CN112190697A - 一种高负载藻蓝蛋白的纳米颗粒及其制备方法与应用 - Google Patents
一种高负载藻蓝蛋白的纳米颗粒及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种高负载藻蓝蛋白的纳米颗粒及其制备方法与应用。本发明将藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液和PVA溶液同时混合,得到含高负载藻蓝蛋白的纳米颗粒的溶液。本发明利用静电作用、氢键、疏水相互作用力合成高稳定的藻蓝蛋白‑单宁酸‑PVA‑PAMMA复合纳米颗粒,通过单宁酸、PVA与藻蓝蛋白形成的氢键作用力与藻蓝蛋白和PAMMA形成的静电作用力维系纳米颗粒的稳定性,具有高负载率、高稳定性的优点,为拓宽藻蓝蛋白基纳米颗粒的应用范围提供了基础。该制备方法具有工艺简单、条件温和、可放大化生产的优点;生产得到的藻蓝蛋白纳米颗粒具有粒径均一、负载率高、可连续生产的优点。
Description
技术领域
本发明属于保健品、功能食品和生物医药领域,特别涉及一种高负载藻蓝蛋白的纳米颗粒及其制备方法与应用。
背景技术
螺旋藻(Spirulina)营养丰富,含有多种生物活性物质,易于大规模培养,作为硒生物有机化的载体前景将十分广阔。藻蓝蛋白是螺旋藻含量最高的生物活性物质之一,可达藻干质量的20%左右,其具有良好的抗氧化、抗肿瘤等作用。藻蓝蛋白不仅可以在体外高效清除氧自由基,而且可以清除动物机体内的多种自由基。现有研究结果表明,藻蓝蛋白具有良好的功能活性与开发前景。然而,藻蓝蛋白在中性pH、30℃条件下表现稳定,但在pH4.0以下、45℃以上时变色显著,其稳定性大幅下降。这种温度、酸度敏感性导致口服藻蓝蛋白的生物利用度差,较大的限制其在食品、生物医药领域的应用。因此,如何提高藻蓝蛋白的稳定性已成为拓展其应用范围的关键问题。
纳米化技术是提高蛋白的稳定性、生物利用度的重要手段。近年来,蛋白纳米颗粒的制备与应用研究得到广泛重视。目前,国内外基本采用化学交联法制备藻蓝蛋白纳米颗粒,作为药物递送的载体。常用的化学交联剂包括戊二醛(Huang et al.,J.Mater.Chem.B,2017,5,3300-3314)、N-羟基丁二酰亚胺、1-乙基-3-(3-二甲氨基丙基)碳二亚胺(Bharathiraja et al.,European Journal of Pharmaceutics and Biopharmaceutics,2018,Pages 20-30)等,此法虽能制备纳米尺度的藻蓝蛋白颗粒,但化学修饰造成藻蓝蛋白生物活性下降,且交联剂也存在一定的毒性。因此,研发稳定性高、毒性小、负载量大的的藻蓝蛋白纳米颗粒具有重要意义。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足,提供一种高负载藻蓝蛋白的纳米颗粒的制备方法。
本发明的另一目的在于提供通过上述制备方法得到的高负载藻蓝蛋白的纳米颗粒。
本发明的再一目的在于提供上述高负载藻蓝蛋白的纳米颗粒的应用。
本发明的目的通过下述技术方案实现:一种高负载藻蓝蛋白的纳米颗粒的制备方法,包括如下步骤:
(1)配制溶液:用水分别将藻蓝蛋白、PAMMA、单宁酸、PVA配制成溶液,再将溶液的pH值调节成6.5~7.5,得到藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液和PVA溶液;
(2)高负载藻蓝蛋白的纳米颗粒的制备:将藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液和PVA溶液同时混合,得到含高负载藻蓝蛋白的纳米颗粒的溶液;其中,藻蓝蛋白、PAMMA、单宁酸和PVA按质量比0.2~2:0.2~1:0.5~2:0.1~1配比混合。
所述的高负载藻蓝蛋白的纳米颗粒的制备方法,包括如下步骤:
(3)高负载藻蓝蛋白的纳米颗粒粉末的制备:在含高负载藻蓝蛋白的纳米颗粒的溶液中加入保护剂,得到溶液A;将溶液A冷冻干燥,粉碎,得到高负载藻蓝蛋白的纳米颗粒粉末。
步骤(1)中所述的水优选为去离子水、超纯水。
步骤(1)中所述的藻蓝蛋白溶液的浓度优选为0.2~2mg/mL;更优选为1.0mg/mL。
步骤(1)中所述的PAMMA溶液的浓度优选为0.2~1mg/mL;更优选为0.5mg/mL。
步骤(1)中所述的单宁酸溶液的浓度优选为0.5~2mg/mL;更优选为1mg/mL。
步骤(1)中所述的PVA溶液的浓度优选为0.1~1mg/mL;更优选为0.5mg/mL。
步骤(1)中所述的pH值的调节剂包括碱和酸。
所述的碱优选为NaOH;更优选为浓度为0.1mol/L的NaOH溶液。
所述的酸优选为HCl;更优选为浓度为0.1mol/L的HCl溶液。
步骤(2)中所述的混合的方式优选为将藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液和PVA溶液分别通过管道输送,同时在混合容器中汇合进行混合。
所述的输送的流速优选为5~20mL/min;更优选10mL/min。
步骤(2)中所述的混合优选为通过快速纳米复合仪混合;
所述的快速纳米复合仪的结构如下:包括四台泵和混合器;混合器包括顶盖、混合部件和出料口;顶盖上设置四个液体入口,四台泵分别通过聚四氟乙烯管道与顶盖的四个液体入口连接;混合部件位于顶盖下方,包括四个凹槽和两端开口的圆台形结构,四个凹槽的汇合处为圆台形结构;液体入口与凹槽连接;圆台形结构上宽下窄,窄处与出料口连接。
所述的泵包括注射泵和蠕动泵。
所述的凹槽优选为深度×宽度=2mm×2mm的凹槽。
所述的圆台形结构优选为底面半径为5mm、截面半径为1.6mm、高度为10mm的圆台形结构。
步骤(3)中所述的保护剂优选为海藻酸钠。
所述的保护剂的用量按在溶液A中的浓度为6~10g/mL计算;更优选为按在溶液A中的浓度为8g/mL计算。
所述的冷冻干燥的时间优选为36~60h;更优选为48h。
所述的粉碎的程度优选为能过40目筛。
一种高负载藻蓝蛋白的纳米颗粒,通过上述制备方法得到。
所述的高负载藻蓝蛋白的纳米颗粒在保健品、功能食品和生物医药领域中进行应用。
本发明相对于现有技术具有如下的优点及效果:
(1)本发明利用静电作用、氢键、疏水相互作用力合成高稳定的藻蓝蛋白-单宁酸(TA)-聚乙烯醇(PVA)-树枝状阳离子聚合物(PAMMA)复合纳米颗粒,通过单宁酸(TA)、PVA与藻蓝蛋白形成的氢键作用力与藻蓝蛋白与PAMMA形成的静电作用力维系纳米颗粒的稳定性,具有高负载率、高稳定性的优点,为拓宽藻蓝蛋白基纳米颗粒的应用范围提供了基础。
(2)本发明提供的制备方法生产得到的藻蓝蛋白纳米颗粒具有粒径均一、负载率高、可连续生产的优点。
(3)本发明提供的方法具有工艺简单、条件温和、可放大化生产的优点。
(4)本发明运用快速纳米复合仪制备得到藻蓝蛋白纳米颗粒的优点是粒度小、PDI小,并可连续生产。而普通的溶液搅拌混合是间歇式生产,得到的藻蓝蛋白纳米颗粒可能反应时间长,产品粒径、PDI更大,如注射泵以10mL/min的流速将藻蓝蛋白溶液、单宁酸乳液、PAMMA溶液、PVA溶液(各10mL)混合时,平均粒径和PDI分别为249nm、0.443。
附图说明
图1是本发明所用的快速纳米复合仪的结构示意图;其中,1-注射泵,2-顶盖,3-混合部件。
图2是单宁酸(TA)和藻蓝蛋白疏水相互作用的结果检测图。
图3是壳聚糖-TA-PVA@藻蓝蛋白纳米颗粒的电子透射照片图。
图4是PEI-TA-PVA@藻蓝蛋白纳米颗粒的电子透射照片图。
图5是PAMMA-TA-PVA@藻蓝蛋白纳米颗粒的电子透射图。
图6是三种负载藻蓝蛋白纳米颗粒的粒度分布检测结果图。
图7是不同阳离子聚合物对荷载藻蓝蛋白纳米颗粒粒径影响的检测结果图。
图8是不同阳离子聚合物对藻蓝蛋白纳米颗粒多分散系数的影响的检测结果图。
图9是不同聚合物组合对藻蓝蛋白负载率影响的检测结果图。
图10是PAMMA-TA-PVA@藻蓝蛋白纳米颗粒在28d储藏期内的粒径变化的检测结果图。
图11是藻蓝蛋白保留率随加热时间的变化结果图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
藻蓝蛋白,食品级,购于浙江宾美生物有限公司;
树枝状聚酰胺(PAMMA),购于美国Sigma-aldrich公司,货号412368;
单宁酸,食品级,购于广州市德晟化工有限公司;
聚乙烯醇(PVA),食品级,购于广州市宏州化工有限公司;
海藻糖,食品级,购于河南旗诺食品配料有限公司;
壳聚糖,食品级,购于南京京润生物科技有限公司;
PEI,购于上海阿拉丁试剂有限公司,货号:E107079。
实施例1
(1)溶液配制
以去离子水为溶剂,分别配制浓度为1.0mg/mL的藻蓝蛋白溶液、0.5mg/mL的PAMMA溶液、1mg/mL的单宁酸溶液、0.5mg/mL的PVA溶液,备用;用0.1mol/L的NaOH或0.1mol/L的HCl将上述溶液的pH调整7。
(2)采用快速纳米复合仪制备藻蓝蛋白纳米颗粒
如图1所示,快速纳米复合仪包括四台注射泵1和混合器;混合器包括顶盖2、混合部件3和出料口;顶盖2上设置四个液体入口,四台注射泵分别通过聚四氟乙烯管道与顶盖的四个液体入口连接;混合部件3位于顶盖下方,包括四个凹槽和两端开口的圆台形结构,四个凹槽的汇合处为圆台形结构;液体入口与凹槽连接;圆台形结构上宽下窄,窄处与出料口连接。其中,凹槽的深度×宽度=2mm×2mm;圆台形结构的底面半径为5mm、截面半径为1.6mm、高度为10mm。
工作时,四个通道的液体通过凹槽在圆台形结构处混合,形成PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒,随后通过出料口排出。
藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液、PVA溶液分别同时通过注射泵,从顶盖的入液口进入到混合器,流速为10mL/min,得到纳米颗粒分散液。
壳聚糖-单宁酸-PVA@藻蓝蛋白纳米颗粒、PEI-单宁酸-PVA@藻蓝蛋白纳米颗粒的制备方法同PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的制备方法,不同之处在于0.5mg/mL的PAMMA溶液分别被0.5mg/mL的壳聚糖溶液、0.5mg/mL的PEI溶液替代。
PAMMA@藻蓝蛋白纳米颗粒的制备方法同PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的制备方法,不同之处在于1mg/mL的单宁酸溶液、0.5mg/mL的PVA溶液被去离子水代替。同理,制备PVA@藻蓝蛋白纳米颗粒、单宁酸@藻蓝蛋白纳米颗粒时,其他两个通道也用去离子水代替。
(3)冷冻干燥
在步骤(2)制备的纳米颗粒分散液中加入海藻糖至浓度为8g/mL,冷冻干燥48h。
(4)粉碎
将步骤(3)得到的高负载藻蓝蛋白的纳米颗粒粉末粉碎,过40目筛。
(5)检测
高负载藻蓝蛋白的纳米颗粒的平均粒度:将高负载藻蓝蛋白的纳米颗粒粉末溶解于去离子水中,配制成0.2mg/mL的分散液,由动态光散射法检测PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的平均粒径,为145nm。
单宁酸与藻蓝蛋白的疏水相互作用:1.0mg/mL的藻蓝蛋白溶液和1mg/mL的单宁酸溶液分别按体积比10:1、15:1、30:1、150:1混合,混匀后于室温下静置5min,随后用荧光光谱仪监测单宁酸与藻蓝蛋白间的疏水相互作用力,得到的结果如图2所示。可见,随着藻蓝蛋白:单宁酸比例的逐渐最大,藻蓝蛋白的荧光发射强度逐渐减小,表明藻蓝蛋白与单宁酸间的疏水相互作用强度逐渐增大。
阳离子聚合物-单宁酸-PVA@藻蓝蛋白的形貌分析:采用电子透射电镜分析了阳离子种类对阳离子聚合物-单宁酸-PVA@藻蓝蛋白颗粒形貌的影响,得到的结果如图3、图4、图5所示。当采用壳聚糖、PEI时,形成尺寸不一、无固定形状的絮状聚集体,而使用PAMMA却能得到球形的纳米颗粒,尺寸介于50~200nm之间。
采用动态光散射法检测荷载藻蓝蛋白的纳米颗粒的平均粒径、粒径分布曲线、多分散系数(PDI),如图6、图7、图8所示。PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的平均粒径为145nm,而壳聚糖、PEI得到的复合颗粒的平均粒径却达355nm、1173nm。此外,相对于采用壳聚糖、PEI得到的复合颗粒而言,PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的PDI也较低,表明PAMMA比壳聚糖、PEI更适合与单宁酸、PVA、藻蓝蛋白形成尺寸均一、粒径更小的纳米颗粒。
采用双辛可宁酸法(BCA)检测藻蓝蛋白的负载率:(1)取1.5mL荷载藻蓝蛋白的纳米颗粒分散液置于超滤离心管(截留分子量1000Da)中,在2000g离心力下离心20min,再用去离子水重悬至1.5mL;(2)超滤离心前后的分散液采用BCA蛋白定量试剂盒法(碧云天公司,货号P0010)检测藻蓝蛋白含量,藻蓝蛋白负载率按照公式(1)计算,得到的结果如图9所示。
藻蓝蛋白负载率=(C0-C1)/C0×100 (1);
公式(1)中,C0、C1分别代表超滤处理前后分散液中藻蓝蛋白的浓度,单位mg/mL。
如图9所示,虽然单独PAMMA也能负载藻蓝蛋白,但负载率仅为85%。单独PVP对藻蓝蛋白几乎无法吸附藻蓝蛋白,其负载率仅为2.8%,而单宁酸对藻蓝蛋白却具有一定的吸附效果,其负载率为25.5%。当使用PAMMA、单宁酸和PVA的组合时,藻蓝蛋白的负载率高达95%,说明单宁酸能联合PAMMA与藻蓝蛋白形成纳米静电复合物,可能归因于单宁酸与藻蓝蛋白间的疏水相互作用。
PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的储藏稳定性:采用动态光散射法,进一步检测PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒在28天储藏期内的粒径变化,得到的结果如图10所示。PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的平均粒径从141nm增至197n m,稳定性良好。
PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的热稳定性:将PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒置于45℃水浴中,评价加热时间对藻蓝蛋白保留率的影响,得到的结果如图11所示。与藻蓝蛋白相比,荷载在PAMMA-单宁酸-PVA纳米颗粒中的藻蓝蛋白具有更强的热稳定性,加热12h后藻蓝蛋白的保留率仍达80%以上。
实施例2
(1)溶液配制
以去离子水为溶剂,分别配制浓度为1.0mg/mL的藻蓝蛋白溶液、0.5mg/mL的PAMMA溶液、2mg/mL的单宁酸溶液、1mg/mL的PVA溶液,备用;用0.1mol/L的NaOH或0.1mol/L的HCl将上述溶液的pH调整7。
(2)采用自制快速纳米复合仪制备藻蓝蛋白纳米颗粒。该设备由四通道的混合器及四台注射泵组成,注射泵与混合器间通过不锈钢管路连接。
藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液、PVA溶液分别设置于第一、第二、第三、第四通道,混合流速为15mL/min,得到纳米颗粒分散液。
(3)冷冻干燥
在步骤(2)制备的纳米颗粒分散液中加入海藻糖至浓度为7g/mL,冷冻干燥48h。
(4)粉碎
将步骤(3)得到的藻蓝蛋白纳米颗粒粉末粉碎,过40目筛。
(5)检测
藻蓝蛋白纳米颗粒的平均粒度:由动态光散射法检测PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的平均粒径,为170nm。
实施例3
(1)溶液配制
以去离子水为溶剂,分别配制浓度为0.2mg/mL的藻蓝蛋白溶液、0.2mg/mL的PAMMA溶液、2mg/mL的单宁酸溶液、0.5mg/mL的PVA溶液,备用;用0.1mol/L的NaOH或0.1mol/L的HCl将上述溶液的pH调整7。
(2)采用自制快速纳米复合仪制备藻蓝蛋白纳米颗粒。该设备由四通道的混合器及四台注射泵组成,注射泵与混合器间通过不锈钢管路连接。
藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液、PVA溶液分别设置于第一、第二、第三、第四通道,混合流速为5mL/min,得到纳米颗粒分散液。
(3)冷冻干燥
在步骤(2)制备的纳米颗粒分散液中加入海藻糖至浓度为7g/mL,冷冻干燥48h。
(4)粉碎
将步骤(3)得到的藻蓝蛋白纳米颗粒粉末粉碎,过40目筛。
(5)检测
藻蓝蛋白纳米颗粒的平均粒度:由动态光散射法检测PAMMA-单宁酸-PVA@藻蓝蛋白纳米颗粒的平均粒径,为160nm。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于包括如下步骤:
(1)配制溶液:用水分别将藻蓝蛋白、PAMMA、单宁酸、PVA配制成溶液,再将溶液的pH值调节成6.5~7.5,得到藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液和PVA溶液;
(2)高负载藻蓝蛋白的纳米颗粒的制备:将藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液和PVA溶液同时混合,得到含高负载藻蓝蛋白的纳米颗粒的溶液;其中,藻蓝蛋白、PAMMA、单宁酸和PVA按质量比0.2~2:0.2~1:0.5~2:0.1~1配比混合。
2.根据权利要求1所述的高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于还包括如下步骤:
(3)高负载藻蓝蛋白的纳米颗粒粉末的制备:在含高负载藻蓝蛋白的纳米颗粒的溶液中加入保护剂,得到溶液A;将溶液A冷冻干燥,粉碎,得到高负载藻蓝蛋白的纳米颗粒粉末。
3.根据权利要求1或2所述的高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于:
步骤(1)中所述的藻蓝蛋白溶液的浓度为0.2~2mg/mL;
步骤(1)中所述的PAMMA溶液的浓度为0.2~1mg/mL;
步骤(1)中所述的单宁酸溶液的浓度为0.5~2mg/mL;
步骤(1)中所述的PVA溶液的浓度为0.1~1mg/mL。
4.根据权利要求1或2所述的高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于:
步骤(2)中所述的混合的方式为将藻蓝蛋白溶液、PAMMA溶液、单宁酸溶液和PVA溶液分别通过管道输送,同时在混合容器中汇合进行混合。
5.根据权利要求4所述的高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于:
步骤(2)中所述的混合为通过快速纳米复合仪混合;
所述的快速纳米复合仪包括四台泵和混合器;混合器包括顶盖、混合部件和出料口;顶盖上设置四个液体入口,四台泵分别通过聚四氟乙烯管道与顶盖的四个液体入口连接;混合部件位于顶盖下方,包括四个凹槽和两端开口的圆台形结构,四个凹槽的汇合处为圆台形结构;液体入口与凹槽连接;圆台形结构上宽下窄,窄处与出料口连接。
6.根据权利要求5所述的高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于:
所述的泵包括注射泵和蠕动泵;
所述的凹槽为深度×宽度=2mm×2mm的凹槽;
所述的圆台形结构为底面半径为5mm、截面半径为1.6mm、高度为10mm的圆台形结构。
7.根据权利要求5所述的高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于:
所述的输送的流速为5~20mL/min;进一步为10mL/min。
8.根据权利要求2所述的高负载藻蓝蛋白的纳米颗粒的制备方法,其特征在于:
步骤(3)中所述的保护剂为海藻酸钠;
所述的保护剂的用量按在溶液A中的浓度为6~10g/mL计算;进一步为按在溶液A中的浓度为8g/mL计算。
9.一种高负载藻蓝蛋白的纳米颗粒,其特征在于:通过权利要求1~8任一项所述的制备方法得到。
10.权利要求9所述的高负载藻蓝蛋白的纳米颗粒在保健品、功能食品和生物医药领域中的应用。
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