM测量Fe3O4@PDA@BSA-Bi2S3，Fe3O4@PDA和Fe3O4颗粒的磁性。从图4b磁化曲线可知，Fe3O4@PDA@BSA-Bi2S3，Fe3O4@PDA和Fe3O4NP的饱和磁化值分别约为6.3emu/g，10.9emu/g和15.3emu/g。进一步表明，表面PDA和BSA-Bi2S3修饰会降低Fe3O4颗粒的磁性
分析图5a、5b可知，XPS峰归因于Bi3+在164.7eV(Bi 4f 5/2)，158.7eV(Bi4f 7/2)和Fe3+/Fe2+在723.3eV(Fe 2p 1/2)和710.6eV(Fe 2p 3/2)分别易于检测到(图2a-b)。与文献中报道的XPS数据的典型特征一致，可以看出在这些主峰的位置没有明显的卫星峰，表明合成的样品没有其他杂质。而且Bi 4f和Fe 2p轨道移动到较低的结合能，这可以归因于聚合物涂层引起的化学环境变化。
实施例5
Fe3O4@PDA@BSA-Bi2S3的光热特性测试。将Fe3O4@PDA@BSA-Bi2S3分散在96孔细胞培养板的培养孔中，用功率为1W/cm2的808nm波长的近红外激光分别照射不同浓度的Fe3O4@PDA@BSA-Bi2S3或蒸馏水(对照组)，通过FLIR E60红外热像仪记录材料分散液温度随时间的变化情况及对应的红外热成像照片。随后用不同功率的激光照射200μg/mL Fe3O4@PDA@BSA-Bi2S3溶液，通过FLIR E60红外热像仪记录材料分散液温度随时间的变化情况及对应的红外热成像照片。为了检测Fe3O4@PDA@BSA-Bi2S3的光热稳定性，用200μg/mL的Fe3O4@PDA@BSA-Bi2S3溶液在0.8W/cm2照射激光5min，自然冷却5min，按此进行10个循环，记录每个周期的溶液温度变化值。
从图6a、6b可知，不同浓度的Fe3O4@PDA@BSA-Bi2S3均可以吸收一定强度的近红外激光。在相同时间内，随着材料浓度的增加，温差逐渐增大，体系对近红外激光的光热转换能力不断加强。从图6c、6d可知，不同激光功率密度照射下的材料均有近红外吸收，且随着功率密度和时间间隔的增加，材料吸收能量的程度不断增强，温差逐渐增加,其中红外热成像照片更鲜明地说明了Fe3O4@PDA@BSA-Bi2S3的光热转化与浓度及激光密度的关系。此外，图6e表明材料在10个循环下升温均保持在20℃以上，即材料在经过多次重复照射后不会发生太大变化，具有良好的光热稳定性。图6f、6g的结果显示，通过Korgel公式计算，材料光热转换的时间常数为223.9。同时在808nm红外激光的照射下，样品的光热转化效率为47.6％。总之，本发明制备的Fe3O4@PDA@BSA-Bi2S3纳米颗粒表现出了良好的光热转换能力。
实施例6
用Uv-Vis光谱仪测试材料产生羟基自由基(·OH)的能力，将H2O2(50mM)加入到3，3'，5，5'-四甲基二苯胺(TMB，0.8mM)和Fe3O4@PDA@BSA-Bi2S3(50μg/mL)混合溶液。通过使用UV-Vis光谱仪(波长：400-800nm，Lambda 25，PerkinElmer，USA)记录混合物的吸光度，为了测量·OH生成量与H2O2浓度依赖的相关性，将H2O2(25，50，100和200mM)与TMB(0.8mM)和Fe3O4@PDA@BSA-Bi2S3混合后，通过UV-Vis光谱仪记录混合物在652nm处的吸光度。为了研究pH对·OH产生的影响，将H2O2(100mM)，TMB(0.8mM)和Fe3O4@PDA@BSA-Bi2S3(50μg/mL)在乙酸钠-乙酸缓冲溶液中混合(pH＝6.0)或PBS(pH＝7.4)，通过UV-Vis光谱仪记录在652nm处的吸光度。进而绘制了米氏方程的初始速度对不同H2O2浓度的关系图。Fe3O4@PDA@BSA-Bi2S3的最大催化速度和Michaelis-Menten常数采用Lineweaver-Burke拟合方法获得。
如图7a-7c所示，表明Fe3O4@PDA@BSA-Bi2S3和TMB混合溶液显示出明显的UV-Vis吸光度，并且这种显色反应取决于H2O2的浓度以及反应速率在pH值为6.0时比7.4时反应更快。这种依赖pH产生·OH与酸性肿瘤微环境起着协同作用，有望促进高效的肿瘤CDT。如图7d、7e所示，通过原始的Michaelis-Menten方程可以转换成方程Lineweaver-Burke，作拟合曲线计算出Fe3O4@PDA@BSA-Bi2S3催化反应的最大反应速率(Vmax)和米氏常数(Km)分别为2.2×10-8M/s和67.04mM。以H2O2为底物的样品的Vmax值与辣根过氧化物酶的Vmax值非常接近。由图7f可知，Fe3O4@PDA@BSA-Bi2S3在600～1100nm波长下的近红外吸收，与其浓度呈正相关。
实施例6
在麻醉状态下心脏刺穿采集KM鼠血液，用PBS溶液洗涤红血球3次，每次在3000rpm下离心3min。将Fe3O4@PDA@BSA-Bi2S3溶液(浓度依次为50，100，200μg/mL)与血液混合，分别取相同体积的PBS和蒸馏水与血液混合(PBS和蒸馏水分别用作阴性和阳性对照)。将上述六组体系在37℃下培养1h后，3000rpm下离心3min，测量上清液在542nm处的吸光度并计算溶血率(HP)。如图8a、8b所示，用不同浓度Fe3O4@PDA@BSA-Bi2S3处理的细胞其溶血率均在5％以下，未观察到明显的溶血现象，证明材料具有良好的血液相容性。
Fe3O4@PDA@BSA-Bi2S3颗粒的细胞相容性与血液相容性测试。将L929细胞接种到96孔板，加入100μL 1640细胞培养基在37℃下CO2恒温培养箱中培养过夜，吸出原有的细胞培养液，分别加入100μL含有50，100，150，200μg/mL Fe3O4@PDA@BSA-Bi2S3的新鲜培养液，每个浓度设置四组平行试验。继续培养24h后吸出培养液，用CCK-8溶液和活细胞/死细胞双染色试剂测试并观察细胞存活情况，用SpectraMax i3酶标仪测450nm处的OD值计算细胞存活率，用Leica DM IL LED倒置相差显微镜观察L929细胞的形态和存活情况。如图8c所示，即使是浓度为200μg/mL的Fe3O4@PDA@BSA-Bi2S3与细胞共培养24h后的L929细胞存活率仍有95.9±5.0％，表明材料基本无细胞毒性。此外，通过倒置差相显微镜观察细胞的形态，浓度为200μg/mL Fe3O4@PDA@BSA-Bi2S3处理的细胞，其细胞状态和染色情况和对照组(用PBS处理的)几乎无差别(图8d)，进一步表明在实验浓度范围内Fe3O4@PDA@BSA-Bi2S3具有良好的细胞相容性。
实施例7
取实施例1中制备的Fe3O4@PDA@BSA-Bi2S3纳米颗粒分散于1.5mL蒸馏水中，
测定溶液在磁共振造影设备和计算机断层扫描设备下，T2序列的MRI信号强度和CT信号强度。如图9a、9c所示，随着Fe浓度的降低，测定的T2-MRI图像将逐渐变亮。证明了Fe3O4@PDA@BSA-Bi2S3纳米颗粒优异的MRI成像功能。另一方面，基于Bi的Fe3O4@PDA@BSA-Bi2S3纳米颗粒对X射线衰减能力，具有CT成像能力。图9b、9d表明了不同浓度的纳米粒子的CT图像及其亨斯菲尔德(HU)值，结果显示CT值与其浓度显示良好的线性相关关系。综上以上结果，合成的Fe3O4@PDA@BSA-Bi2S3纳米颗粒具有同时作为MRI/CT成像造影剂能力。
实施例8
Fe3O4@PDA@BSA-Bi2S3的体内血液相容性及组织相容性评价，将12只昆明鼠随机分为4组：对照组尾静脉注射200μL PBS；实验组尾静脉注射200μL Fe3O4@PDA@BSA-Bi2S3纳米材料(溶剂为PBS，1mg/mL)。在分别喂养1天、7天、14天后，心脏穿刺取血，测定各项血液参数进行活体水平血液相容性评价。血常规评价指标包括白细胞、红细胞、血红蛋白、红细胞比容、红细胞平均体积、红细胞平均血红蛋白量、红细胞平均血红蛋白浓度、红细胞分布宽度、血小板含量。从图10a-10j可知，各参数波动小，均在正常范围之内，证明Fe3O4@PDA@BSA-Bi2S3纳米颗粒具有良好的血液相容性。
将12只昆明鼠随机分为4组：对照组尾静脉注射200μL PBS；实验组尾静脉注射200μL Fe3O4@PDA@BSA-Bi2S3纳米材料(溶剂为PBS，1mg/mL)。在分别喂养1天、7天、14天后，麻醉处死，取各组别昆明鼠的心、肝、脾、肺、肾等重要组织，用戊二醛固定，苏木精—伊红染色，观察组织切片情况。由图11可知，与对照组相比，实验组各主要器官均无明显的组织损伤和病变，表明材料具有良好的组织相容性。

Claims (10)

1.一种四氧化三铁/硫化铋纳米复合材料，其特征在于，所述纳米复合材料为由Fe3O4@PDA与BSA-Bi2S3同步反应及表面修饰，制得的Fe3O4@PDA@BSA-Bi2S3纳米颗粒。
2.权利要求1所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，包括以下步骤：
步骤1)：将铁源、分散剂依次加入到二乙二醇中，超声使其分散均匀，然后加入乙酸钠，搅拌混合均匀后，并转移至对位聚苯内衬的不锈钢反应釜中密封反应；接着依次经离心分离、洗涤、真空干燥，得到Fe3O4；将Fe3O4和多巴胺均匀分散至Tris-HCl缓冲溶液中反应，依次离心分离、洗涤、冷冻干燥后，得到Fe3O4@PDA纳米颗粒；
步骤2)：将铋源分散于溶剂中，然后滴加到牛血清蛋白溶液中，搅拌使之充分溶解、混合均匀，加入氢氧化钠调节pH值至12，反应后透析，得到BSA-Bi2S3颗粒；
步骤3)：将Fe3O4@PDA纳米颗粒分散到Na2HPO4-NaH2PO4缓冲溶液中，超声分散后加入BSA-Bi2S3颗粒，采用细胞超声粉碎机将BSA-Bi2S3修饰到Fe3O4@PDA纳米颗粒表面，反应结束后离心分离、洗涤，得到Fe3O4@PDA@BSA-Bi2S3纳米颗粒。
3.如权利要求2所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，所述步骤1)中的铁源为六水合氯化铁或无水氯化铁，其在二乙二醇中的浓度为10-30mg/mL；分散剂为柠檬酸钠、聚乙烯吡咯烷酮和聚苯乙烯磺酸钠-马来酸共聚物中的任意一种，其在二乙二醇中的浓度为15-20mg/mL；铁源与分散剂的质量比为1：(5-10)。
4.如权利要求2所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，所述步骤1)中的超声时间为5-20min，搅拌时间为10-60min，密封反应的温度为200-220℃，反应时间为7-10h。
5.如权利要求2所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，所述步骤1)、步骤3)中离心分离的转速为8000-12000r/min，洗涤采用蒸馏水洗涤3-5次。
6.如权利要求2所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，所述步骤2)中的溶剂为pH<5的酸性溶液；铋源为五水硝酸铋或氯化铋，其浓度为3-5mg/mL；反应的时间为12-15h。
7.如权利要求6所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，所述酸性溶液为硝酸或盐酸。
8.如权利要求2所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，所述步骤3)中超声分散的时间为10-60min；细胞超声粉碎机的功率比为50-80％，超声开关时间分别为3s和5s，细胞超声粉碎机的处理时长为3-5h。
9.如权利要求2所述的四氧化三铁/硫化铋纳米复合材料的制备方法，其特征在于，所述步骤3)中的洗涤使用蒸馏水，清洗次数为3-5次。
10.权利要求1所述的四氧化三铁/硫化铋纳米复合材料四氧化三铁/硫化铋纳米复合材料作为药物分子在造影剂中的应用。
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