油酰海藻酸纳米粒口服运送载体的制备与性质研究
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摘要
纳米载体系统能够改善营养物质的溶解性、稳定性、生物利用度等性质。海藻酸钠具有良好的生物可降解性和生物相容性，在食品医药领域都得到了广泛应用。本论文首先制备得到了油酰海藻酸，并且分别用超声辅助分子自组装法和乳化法构建了油酰海藻酸纳米粒，在纳米粒中分别包埋了维生素D_3和维生素E，并研究了包埋效率和缓释效果。最后以Caco-2细胞模型和外翻肠模型，考察了生物相容性、吸收和跨膜转运作用。
首先，在无有机溶剂的条件下，将油酰基团接枝到海藻酸分子上，制备得到油酰海藻酸（OAE），利用红外光谱和核磁共振的方法检测酯化产物的形成。然后用响应面分析的方法对合成过程进行了优化，经优化得到的最佳试验参数为：4.95ml甲酸，11.27ml油酰氯，反应时间20min，反应温度50℃。此时取代度为5%，产率93.99%。经实验验证，在以上最优条件下，所得产品的取代度为4.93%，产率92.27%，与软件优化结果基本相符。
通过超声辅助分子自组装法制备得到OAE纳米粒，利用荧光光谱技术、透射电子显微镜、动态激光散射粒度仪对纳米粒的理化性质进行了测定，并且研究了OAE纳米粒在模拟胃肠液中的稳定性。结果表明得到了球形规则、形态完整、粒径较小的纳米粒。随着OAE取代度增加，OAE纳米粒的粒径由559.3±9.5nm降到305.3±6.3nm，临界聚集浓度（CAC）由0.38mg/ml降到0.25mg/ml。与蒸馏水中相比，OAE纳米粒在模拟胃液中仍然保持完整球形结构，在模拟肠液中的形状变得不规则。OAE纳米粒在模拟胃液中的粒径变小，模拟肠液中的粒径变大。OAE纳米粒在模拟胃液中，具有较高的热力学稳定性，在模拟肠液中具有较低的热力学稳定性。
以VD_3为模式营养物，利用超声辅助分子自组装法将其包埋到纳米粒中。随着加入VD_3量的增多，OAE纳米粒的包封率从67.6±2.76%降低到45.8±1.55%，负载率从0.33±0.02升高至0.91±0.03%。并且研究了在模拟胃肠液中的缓释，结果表明纳米粒具有缓释作用。
以VE为模式营养物，分别利用超声法和乳化法制备得到了载VE的OAE纳米粒，两者都能制备得到纳米粒，但纳米乳剂具有比较高的载VE的能力。
通过离心的方法将纳米粒进行分级分离，些过程受到纳米粒Zeta电位、离心速度的影响，zeta电位的绝对值越小，离心速度越快，纳米粒的沉降越快。本章还通过差速离心的方法将一组纳米粒按照大小分成了四组组米粒。随着离心速度升高，粒径从707.2±32.3nm降到78.2±19.9nm，负载率从12.35±1.92%降低至4.94±0.46%，它们的PDI值均小于0.47±0.03。
通过离心的方法成功分离出四组粒径大小不同的纳米粒，它们具有相似的zeta电位，粒径大的纳米粒具有较高的载VE的能力。并且研究了粒径对VE的稳定性、纳米粒的分散稳定性的影响。随着粒径降低，VE的稳定性升高，纳米粒的分散稳定性提高。
利用MTT法检测了OAE纳米粒的粒径对细胞毒性的影响，结果表明四组纳米粒对细胞均无毒。Transwell的跨膜转运实验表明，OAE纳米粒能够提高VE的透过性。随着粒米粒的粒径从80nm升高到700nm，表观渗透系数从2.72±0.66×10~(-4)降到0.94±0.43×10~(-4)cm/s。
利用wistar大鼠肠环外翻法研究了OAE纳米粒的细胞吸收和胞吞机制。4℃的吸收远低于37℃，此结果表明纳米粒主要通过主动运输吸收。NP80和NP130主要通过网格蛋白介导的内吞作用吸收，NP370主要通过小凹蛋白介导的内吞作用吸收，NP700主要通过巨胞饮作用进入细胞。
Nanoparticle systems can improve the properties of nutritions, such as solubility,stability and bioavailability. Sodium alginate with good biodegradability andbiocompatibility has been widely applied in food and medicine areas. In this paper,the oleoyl alginate ester (OAE) was synthesized at first. OAE nanoparticles wereprepared through self-aggregate and emulsification method separately. The vitamin D_3and vitamin E were loaded into nanoparticles separately. The loading efficiency andrelease properties were also evaluated. Finally, the biocompatibility, uptake andtransport properties were evaluated using human Caco-2model and everted intestinalring model.
First of all, oleoyl group was grafted to alginate without any organic solvents.Formation of an ester linkage between alginate and oleoyl was confirmed by FT-IRand1H NMR spectra. Response surface methodology (RSM) was employed tooptimize the process. The optimum synthesis conditions of OAE were found to bealginate amount of0.5g, formic acid amount of4.95mL, oleoyl chloride amount of11.27mL, reaction temperature of50℃and reaction time of20min. Under theseconditions, the maximum degree of substitution (DS) and yield of OAE wereobserved to be4.93%and92.27%respectively, which were in accordance with thecorresponding predicted values.
The physicochemical properties of the OAE nanoparticals were investigatedusing fluorescence spectroscopy, dynamic light scattering (DLS) and transmissionelectron microscopy. Stability of Nanoparticles in SGF and SIF was also evaluated.The results indicated the prepared nanoparticles had spherical shape and goodstructural integrity with small size. As the DS of OAE increased, the size of OAEnanopartiles decreased from559.3±9.5nm to305.3±6.3nm, whereas the CACdecreased from0.38mg/ml to0.25mg/ml. Compared to the nanoparticles in distilledwater, nanoparticles in SGF still had spherical shape and good structural integrity, whereas nanoparticles in SGF were in big irregular shape. The size decreased in SGFwhile increased in SIF. The CAC values of nanoparticles indicating higherthermodynamic stability but lower thermodynamic stability
VD_3was chosen as a model nutrient and entrapped into the OAE nanoparticlesthrough self-aggreagation. As the concentration of vitamin D_3increased, the loadingefficiency decreased from67.6±2.76to45.8±1.55%, whereas the loading capacityincreased from0.33±0.02to0.91±0.03%. In vitro vitaminD_3release studyindicated controlled release in gastrointestinal fluid.
VE was chosen as a model nutrient and entrapped into the OAE nanoparticlesthrough emulsification method. Both methods were able to prepare nanoparticles, butemulsion had greater ability to encapsulate VE.
The size separation by centrifugation was affected by zeta potential and speed ofcentrifugation.The smaller the absolute value of zeta potentioal and the faster thecentrifugation speed was, the higher the sedimentation velocity of nanoparticles.Fourbatches of nanoparticles were also separated by differential centrifugation from theinitial batch of nanoparticles. The size of nanoparticles decreased from707.2±32.3nm to78.2±19.9nm with increasing speed of centrifugation. The loading capacitydecreased from12.35±1.92%to4.94±0.46%. The PDI of four batches ofnanoparticles was below0.47±0.03.
Four batches of nanoparticles with similar zeta potential were separated from theinitial batch of nanoparticles by means of centrifugation. The bigger nanoparticles hadhigher ability to encapsulated VE. In vitro release, stability of vitamin E innanoparticles and the dispersion stability of nanoparticles was also evalutated. As theparticle size decreased, the in vitro release slowed, stability of vitamin E increased,dispersion stability of nanoparticles enhanced.
The cytotoxicity of OAE nanoparticles with different sizes was analyzed by theMTT assay, which indicated limited damage to the epithelial cells. All of thenanoparticles demonstrated a higher Papp values for vitamin E-loaded nanoparticlesthan for the free vitamin E solution. As the particle sizes increased from80nm to700nm, the Papp values decreased from (2.72±0.66)×10~(-4)to (0.94±0.43)×10~(-4)cm/s.
The uptake and machanism of OAE nanoparticles was analyzed by the evertedrings of wistar rats. The uptake at4℃was very low compared to37℃. Endocytosisof NP80and NP130occurs mainly via clathrin-mediated endocytosis. NP370wasinternalized by caveolae-mediated endocytosis. NP700was internalized bymacropinocytosis.
首先，在无有机溶剂的条件下，将油酰基团接枝到海藻酸分子上，制备得到油酰海藻酸（OAE），利用红外光谱和核磁共振的方法检测酯化产物的形成。然后用响应面分析的方法对合成过程进行了优化，经优化得到的最佳试验参数为：4.95ml甲酸，11.27ml油酰氯，反应时间20min，反应温度50℃。此时取代度为5%，产率93.99%。经实验验证，在以上最优条件下，所得产品的取代度为4.93%，产率92.27%，与软件优化结果基本相符。
通过超声辅助分子自组装法制备得到OAE纳米粒，利用荧光光谱技术、透射电子显微镜、动态激光散射粒度仪对纳米粒的理化性质进行了测定，并且研究了OAE纳米粒在模拟胃肠液中的稳定性。结果表明得到了球形规则、形态完整、粒径较小的纳米粒。随着OAE取代度增加，OAE纳米粒的粒径由559.3±9.5nm降到305.3±6.3nm，临界聚集浓度（CAC）由0.38mg/ml降到0.25mg/ml。与蒸馏水中相比，OAE纳米粒在模拟胃液中仍然保持完整球形结构，在模拟肠液中的形状变得不规则。OAE纳米粒在模拟胃液中的粒径变小，模拟肠液中的粒径变大。OAE纳米粒在模拟胃液中，具有较高的热力学稳定性，在模拟肠液中具有较低的热力学稳定性。
以VD_3为模式营养物，利用超声辅助分子自组装法将其包埋到纳米粒中。随着加入VD_3量的增多，OAE纳米粒的包封率从67.6±2.76%降低到45.8±1.55%，负载率从0.33±0.02升高至0.91±0.03%。并且研究了在模拟胃肠液中的缓释，结果表明纳米粒具有缓释作用。
以VE为模式营养物，分别利用超声法和乳化法制备得到了载VE的OAE纳米粒，两者都能制备得到纳米粒，但纳米乳剂具有比较高的载VE的能力。
通过离心的方法将纳米粒进行分级分离，些过程受到纳米粒Zeta电位、离心速度的影响，zeta电位的绝对值越小，离心速度越快，纳米粒的沉降越快。本章还通过差速离心的方法将一组纳米粒按照大小分成了四组组米粒。随着离心速度升高，粒径从707.2±32.3nm降到78.2±19.9nm，负载率从12.35±1.92%降低至4.94±0.46%，它们的PDI值均小于0.47±0.03。
通过离心的方法成功分离出四组粒径大小不同的纳米粒，它们具有相似的zeta电位，粒径大的纳米粒具有较高的载VE的能力。并且研究了粒径对VE的稳定性、纳米粒的分散稳定性的影响。随着粒径降低，VE的稳定性升高，纳米粒的分散稳定性提高。
利用MTT法检测了OAE纳米粒的粒径对细胞毒性的影响，结果表明四组纳米粒对细胞均无毒。Transwell的跨膜转运实验表明，OAE纳米粒能够提高VE的透过性。随着粒米粒的粒径从80nm升高到700nm，表观渗透系数从2.72±0.66×10~(-4)降到0.94±0.43×10~(-4)cm/s。
利用wistar大鼠肠环外翻法研究了OAE纳米粒的细胞吸收和胞吞机制。4℃的吸收远低于37℃，此结果表明纳米粒主要通过主动运输吸收。NP80和NP130主要通过网格蛋白介导的内吞作用吸收，NP370主要通过小凹蛋白介导的内吞作用吸收，NP700主要通过巨胞饮作用进入细胞。
Nanoparticle systems can improve the properties of nutritions, such as solubility,stability and bioavailability. Sodium alginate with good biodegradability andbiocompatibility has been widely applied in food and medicine areas. In this paper,the oleoyl alginate ester (OAE) was synthesized at first. OAE nanoparticles wereprepared through self-aggregate and emulsification method separately. The vitamin D_3and vitamin E were loaded into nanoparticles separately. The loading efficiency andrelease properties were also evaluated. Finally, the biocompatibility, uptake andtransport properties were evaluated using human Caco-2model and everted intestinalring model.
First of all, oleoyl group was grafted to alginate without any organic solvents.Formation of an ester linkage between alginate and oleoyl was confirmed by FT-IRand1H NMR spectra. Response surface methodology (RSM) was employed tooptimize the process. The optimum synthesis conditions of OAE were found to bealginate amount of0.5g, formic acid amount of4.95mL, oleoyl chloride amount of11.27mL, reaction temperature of50℃and reaction time of20min. Under theseconditions, the maximum degree of substitution (DS) and yield of OAE wereobserved to be4.93%and92.27%respectively, which were in accordance with thecorresponding predicted values.
The physicochemical properties of the OAE nanoparticals were investigatedusing fluorescence spectroscopy, dynamic light scattering (DLS) and transmissionelectron microscopy. Stability of Nanoparticles in SGF and SIF was also evaluated.The results indicated the prepared nanoparticles had spherical shape and goodstructural integrity with small size. As the DS of OAE increased, the size of OAEnanopartiles decreased from559.3±9.5nm to305.3±6.3nm, whereas the CACdecreased from0.38mg/ml to0.25mg/ml. Compared to the nanoparticles in distilledwater, nanoparticles in SGF still had spherical shape and good structural integrity, whereas nanoparticles in SGF were in big irregular shape. The size decreased in SGFwhile increased in SIF. The CAC values of nanoparticles indicating higherthermodynamic stability but lower thermodynamic stability
VD_3was chosen as a model nutrient and entrapped into the OAE nanoparticlesthrough self-aggreagation. As the concentration of vitamin D_3increased, the loadingefficiency decreased from67.6±2.76to45.8±1.55%, whereas the loading capacityincreased from0.33±0.02to0.91±0.03%. In vitro vitaminD_3release studyindicated controlled release in gastrointestinal fluid.
VE was chosen as a model nutrient and entrapped into the OAE nanoparticlesthrough emulsification method. Both methods were able to prepare nanoparticles, butemulsion had greater ability to encapsulate VE.
The size separation by centrifugation was affected by zeta potential and speed ofcentrifugation.The smaller the absolute value of zeta potentioal and the faster thecentrifugation speed was, the higher the sedimentation velocity of nanoparticles.Fourbatches of nanoparticles were also separated by differential centrifugation from theinitial batch of nanoparticles. The size of nanoparticles decreased from707.2±32.3nm to78.2±19.9nm with increasing speed of centrifugation. The loading capacitydecreased from12.35±1.92%to4.94±0.46%. The PDI of four batches ofnanoparticles was below0.47±0.03.
Four batches of nanoparticles with similar zeta potential were separated from theinitial batch of nanoparticles by means of centrifugation. The bigger nanoparticles hadhigher ability to encapsulated VE. In vitro release, stability of vitamin E innanoparticles and the dispersion stability of nanoparticles was also evalutated. As theparticle size decreased, the in vitro release slowed, stability of vitamin E increased,dispersion stability of nanoparticles enhanced.
The cytotoxicity of OAE nanoparticles with different sizes was analyzed by theMTT assay, which indicated limited damage to the epithelial cells. All of thenanoparticles demonstrated a higher Papp values for vitamin E-loaded nanoparticlesthan for the free vitamin E solution. As the particle sizes increased from80nm to700nm, the Papp values decreased from (2.72±0.66)×10~(-4)to (0.94±0.43)×10~(-4)cm/s.
The uptake and machanism of OAE nanoparticles was analyzed by the evertedrings of wistar rats. The uptake at4℃was very low compared to37℃. Endocytosisof NP80and NP130occurs mainly via clathrin-mediated endocytosis. NP370wasinternalized by caveolae-mediated endocytosis. NP700was internalized bymacropinocytosis.
引文
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