CN106544756B - 一种具有pH诱导与光学检测药物释放行为的上转化发光二氧化硅复合纤维的制备方法 - Google Patents
一种具有pH诱导与光学检测药物释放行为的上转化发光二氧化硅复合纤维的制备方法 Download PDFInfo
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Abstract
本发明采用表面改性的方法制备出一种具有pH诱导与光学检测药物释放行为的上转换发光二氧化硅复合纤维。采用稀土元素镱和铒的双掺，可实现良好的上转换发光效应方法简便，可操作性强。先将上转换发光二氧化硅复合纤维表面氨基改性，再通过静电结合的方式在纤维的表面加载一层PAA高分子层，改性后的纤维具有强上转换发光性能。所得材料尺寸分布均一、具有较强上转换发光效应的PAA改性二氧化硅复合纤维。所得纳米纤维发光性能良好、产量大，可在实现不同pH环境中的可控肿瘤药物释放行为的同时，达到药物释放动力学的光学检测。该类新型复合纳米材料在药物传递、组织工程、发光器件制备以及生物组织成像等领域有广泛应用前景。
Description
技术领域
本发明属于应用型无机先进纳米材料技术领域，特别涉及一种具有pH诱导与光学检测药物释放行为的上转化发光二氧化硅复合纤维及其制备方法，可应用于药物传递、骨组织工程、发光器件制备、生物组织成像及药物示踪等领域。
背景技术
稀土元素上转换发光材料是一类重要的发光材料，稀土元素拥有丰富的能级，可以由长波段光源激发，激发出较短波段的光。且发出的光可以通过各种条件来控制。光学性能优异，因此得到了广泛关注和研究。
氟化钙的声子能量低、化学稳定性好，其独特的氟化钙结构允许掺杂一定量的稀土元素，适合作为稀土元素的基体材料。二氧化硅作为药物传递材料在生物医学领域已有较多应用，生物相容性良好。因此上转换发光的氟化钙纳米颗粒与二氧化硅的复合纤维是一个研究热点。
由于本发明结合溶胶凝胶法通过静电纺丝制备得到的CaF2:Yb,Er@SiO2纳米纤维直径均匀可控，并通过表面改性的方法得到PAA改性的CaF2:Yb,Er@SiO2纳米纤维，具有pH诱导与光学检测药物释放行为，方法更为简单，产量大，可重复性强。
发明内容
本发明所要解决的问题是提供一种发光效率和发光强度较大的PAA改性的具有pH诱导与光学检测药物释放行为的上转化发光二氧化硅复合纤维及其制备方法。
本发明的目的是通过以下技术方案实现的：一种具有pH诱导与光学检测药物释放行为的上转化发光二氧化硅复合纤维的制备方法，包括以下步骤：
(1)按照化学通式Ca1-0.18-0.02F2:0.18Yb3+,0.02Er3+中各元素的摩尔计量比，称取四水合硝酸钙、五水合硝酸铒及五水合硝酸镱，总量为4mmol，然后与8mmol的柠檬酸三钠，加入到80毫升去离子水中，混合均匀后得到溶液A。再将8mmol氟硼酸钠加入40毫升去离子水中，得到溶液B。将溶液B逐滴加入到溶液A中，并用氨水调节溶液的pH，使pH＝7。将上述混合溶液搅拌30min后，放入水热反应釜中，180℃水热反应24小时。待反应釜冷却至室温后，离心清洗，得到白色沉淀物，并放于80℃烘箱中干燥，即可得到稀土掺杂氟化钙上转换发光纳米颗粒。
(2)配制生物玻璃先驱体溶液：将1.67g正硅酸四乙酯加入含有200微升乙酸和600微升水的10mL乙醇溶液中，加入0.6-1.2g分子量为1300000的PVP。搅拌均匀后，再加入3mL浓度为3mg/mL的稀土掺杂氟化钙上转换发光纳米颗粒的乙醇溶液。继续搅拌1.5h得到纺丝前驱体。
(3)将纺丝先驱体转移到注射器中，利用静电纺丝装置将纺丝先驱体以一定速度纺成纤维状，以接地的带有铝箔的平板作为接收装置，然后放入烘箱干燥12h。最后放入马弗炉中550℃烧结5h，即可得到具有上转换发光效应的氟化钙颗粒与二氧化硅纤维复合材料(即为CaF2:Yb,Er@SiO2纳米纤维)。
(4)氨基改性的CaF2:Yb,Er@SiO2纳米纤维：先将50mg CaF2:Yb,Er@SiO2纳米纤维加入到40mL的DMF，再加入0.4mL的APTES。然后在80℃搅拌反应24小时。反应产物用DMF离心清洗三次，得到白色沉淀物，并放于80℃烘箱中干燥，即可得到氨基改性的CaF2:Yb,Er@SiO2纳米纤维。
(5)PAA改性的CaF2:Yb,Er@SiO2纳米纤维：30mg上述氨基改性的CaF2:Yb,Er@SiO2纳米纤维加入到100mL的水中。再将10mL的PAA(50vol％)水溶液加入上述溶液，室温搅拌24h。最后用离心水洗三次，得到白色沉淀物，并放于37℃烘箱中干燥12h，即可得到PAA改性的CaF2:Yb,Er@SiO2纳米纤维。
进一步地，静电纺丝的流速控制在0.8mL/h，电压值范围为6-8kV
本发明的有益效果在于：本发明在制备过程中利用3-氨丙基三乙氧基硅烷在CaF2:Yb,Er@SiO2纤维表面改性氨基，然后利用氨基与聚丙烯酸的静电作用，最终得到发光性能良好且具有pH诱导与光学检测药物释放性能的聚丙烯酸改性的CaF2:Yb,Er@SiO2纳米纤维。聚丙烯酸改性的CaF2:Yb,Er@SiO2纳米纤维可以实现980nm红外光激发，发射出550-560nm波段的绿光和660-670nm波段的红光。上转换发光效率高，发光强度大，且可以调节光的强度和颜色。生物相容性好，光学信号强，在生物医学中有广泛应用前景，如用作多功能药物传递、组织工程或细胞成像等领域有重要应用。制备方法绿色无污染，可控性强，实现了聚丙烯酸改性的CaF2:Yb,Er@SiO2纳米纤维的制备，且具有pH诱导与光学检测药物释放行为。该制备方法工艺简单，产量大，易于工业化生产。
附图说明
图1为实施例制备的CaF2:Yb,Er@SiO2纤维的扫描电镜照片。可以看出纤维直径约为600nm,且尺寸分布均匀。
图2为实施例制备的氨基改性和聚丙烯酸改性前后的CaF2:Yb,Er@SiO2纤维的红外图谱，纤维改性氨基之后出现1560cm-1的吸收峰，改性PAA后表面出现C＝O在1717cm-1处的吸收峰。
图3为实施例制备的氨基改性和聚丙烯酸改性前后的CaF2:Yb,Er@SiO2纤维的ZETA电位图，二氧化硅纤维本身因表面的Si-OH呈现负电性，表面改性氨基后则表现为正电，最后改性PAA后，材料呈现负电。结合红外能够确定纤维表面改性成功。
图4为实施例制备的稀聚丙烯酸改性前后的CaF2:Yb,Er@SiO2纤维的材料的上转换荧光光谱图，可以看出纤维改性前后均呈现上转换发光。
图5为实施例制备的稀聚丙烯酸改性前后的CaF2:Yb,Er@SiO2纤维的材料在不同pH条件下的药物释放曲线。由图可以看出改性后纤维具有pH敏感药物释放功能。
图6为实施例制备的稀聚丙烯酸改性前后的CaF2:Yb,Er@SiO2纤维的材料在药物释放过程中的上转换发光强度变化。(a)和(b)分别为7.4和4.7时，药物释放过程中绿光的变化曲线，(c)为7.4和4.7时药物释放过程中绿光强度与红光强度比值(I550/I660)的变化曲线，由图可看出可以用光来监测药物释放过程中的药物释放性能。药物在释放过程中的释放行为对于治疗效果有很大的影响，而光监测药物释用来调控药物的释放性能，具有重大意义。
具体实施方式
本发明制备出聚丙烯酸改性后的CaF2:Yb,Er@SiO2纤维，并对其进行药物加载，该材料具有很好的pH诱导药物释放性能以及能够用光来监测药物释放行为。图4为制备得到的聚丙烯酸改性前后的CaF2:Yb,Er@SiO2纤维的材料的上转换荧光光谱图，可以看出改性后复合材料在980nm光照射下依然有很强的上转换发光效应。采用稀土元素镱和铒的双掺，可实现良好的上转换发光效应方法简便，可操作性强。先将上转换发光二氧化硅复合纤维表面氨基改性，再通过静电结合的方式在纤维的表面加载一层PAA高分子层，改性后的纤维具有强上转换发光性能。所得材料为平均粒径600nm、尺寸分布均一、且具有较强上转换发光效应的PAA改性二氧化硅复合纤维。
下面结合附图和具体实施例来详细说明本发明的技术方案，但本发明不局限于实施例，本领域技术人员可以根据实际情况进行调整。
实施例1 PAA改性后的复合纤维在不同pH条件下的药物释放性能
(1)按照化学通式Ca1-0.18-0.02F2:0.18Yb3+,0.02Er3+中各元素的摩尔计量比，称取四水合硝酸钙、五水合硝酸铒及五水合硝酸镱，总量为4mmol，然后与8mmol的柠檬酸三钠，加入到80毫升去离子水中，混合均匀后得到溶液A。再将8mmol氟硼酸钠加入40毫升去离子水中，得到溶液B。将溶液B逐滴加入到溶液A中，并用氨水调节溶液的pH，使pH＝7。将上述混合溶液搅拌30min后，放入水热反应釜中，180℃水热反应24小时。待反应釜冷却至室温后，离心清洗，得到白色沉淀物，并放于80℃烘箱中干燥，即可得到稀土掺杂氟化钙上转换发光纳米颗粒。
(2)配制生物玻璃先驱体溶液：将1.67g正硅酸四乙酯加入含有200微升乙酸和600微升水的10mL乙醇溶液中，加入0.6g分子量为1300000的PVP。搅拌均匀后，再加入3mL浓度为3mg/mL的稀土掺杂氟化钙上转换发光纳米颗粒的乙醇溶液。继续搅拌1.5h得到纺丝前驱体。
(3)将纺丝先驱体转移到注射器中，利用静电纺丝装置将纺丝先驱体以一定速度纺成纤维状，以接地的带有铝箔的平板作为接收装置，然后放入烘箱干燥12h。静电纺丝的流速控制在0.8mL/h，电压值范围为6-8kV。最后放入马弗炉中550℃烧结5h，即可得到具有上转换发光效应的氟化钙颗粒与二氧化硅纤维复合材料(即为CaF2:Yb,Er@SiO2纳米纤维)。
(4)氨基改性的CaF2:Yb,Er@SiO2纳米纤维：先将50mg CaF2:Yb,Er@SiO2纳米纤维加入到40mL的DMF，再加入0.4mL的APTES。然后在80℃搅拌反应24小时。反应产物用DMF离心清洗三次，得到白色沉淀物，并放于80℃烘箱中干燥，即可得到氨基改性的CaF2:Yb,Er@SiO2纳米纤维。
(5)PAA改性的CaF2:Yb,Er@SiO2纳米纤维：30mg上述氨基改性的CaF2:Yb,Er@SiO2纳米纤维加入到100mL的水中。再将10mL的PAA(50vol％)水溶液加入上述溶液，室温搅拌24h。最后用离心水洗三次，得到白色沉淀物，并放于37℃烘箱中干燥12h，即可得到PAA改性的CaF2:Yb,Er@SiO2纳米纤维。
取50mg的PAA改性的CaF2:Yb,Er@SiO2纳米纤维，加入20mL浓度为1mg/mL的DOX(盐酸阿霉素，一种抗癌药)水溶液中，避光搅拌24h。离心水洗三次后得到载药的纤维。将得到的药物加载后的纤维浸没在20mL的PBS(磷酸缓冲溶液)中，每隔固定时间10mL溶液，并加入10mL新的PBS(磷酸缓冲溶液)。再经过紫外测试吸光度，数据处理得到材料的不同pH条件下的释放曲线。本实施例中pH分别取7.4,5.8和4.7。图5为改性后的复合纤维在这三个不同pH条件下的药物释放曲线。由图可以看出，在释放时间为20h时，pH为7的载药纤维药物释放量约为20％，pH为5.8的载药纤维药物释放量约为50％，而pH为4.7的载药纤维药物释放量则高达约65％。由三条不同pH的释放曲线可以看出，载药纤维在低pH条件下，药物释放率更高。这是由于药物分子表面呈正电，而纤维表面负电性，两者静电结合。低pH条件下，易促使药物分子的释放。基于材料的PH敏感性可知，该材料可通过PH来诱导。本实施示例得到CaF2:Yb,Er@SiO2,并成功对此发光纤维进行聚丙烯酸表面改性。从图1中可以看出，所得纳米纤维形状规则，尺寸均一。图2和图3则从红外和ZETA电位两个方面证实本实验方法成功将聚丙烯酸改性至发光纤维表面。并且从图4中可以看出，所得聚丙烯酸改性后纳米纤维的可以发出很强的红光和绿光信号。
图6为药物释放过程中光学信号的变化情况；(a)和(b)分别为7.4和4.7时，药物释放过程中绿光的变化。可以看出，在药物释放的过程中，随着释放时间的增加，绿光波段光学信号强度逐渐增强，而红光波段光学信号强度基本不变。这是由于DOX会吸收绿光波段的光，而对红光波段的光无吸收。在药物释放的过程中，随着药物的释放，绿光强度会逐渐增加，而红光波段光强不变，因此可以用红绿光比来用检测药物的释放。
Claims (2)
1.一种具有pH诱导与光学检测药物释放行为的上转化发光二氧化硅复合纤维的制备方法，其特征在于，包括以下步骤：
(1)按照化学通式Ca1-0.18-0.02F2:0.18Yb3+,0.02Er3+中各元素的摩尔计量比，称取四水合硝酸钙、五水合硝酸铒及五水合硝酸镱，总量为4mmol，然后与8mmol的柠檬酸三钠，加入到80毫升去离子水中，混合均匀后得到溶液A；再将8mmol氟硼酸钠加入40毫升去离子水中，得到溶液B；将溶液B逐滴加入到溶液A中，并用氨水调节溶液的pH，使pH＝7；将上述混合溶液搅拌30min后，放入水热反应釜中，180℃水热反应24小时；待反应釜冷却至室温后，离心清洗，得到白色沉淀物，并放于80℃烘箱中干燥，即可得到稀土掺杂氟化钙上转换发光纳米颗粒；
(2)配制生物玻璃先驱体溶液：将1.67g正硅酸四乙酯加入到含有200微升乙酸和600微升水的10mL乙醇溶液中，加入0.6-1.2g分子量为1300000的PVP；搅拌均匀后，再加入3mL浓度为3mg/mL的稀土掺杂氟化钙上转换发光纳米颗粒的乙醇溶液；继续搅拌1.5h得到纺丝前驱体；
(3)将纺丝先驱体转移到注射器中，利用静电纺丝装置将纺丝先驱体以一定速度纺成纤维状，以接地的带有铝箔的平板作为接收装置，然后放入烘箱干燥12h；最后放入马弗炉中550℃烧结5h，即可得到具有上转换发光效应的CaF2:Yb,Er@SiO2纳米纤维；
(4)氨基改性的CaF2:Yb,Er@SiO2纳米纤维的制备：先将50mg CaF2:Yb,Er@SiO2纳米纤维加入到40mL的DMF，再加入0.4mL的APTES；然后在80℃搅拌反应24小时；反应产物用DMF离心清洗三次，得到白色沉淀物，并放于80℃烘箱中干燥，即可得到氨基改性的CaF2:Yb,Er@SiO2纳米纤维；
(5)PAA改性的CaF2:Yb,Er@SiO2纳米纤维：30mg上述氨基改性的CaF2:Yb,Er@SiO2纳米纤维加入到100mL的水中；再将10mL浓度为50vol％的PAA水溶液加入上述溶液，室温搅拌24h；最后用离心水洗三次，得到白色沉淀物，并放于37℃烘箱中干燥12h，即可得到PAA改性的CaF2:Yb,Er@SiO2纳米纤维。
2.根据权利要求1所述的具有pH诱导与光学检测药物释放行为的上转化发光二氧化硅复合纤维的制备方法，其特征在于，静电纺丝的流速控制在0.8mL/h，电压值范围为6-8kV。
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