CN105832699B - 一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法及应用 - Google Patents
一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法及应用 Download PDFInfo
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Abstract
本发明首先采用溶剂热法制备Fe2O3纳米粒子，结合模板法和水热法，在不加入任何表面活性剂的条件下，以TEOS为硅源，在温和的条件下制备出形貌可控的Fe3O4@SiO2蛋黄‑蛋壳结构中空复合微球，用浓度的盐酸腐蚀Fe2O3@SiO2复合微球得到Fe2O3@SiO2蛋黄‑蛋壳结构中空复合微球，再经还原后制得具有超顺磁性Fe3O4@SiO2蛋黄‑蛋壳结构中空复合微球。所制得的Fe3O4@SiO2蛋黄‑蛋壳结构中空复合微球比表面积为173m2/g，载药量为139mg/g，以盐酸阿霉素为药物模型，在pH为7.4的PBS缓冲溶液中72h内药物的释放率最高达到68.4%，表现出良好的药物缓释性能。
Description
技术领域
本发明属于生物医学材料领域，尤其涉及一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法及应用。
背景技术
近年来，随着医药技术的不断发展，药物缓控释制剂逐渐成为了制剂学研究的重点，而药物缓控释技术的关键是药物载体的选择。到目前为止，应用较为广泛的载体材料包括高分子载体、嵌状聚合物胶束载体、树状大分子载体、脂质体载体和无机物载体。无机纳米材料，如介孔材料、纳米管、中空微球等由于具有化学稳定性好、粒子形态和大小可控、表面及孔道易于修饰，还有其独特的光学、磁学和电学等性能而逐渐成为药物缓控释领域研究的研究热点。
中空微球是一种具有特殊结构的核壳材料，它内部的空腔可容纳大量的药物分子，多孔壳层可作为药物释放的通道，因而被认为是药物缓控释领域最具有应用潜力的材料。它最大的优点是比表面积大，可通过调节壳层厚度、孔径、孔形貌和表面改性等手段来改善药物的负载率及缓释性能。包埋了具有磁学、光学性质材料的中空微球更是在靶向治疗、磁控释放领域引起了高度重视。
磁性纳米材料具有超顺磁性和较高的磁饱和强度，因此在磁共振成像、靶向药物和磁靶向热疗等生物医学领域都表现出很大的应用前景。目前，磁性载体粒子研究最多的是磁性微球，但微球的粒径和承载能力是影响其实际应用的两大主要问题。众所周知，载体粒径只有达到纳米级才能有效地避免巨噬细胞的吞噬，维持在体内的长循环。另一方面由于磁性微粒本身具有磁性，易于团聚，不利于磁性粒子在体内的分布。现在，减少团聚的普遍做法是加入表面活性剂，但这种做法不仅改变了粒子的表面性质，影响其承载能力，而且由于表面活性剂的存在使其生物相容性降低。
二氧化硅对磁性纳米材料进行表面修饰时，不仅可以保护磁性核不被氧化或者腐蚀，而且也将内核磁性纳米粒子与表面修饰的其它功能化分子隔开，避免了功能修饰层与磁性纳米粒子之间的相互影响。另外，可以屏蔽磁性纳米粒子之间的偶极相互作用，阻止粒子发生团聚，提高核壳粒子在水中的悬浮特性和生物相容性。Stober法和溶胶凝胶法是二氧化硅修饰Fe3O4纳米粒子的常用方法，壳层厚度可以用TEOS和H2O的比例调节，为制备高质量的磁性微球提供了保证，这又为磁性微球的表面生物修饰和硅球在生物医学中的应用提供了重要保障。
因此，设计一种形貌可控、稳定性高、生物相容性好，承载能力高，缓释性能显著且具有靶向运输作用的载体材料在***等重大疾病领域上将具有非常重要的意义。
发明内容
本发明的目的在提供一种稳定性高、生物相容性好，承载能力高，缓释性能显著且具有靶向运输作用的Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法及应用。
为实现上述目的，本发明采用的技术方案是，一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法，包括以下步骤：①将FeCl3•6H2O、尿素、柠檬酸三钠加入到水中搅拌溶解，之后加入聚丙烯酸钠（分子量为20000~2000000，室温下凝胶状），搅拌均匀后转移到反应釜中，在170~200℃条件下水热反应3~6h，冷却至室温后，所得橙黄色固体用乙醇洗涤，再用水洗，然后在55~65℃干燥，得Fe2O3纳米微球；②将步骤①制备的Fe2O3纳米微球按固液比1g:200ml~1g:350ml分散到10-90vol%的乙醇中，加入TEOS（正硅酸乙酯）的乙醇溶液， 20~30℃下超声处理2~4h，随后加入氨水，搅拌均匀，室温下反应1~3h，所得固体用乙醇洗涤，再用水洗，然后在55~65℃下干燥即制得Fe2O3@ SiO2复合微球；③将步骤②得到的Fe2O3@ SiO2复合微球分散到盐酸中，搅拌反应6~12h，所得固体离心分离后用乙醇和水洗涤，55~65℃下干燥即制得Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球；④将步骤③得到的Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球在管式炉350~500℃下、氢气和氮气体积比为1:8~1:3的混合气下保持60~120min，然后冷却至室温，乙醇洗涤，再用水洗，磁分离，干燥后即得Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球。
步骤①中FeCl3•6H2O和尿素的质量比为1:1~5:1，FeCl3•6H2O和柠檬酸三钠的质量比为1:2~1:5，FeCl3•6H2O和水的质量比为1:60~1:30，水和聚丙烯酸钠的质量比为0.75:1~3:1。
步骤②中TEOS的乙醇溶液中TEOS的体积分数为0.5~5%；10-90vol%的乙醇和TEOS的乙醇溶液的体积比为3:1~5:1；10-90vol%的乙醇和氨水的体积比为5:1~9:1；氨水的浓度为6~14.5 mol/L。
所述步骤③中盐酸的浓度为4~12mol/L， Fe2O3@ SiO2复合微球与盐酸的固液比为1g:300ml~1g:500ml。
所述的 Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球作为药物载体的应用：将盐酸阿霉素溶解在pH=7.4的磷酸缓冲溶液中，然后加入Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球，室温下搅拌24h，磁分离即得负载盐酸阿霉素的Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球。
本发明产生的有益效果是：本发明首先采用溶剂热法制备Fe2O3纳米粒子，粒径在200nm左右，经过柠檬酸钠改性后在水溶液中具有良好的单分散性；结合模板法和水热法，在不加入任何表面活性剂的条件下，以TEOS为硅源，在温和的条件下制备出形貌可控的Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球，该过程采用超声辅助合成，保障了复合微球的高度分散性；用一定浓度的盐酸腐蚀Fe2O3@SiO2复合微球得到Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球，再经氢气还原后制得具有超顺磁性Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球。以盐酸阿霉素为药物模型，实现对其载药释药的性能研究。所制得的Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球比表面积为173m2/g，载药量为139mg/g，在pH为7.4的PBS缓冲溶液中72h内药物的释放率最高达到68.4%，表现出良好的药物缓释性能。
附图说明
图1为实施例1制备得到的Fe2O3纳米微球的透射电子显微镜照片；
图2为实施例1制备得到的Fe2O3@ SiO2复合微球透射电子显微镜照片；
图3为实施例1制备得到的Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球透射电子显微镜照片；
图4为实施例1制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球透射电子显微镜照片；
图5为实施例1制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球的XRD图；
图6为实施例1制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球的IR图；
图7为实施例1制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球在pH为7.4的PBS缓冲溶液中72h内药物的释放曲线图；
图8为实施例2制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球透射电子显微镜照片；
图9为实施例3制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球透射电子显微镜照片。
具体实施方式
为了便于理解本发明，下文将结合说明书附图和较佳的实施例对本发明作更全面、细致地描述，但本发明的保护范围并不限于以下具体的实施例。
实施例1
一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法，包括以下步骤：①将FeCl3•6H2O、尿素、柠檬酸三钠加入到水中搅拌溶解，之后加入聚丙烯酸钠，搅拌均匀后转移到反应釜中，在190℃条件下水热反应3.5h，冷却至室温后，所得橙黄色固体用乙醇洗涤，再用水洗，然后在60℃干燥，得Fe2O3纳米微球；②将步骤①制备的Fe2O3纳米微球按固液比1:250分散到60vol%的乙醇中，加入TEOS（正硅酸乙酯）的乙醇溶液，25℃下超声处理3h，随后加入氨水，搅拌3min，室温下反应2h，所得固体用乙醇洗涤，再用水洗，然后在60℃下干燥即制得Fe2O3@ SiO2复合微球；③将步骤②得到的Fe2O3@ SiO2复合微球分散到盐酸中，搅拌反应8h，所得固体离心分离后用乙醇和水洗涤后60℃下干燥即制得Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球；④将步骤③得到的Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球在管式炉500℃下、氢气和氮气体积比为1:7的混合气下保持120min，然后冷却至室温，乙醇洗涤，再用水洗，磁分离，干燥后即得Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球。
步骤①中FeCl3•6H2O和尿素的质量比为5:1，FeCl3•6H2O和柠檬酸三钠的质量比为1:5，FeCl3•6H2O和水的质量比为1:30，水和聚丙烯酸钠的质量比为0.75:1。
步骤②中TEOS的乙醇溶液中TEOS的体积分数为0.5%；60vol%的乙醇和TEOS的乙醇溶液的体积比为3:1；60vol%的乙醇和氨水的体积比为6:1；氨水的浓度为10.5 mol/L。
所述步骤③中盐酸的浓度为6mol/L， Fe2O3@ SiO2复合微球与盐酸的固液比为1g:300ml。
实施例1制备的Fe2O3纳米微球的透射电子显微镜照片如图1所示，从图1可以看出，Fe2O3纳米微球排列规整，尺寸在200nm左右，具有很好的单分散性；实施例1制备得到的Fe2O3@ SiO2复合微球透射电子显微镜照片如图2所示，从图2可以看出，SiO2成功的包覆在Fe2O3纳米微球表面，尺寸约为50nm，且包覆过SiO2壳层后仍保持良好的单分散性；实施例1制备得到的Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球的透射电子显微镜照片如图3所示，从图3可以看出，Fe2O3@ SiO2复合微球经过6mol/L盐酸的腐蚀，Fe2O3核被部分腐蚀，形成蛋黄-蛋壳结构中空Fe2O3@ SiO2复合微球，SiO2壳层后仍保持其完整性；实施例1制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球透射电子显微镜照片如图4所示，从图4可以看出，经管式炉煅烧处理，Fe2O3@ SiO2蛋黄-蛋壳结构中空复合成为具有超顺磁性的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球，对比可知，微球核经煅烧之后变小，空腔变大。
药物缓控释性能测试：
（1）药物载入
以pH=7.4的磷酸缓冲溶液（PBS）为溶剂，将盐酸阿霉素（DOX）溶解在PBS中，配成一定浓度的溶液（0.2mg/mL），记为DOX-PBS。称取5mg的实施例1制备的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球，加入10mL DOX-PBS溶液，超声使其溶解，然后将容器密封，室温下搅拌24h，使样品充分吸附药物。最后将样品磁分离，用紫外分光光度计检测上清液在480nm处的吸光度，用差减法计算单位质量中空微球的载药量，样品60℃干燥，制得的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球比表面积为173m2/g，载药量为139mg/g。载药量Qe = 载上的 DOX的质量/载体样品的质量，可按下面公式计算：
式中C0—药物起始浓度（mg/mL）；
Ce—反应完成时的浓度（mg/mL）；
V —药物溶液的体积（mL）；
M —载体质量（g）。
（2）药物释放
用pH=7.4的磷酸盐缓冲溶液（PBS）来模拟人体体液进行药物体外释放的研究。将载有DOX药物的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球分散到10mL的PBS溶液中，密封后放到37℃的恒温振荡器中缓慢震荡，每隔2h对溶液进行离心分离，直到释放72h，用紫外分光光度计检测离心上清液在480nm处的吸光度，然后在反应器中重新补充10mLpH=7.4的磷酸盐缓冲溶液继续释放。根据标定好的标准曲线计算每段时间间隔释放的药物的质量，进而得到累积的药物释放率。计算公式如下：，Mt是t时间缓冲溶液中所释放出的盐酸阿霉素的质量，M0是Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球中所含盐酸阿霉素的质量。由图7可知，在pH为7.4的PBS缓冲溶液中72h内药物的释放率达到68.4%，表现出良好的药物缓释性能。
实施例2
一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法，包括以下步骤：①将FeCl3•6H2O、尿素、柠檬酸三钠加入到水中搅拌溶解，之后加入聚丙烯酸钠，搅拌均匀后转移到反应釜中，在170℃条件下水热反应3h，冷却至室温后，所得橙黄色固体用乙醇洗涤，再用水洗，然后在55℃干燥，得Fe2O3纳米微球；②将步骤①制备的Fe2O3纳米微球按固液比1g:200ml分散到90vol%的乙醇中，加入TEOS（正硅酸乙酯）的乙醇溶液，20℃下超声处理4h，随后加入氨水，搅拌1min，室温下反应3h，所得固体用乙醇洗涤，再用水洗，然后在65℃下干燥即制得Fe2O3@ SiO2复合微球；③将步骤②得到的Fe2O3@ SiO2复合微球分散到盐酸中，搅拌反应6h，所得固体离心分离后用乙醇和水洗涤，55℃下干燥即制得Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球；④将步骤③得到的Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球在管式炉450℃下、氢气和氮气体积比为1:8的混合气下保持100min，然后冷却至室温，乙醇洗涤，再用水洗，磁分离，干燥后即得Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球。
步骤①中FeCl3•6H2O和尿素的质量比为3:1，FeCl3•6H2O和柠檬酸三钠的质量比为1:2，FeCl3•6H2O和水的质量比为1:60，水和聚丙烯酸钠的质量比为3:1。
步骤②中TEOS的乙醇溶液中TEOS的体积分数为5%；90vol%的乙醇和TEOS的乙醇溶液的体积比为4:1；90vol%的乙醇和氨水的体积比为9:1；氨水的浓度为14.5 mol/L。
所述步骤③中盐酸的浓度为4mol/L，Fe2O3@ SiO2复合微球与盐酸的固液比为1g:500ml。
实施例3
一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法，包括以下步骤：①将FeCl3•6H2O、尿素、柠檬酸三钠加入到水中搅拌溶解，之后加入聚丙烯酸钠，搅拌均匀后转移到反应釜中，在200℃条件下水热反应6h，冷却至室温后，所得橙黄色固体用乙醇洗涤，再用水洗，然后在65℃干燥，得Fe2O3纳米微球；②将步骤①制备的Fe2O3纳米微球按固液比1g:350ml分散到10vol%的乙醇中，加入TEOS（正硅酸乙酯）的乙醇溶液，30℃下超声处理2h，随后加入氨水，搅拌5min，室温下反应1h，所得固体用乙醇洗涤，再用水洗，然后在55℃下干燥即制得Fe2O3@ SiO2复合微球；③将步骤②得到的Fe2O3@ SiO2复合微球分散到盐酸中，搅拌反应12h，所得固体离心分离后用乙醇和水洗涤，65℃下干燥即制得Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球；④将步骤③得到的Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球在管式炉350℃下、氢气和氮气体积比为1:3的混合气下保持60min，然后冷却至室温，乙醇洗涤，再用水洗，磁分离，干燥后即得Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球。
步骤①中FeCl3•6H2O和尿素的质量比为1:1，FeCl3•6H2O和柠檬酸三钠的质量比为1:3，FeCl3•6H2O和水的质量比为1:45，水和聚丙烯酸钠的质量比为2:1。
步骤②中TEOS的乙醇溶液中TEOS的体积分数为2.5%；10vol%的乙醇水溶液和TEOS的乙醇溶液的体积比为5:1；10vol%的乙醇和氨水的体积比为5:1；氨水的浓度为6 mol/L。
所述步骤③中盐酸的浓度为12mol/L， Fe2O3@ SiO2复合微球与盐酸的固液比为1g:400ml。
图8为实施例2制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球透射电子显微镜照片，图9为实施例3制备得到的Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球透射电子显微镜照片，本发明可以通过控制TEOS的量来控制复合微球的壳层厚度，调控盐酸的浓度，影响Fe2O3@ SiO2复合微球的腐蚀程度，从而控制Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球的结构和形貌。
Claims (1)
1.一种Fe3O4@SiO2蛋黄-蛋壳结构中空复合微球的制备方法，其特征在于，包括以下步骤：①将FeCl3•6H2O、尿素、柠檬酸三钠加入到水中搅拌溶解，之后加入聚丙烯酸钠，搅拌均匀后转移到反应釜中，在170~200℃条件下水热反应3~6h，冷却至室温后，所得橙黄色固体用乙醇洗涤，再用水洗，然后在55~65℃干燥，得Fe2O3纳米微球；②将步骤①制备的Fe2O3纳米微球按固液比1g:200ml~1g:350ml分散到10-90vol%的乙醇中，加入TEOS的乙醇溶液， 20~30℃下超声处理2~4h，随后加入氨水，搅拌均匀，室温下反应1~3h，所得固体用乙醇洗涤，再用水洗，然后在55~65℃下干燥即制得Fe2O3@ SiO2复合微球；③将步骤②得到的Fe2O3@SiO2复合微球分散到盐酸中，搅拌反应6~12h，所得固体离心分离后用乙醇和水洗涤后55~65℃下干燥即制得Fe2O3@ SiO2蛋黄-蛋壳结构中空复合微球；④将步骤③得到的Fe2O3@SiO2蛋黄-蛋壳结构中空复合微球在350~500℃下、氢气和氮气体积比为1:8~1:3的混合气下保持60~120min，然后冷却至室温，乙醇洗涤，再用水洗，磁分离，干燥后即得Fe3O4@ SiO2蛋黄-蛋壳结构中空复合微球；步骤①中FeCl3•6H2O和尿素的质量比为1:1~5:1，FeCl3•6H2O和柠檬酸三钠的质量比为1:2~1:5，FeCl3•6H2O和水的质量比为1:60~1:30，水和聚丙烯酸钠的质量比为0.75:1~3:1；步骤 ②中TEOS的乙醇溶液中TEOS的体积分数为0.5~5%；10-90vol%的乙醇和TEOS的乙醇溶液的体积比为3:1~5:1；10-90vol%的乙醇和氨水的体积比为5:1~9:1；氨水的浓度为6~14.5 mol/L；所述步骤 ③中盐酸的浓度为4~12mol/L， Fe2O3@SiO2复合微球与盐酸的固液比为1g:300ml~1g:500ml。
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| CN108807905B (zh) * | 2018-06-12 | 2021-03-12 | 河南师范大学 | 一种可调空腔结构的氧化铁@氧化钛复合负极材料的制备方法 |
| CN109513405B (zh) * | 2018-12-05 | 2020-10-27 | 湘潭大学 | 一种Yolk/shell胶囊及其制备方法和用途 |
| CN111484769B (zh) * | 2019-05-14 | 2022-11-15 | 广东聚华印刷显示技术有限公司 | 复合材料及其制备方法、包含其的墨水，以及成膜方法 |
| CN110251482B (zh) * | 2019-07-24 | 2020-07-31 | 河南大学 | 一种单分散空心普鲁士蓝纳米微球、其制备方法及应用 |
| CN112516956A (zh) * | 2020-11-12 | 2021-03-19 | 蚌埠学院 | 一种磁性复合纳米材料的制备方法及其应用 |
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2016
- 2016-03-18 CN CN201610155881.3A patent/CN105832699B/zh not_active Expired - Fee Related
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| "多功能Fe3O4@SiO2蛋黄-蛋壳纳米胶囊的制备及在药物输送和荧光成像中的应用";张凌宇 等;《中国化学会第十三届胶体与界面化学会议论文摘要集》;20110720;第409页 * |
| An Efficient Route to Rattle-Type Fe3O4@SiO2 Hollow Mesoporous Spheres Using Colloidal Carbon Spheres Templates;Zhu Y. F.,et al.;《Chemistry of Materials》;20091231;第21卷(第12期);第2547-2553页 * |
| Fe3O4/SiO2核壳复合磁性微球的制备和表征;熊珊 等;《硅酸盐学报》;20150731;第43卷(第7期);第946-951页 * |
| 正交试验优化核壳型Fe3O4@SiO2磁性复合微球的制备工艺;吴文兵 等;《广州化工》;20150531;第40卷(第9期);第126-128页 * |
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