疏水改性多糖及其叶酸偶合体作为纳米药物载体的研究
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摘要
本研究对生物相容性良好的天然多糖进行了疏水改性,以通过自组装的方法制备纳米粒;再将疏水改性多糖与叶酸偶联制备对肿瘤细胞具有靶向作用的载体材料,为肿瘤靶向制剂载体的开发提供实验数据和科学依据。主要研究内容及结果如下:
1.乙酰普鲁兰及其叶酸偶联体作为纳米药物载体的研究
通过乙酰化反应合成了疏水性的乙酰普鲁兰(PA),然后以N,N'-二环己基碳二亚胺(DCC)为偶联剂,4-二甲氨基吡啶(DMAP)为催化剂,将叶酸与PA偶联(FPA);采用傅立叶红外光谱(FT-IR)、氢核磁光谱(1~H NMR)和X射线晶体衍射(XRD)等方法对产物进行了结构表征;溶解性研究表明PA及FPA不溶于水,但可溶于多种有机溶剂。采用溶剂扩散法制备了PA及FPA纳米粒,并考察了各种制备条件对纳米粒形成的影响以确定最佳制备方法,结果表明,纳米粒粒径受到乙酰基取代度、材料浓度、水相中PVA浓度、有机相/水相比值以及有机溶剂的种类等因素影响。以表阿霉素(epirubicin,EPI)为模型药物考察了乙酰基取代度、药物/材料比值及脱盐酸时三乙胺/表阿霉素摩尔比对纳米粒载药的影响;动态光散射粒径分析显示载药纳米粒粒径随载药量增加而增大,透射电镜观察纳米粒载药前后均为球形。采用透析法测定纳米粒中表阿霉素的体外释放,药物释放速度依次为:FPA＞PA1＞PA2＞PA3;不同pH释放介质药物释放速度依次为:pH6.4＞pH7.0＞pH7.4。
采用激光共聚焦显微镜观察游离EPI、PA/EPI纳米粒和FPA/EPI纳米粒温育不同时间KB细胞摄取的情况,结果表明,三种表阿霉素制剂在细胞内的分布有一个动态变化过程,以游离表阿霉素最容易进入细胞核,其次为FPA/EPI纳米粒,最后为PA/EPI纳米粒。流式细胞分析仪检测结果表明,各种表阿霉素制剂进入细胞量在4h内随温育时间的延长而增加,温育1h细胞内荧光强度依次为:游离EPI＞PA/EPI NPs＞FPA/EPI NPs＞FPA/EPI NPs+FA;温育4h细胞内荧光强度依次为:FPA/EPI NPs≥EPI＞PA/EPI NPs＞FPA/EPI NPs+FA;游离叶酸可明显减少FPA纳米粒进入细胞量,提示FPA纳米粒通过叶酸受体途径进入细胞。用MTT法测定了空白PA及FPA纳米粒对KB及L929细胞的毒性,结果表明两种空白纳米粒均无明显的毒性;游离表阿霉素、PA/EPI及FPA/EPI纳米粒对KB细胞的毒性随温育时间的延长而增加,FPA纳米粒表现得尤其明显;FPA/EPI纳米粒在KB细胞的毒性可被过量游离叶酸抑制,提示FPA纳米粒与游离叶酸竞争细胞膜表面叶酸受体。对L929细胞的毒性实验结果表明,在相同的浓度下纳米粒包载表阿霉素的毒性弱于游离表阿霉素。
2.脱氧胆酸修饰壳聚糖及其叶酸偶联体作为纳米药物载体的研究
脱氧胆酸及叶酸结构中的羧基通过与壳聚糖结构中的氨基偶联,生成脱氧胆酸修饰壳聚糖(CS-DA)及其叶酸偶联体(FA-CS-DA)。采用FT-IR、1~H NMR、XRD等方法对该产物结构进行了表征,结果表明叶酸通过化学键偶联于CS-DA。CS-DA1～3中脱氧胆酸的取代度用元素分析法进行测定分别为9.6、7.7及2.8:FA-CS-DA1,2中叶酸的取代度用紫外法分析分别为170μmol/g聚合物及186μmol/g聚合物。采用透析-超声法制备了CS-DA及FA-CS-DA自组装纳米粒,荧光探针法研究其自组装行为,结果显示,CS-DA的临界胶束浓度(CMC)因脱氧胆酸取代度不同而在0.015mg/ml～0.046mg/ml内变化,FA-CS-DA1和FA-CS-DA2的CMC分别为0.028mg/ml和0.049mg/ml;CS-DA纳米粒粒径为115.7nm～196.5nm,FA-CS-DA粒径为200nm～350nm。用超声法将全反式维甲酸(ATRA)包裹于CS-DA和FA-CS-DA纳米粒中,其包载率达12%,粒径随ATRA载药量增加而增加。
用荧光素异硫氰酸酯标记的纳米粒进行了纳米粒的体外摄取研究(KB细胞),并采用荧光分光光度法测定了纳米粒的摄取量,结果显示,在0.5～2h内纳米粒摄取量随温育时间增加而增加,细胞对相同浓度FA-CS-DA纳米粒摄取量高于CS-DA纳米粒,且KB细胞对FA-CS-DA纳米粒的摄取可被过量游离叶酸所抑制,提示叶酸受体参与了FA-CS-DA与KB细胞的结合和/或摄取。
总之,疏水改性多糖及其叶酸偶联体可通过自组装的方法制备纳米粒,制备方法简单可行,该纳米粒可作为药物载体包载双亲性或疏水性药物,从而延缓药物的释放和增加药物的稳定性。叶酸偶联多糖纳米粒在叶酸高表达KB细胞主要通过叶酸受体途径进入细胞,对肿瘤细胞表现一定靶向作用,有望成为一种新型肿瘤靶向药物载体。
In present study,natural polysaccharides were hydrophobized and conjugated with folic acid to provide tumor targeted drug delivery carriers.The paper includes two parts as following:
1.Study of pullulan acetate and its folate conjugate as nano-drug delivery carriers
Pullulan acetate(PA),as hydrophobized pullulan,was synthesized by the reaction of pullulan with acetic anhydride.Then folate was coupled to PA(FPA) by N,N'-Dicyclohexylcarbodiimide(DCC) and 4-Dimethylamino-pyridine(DMAP) mediated ester formation.The products were characterized by FT-IR,~1H NMR spectroscopy and X-ray diffraction(XRD).PA and FPA were insoluble in water, whereas completely soluble in common organic solvents.The solvent diffusion method was used to prepare PA and FPA nanoparticles and investigated various factors to determine the optimization method.The diameters of nanoparticles were affected by degree substitution of acetate,concentration of materials solution,PVA concentration in aqueous phase,organic solvent phase/ aqueous phase ratio and kind of organic solvent. The optimization method was explored.Epirubicin(EPI) was loaded into the nanoparticles as a model drug and investigated various affect factors.The results revealed that drug loading efficiencies of PA nanoparticles increased as the degree of acetate substitution,drug/materials ratio and ethylamine/epirubicin molar ratio.The TEM indicated that PA and FPA nanoparticles could form spherical nanoparticles.The size of nanoparticles was increased with the EPI-loading content increasing.The release behavior of EPI from PA or FPA nanoparticles was studied in vitro by dialysis method and the results showed that total EPI release rate was controlled by the degree substitution of acetate(FPA＞PA1＞PA2＞PA3) and pH value of release medium (pH6.4＞pH7.0＞pH7.4).
The analysis of intracellular distribution of EPI was carried out in KB cells. Examination was done with inverted confocal laser scanning microscope.The results revealed that free EPI,PA/EPI and FPA/EPI nanoparticles gained access to the cell,but the route and the kinetics of uptake were difference apparently.Experiments tracking EPI fluorescence indicated that free EPI was rapidly internalized and localized in the nucleus,followed by the FPA/EPI nanoparticles and the last for PA/EPI nanoparticles. Cellular uptake extents of PA/EPI and FPA/EPI nanoparticles were evaluated using flow cytometry.Delivery of EPI by various EPI formulations to KB cells increased continuously with time of exposure.After lh incubation,fluorescence intensity in cells was:free EPI＞PA/EPI NPs＞FPA/EPI NPs＞FPA/EPI NPs + FA.By 4 h,the order of fluorescence intensity was:FPA/EPI NPs≥EPI＞PA/EPI NPs＞FPA/EPI NPs+FA.In addition,for FPA/EPI nanoparticles,more fluorescently labeled cells can be clearly visualized in the absence of folate in the medium than presence of 1mM folate, suggesting FPA/EPI nanoparticles were endocytosed in a folate receptor-mediated manner.
The blank PA and FPA nanoparticles showed no significant cytotoxicity in KB and L929 cells by MTT assay.Cytotoxicity of free EPI,EPI-loaded PA and FPA nanoparticles increased with the time of incubation,especially FPA/EPI nanoparticles. The cytotoxicity of FPA/EPI NPs against KB cells was inhibited by excess free folate, which suggested that free folate molecules prevented the cellular uptake of FPA nanoparticles by competitive binding to the folate receptors on the cell surface.The free EPI exhibited a higher cytotoxicity than the EPI loaded PA and FPA nanoparticles against L929 cells for the same concentration of EPI.
2.Study of deoxycholic acid-bearing chitosan and its folate conjugate as nano-drug delivery carriers
Folate(FA) modified deoxycholic acid-beating chitosan(FA-CS-DA) was synthesized by the reaction of conjugate carboxyl groups of FA and DA to the amino groups of chitosan.The structures were characterized by FTIR,~1H NMR and XRD.The degree of deoxycholic acid(DA) group substitution(DS) was determined by elemental analysis was 9.6,7.7 and 2.8,respectively.An extent of folate conjugation with deoxycholic acid-beating chitosan(FA-CS-DA1,2) measured by spectrophotometric was 170μmol/g polymer and 186μmol/g polymer,respectively.CS-DA and FA-CS-DA self-aggregated nanoparticles were prepared by dialysis method in physiological saline.The critical micelle concentration(CMC) of CS-DA conjugates depended on the DS of deoxycholic acid over a range of 0.015mg/ml～0.046 mg/ml,and that FA-CS-DA1 and FA-CS-DA2 conjugates were 0.028mg/ml and 0.049mg/ml,respectively.The mean diameters of CS-DA self-assembled nanoparticles were 115.7nm～196.5nm,and the mean diameters of FA-CS-DA were about 200 nm～300nm.All trans-retinoic acid(ATRA) efficiently loaded into CS-DA and FA-CS-DA nanoparticles up to 12 wt%using ultrasonication method.The size of diameter increased with the increasing of EPMoaded content.
Cell uptake studies were carried out in KB cells using fluorescein isothiocyanate labeled nanoparticles.The nanoparticles were taken up to the cells were increased with the time of incubation for 0.5～2h.The levels of FA-CS-DA nanoparticles were higher than those of CS-DA nanoparticles.The association of FA-CS-DA nanoparticles to KB cells was inhibited by an excess amount of folic acid,suggesting that the binding and/or uptake were mediated by the folate receptors.
In conclusion,these hydrophobized polysaccharides and their folate conjugates could form nanoparticles by self-aggregate manner.The methods of preparing nanoparticles were simple and feasible.The self-aggregate nanoparticles could be used as drug delivery carriers of both amphipathic and hydrophobic drugs,which could control release of drugs and protect them.The folate conjugate nanoparticles were taken up by KB cells mainly mediated by folic acid receptor,which indicated that folate conjugated nanoparticles offer considerable potential for employment as cancer-targeted carriers for the efficient delivery of anticancer drugs.
1.乙酰普鲁兰及其叶酸偶联体作为纳米药物载体的研究
通过乙酰化反应合成了疏水性的乙酰普鲁兰(PA),然后以N,N'-二环己基碳二亚胺(DCC)为偶联剂,4-二甲氨基吡啶(DMAP)为催化剂,将叶酸与PA偶联(FPA);采用傅立叶红外光谱(FT-IR)、氢核磁光谱(1~H NMR)和X射线晶体衍射(XRD)等方法对产物进行了结构表征;溶解性研究表明PA及FPA不溶于水,但可溶于多种有机溶剂。采用溶剂扩散法制备了PA及FPA纳米粒,并考察了各种制备条件对纳米粒形成的影响以确定最佳制备方法,结果表明,纳米粒粒径受到乙酰基取代度、材料浓度、水相中PVA浓度、有机相/水相比值以及有机溶剂的种类等因素影响。以表阿霉素(epirubicin,EPI)为模型药物考察了乙酰基取代度、药物/材料比值及脱盐酸时三乙胺/表阿霉素摩尔比对纳米粒载药的影响;动态光散射粒径分析显示载药纳米粒粒径随载药量增加而增大,透射电镜观察纳米粒载药前后均为球形。采用透析法测定纳米粒中表阿霉素的体外释放,药物释放速度依次为:FPA＞PA1＞PA2＞PA3;不同pH释放介质药物释放速度依次为:pH6.4＞pH7.0＞pH7.4。
采用激光共聚焦显微镜观察游离EPI、PA/EPI纳米粒和FPA/EPI纳米粒温育不同时间KB细胞摄取的情况,结果表明,三种表阿霉素制剂在细胞内的分布有一个动态变化过程,以游离表阿霉素最容易进入细胞核,其次为FPA/EPI纳米粒,最后为PA/EPI纳米粒。流式细胞分析仪检测结果表明,各种表阿霉素制剂进入细胞量在4h内随温育时间的延长而增加,温育1h细胞内荧光强度依次为:游离EPI＞PA/EPI NPs＞FPA/EPI NPs＞FPA/EPI NPs+FA;温育4h细胞内荧光强度依次为:FPA/EPI NPs≥EPI＞PA/EPI NPs＞FPA/EPI NPs+FA;游离叶酸可明显减少FPA纳米粒进入细胞量,提示FPA纳米粒通过叶酸受体途径进入细胞。用MTT法测定了空白PA及FPA纳米粒对KB及L929细胞的毒性,结果表明两种空白纳米粒均无明显的毒性;游离表阿霉素、PA/EPI及FPA/EPI纳米粒对KB细胞的毒性随温育时间的延长而增加,FPA纳米粒表现得尤其明显;FPA/EPI纳米粒在KB细胞的毒性可被过量游离叶酸抑制,提示FPA纳米粒与游离叶酸竞争细胞膜表面叶酸受体。对L929细胞的毒性实验结果表明,在相同的浓度下纳米粒包载表阿霉素的毒性弱于游离表阿霉素。
2.脱氧胆酸修饰壳聚糖及其叶酸偶联体作为纳米药物载体的研究
脱氧胆酸及叶酸结构中的羧基通过与壳聚糖结构中的氨基偶联,生成脱氧胆酸修饰壳聚糖(CS-DA)及其叶酸偶联体(FA-CS-DA)。采用FT-IR、1~H NMR、XRD等方法对该产物结构进行了表征,结果表明叶酸通过化学键偶联于CS-DA。CS-DA1～3中脱氧胆酸的取代度用元素分析法进行测定分别为9.6、7.7及2.8:FA-CS-DA1,2中叶酸的取代度用紫外法分析分别为170μmol/g聚合物及186μmol/g聚合物。采用透析-超声法制备了CS-DA及FA-CS-DA自组装纳米粒,荧光探针法研究其自组装行为,结果显示,CS-DA的临界胶束浓度(CMC)因脱氧胆酸取代度不同而在0.015mg/ml～0.046mg/ml内变化,FA-CS-DA1和FA-CS-DA2的CMC分别为0.028mg/ml和0.049mg/ml;CS-DA纳米粒粒径为115.7nm～196.5nm,FA-CS-DA粒径为200nm～350nm。用超声法将全反式维甲酸(ATRA)包裹于CS-DA和FA-CS-DA纳米粒中,其包载率达12%,粒径随ATRA载药量增加而增加。
用荧光素异硫氰酸酯标记的纳米粒进行了纳米粒的体外摄取研究(KB细胞),并采用荧光分光光度法测定了纳米粒的摄取量,结果显示,在0.5～2h内纳米粒摄取量随温育时间增加而增加,细胞对相同浓度FA-CS-DA纳米粒摄取量高于CS-DA纳米粒,且KB细胞对FA-CS-DA纳米粒的摄取可被过量游离叶酸所抑制,提示叶酸受体参与了FA-CS-DA与KB细胞的结合和/或摄取。
总之,疏水改性多糖及其叶酸偶联体可通过自组装的方法制备纳米粒,制备方法简单可行,该纳米粒可作为药物载体包载双亲性或疏水性药物,从而延缓药物的释放和增加药物的稳定性。叶酸偶联多糖纳米粒在叶酸高表达KB细胞主要通过叶酸受体途径进入细胞,对肿瘤细胞表现一定靶向作用,有望成为一种新型肿瘤靶向药物载体。
In present study,natural polysaccharides were hydrophobized and conjugated with folic acid to provide tumor targeted drug delivery carriers.The paper includes two parts as following:
1.Study of pullulan acetate and its folate conjugate as nano-drug delivery carriers
Pullulan acetate(PA),as hydrophobized pullulan,was synthesized by the reaction of pullulan with acetic anhydride.Then folate was coupled to PA(FPA) by N,N'-Dicyclohexylcarbodiimide(DCC) and 4-Dimethylamino-pyridine(DMAP) mediated ester formation.The products were characterized by FT-IR,~1H NMR spectroscopy and X-ray diffraction(XRD).PA and FPA were insoluble in water, whereas completely soluble in common organic solvents.The solvent diffusion method was used to prepare PA and FPA nanoparticles and investigated various factors to determine the optimization method.The diameters of nanoparticles were affected by degree substitution of acetate,concentration of materials solution,PVA concentration in aqueous phase,organic solvent phase/ aqueous phase ratio and kind of organic solvent. The optimization method was explored.Epirubicin(EPI) was loaded into the nanoparticles as a model drug and investigated various affect factors.The results revealed that drug loading efficiencies of PA nanoparticles increased as the degree of acetate substitution,drug/materials ratio and ethylamine/epirubicin molar ratio.The TEM indicated that PA and FPA nanoparticles could form spherical nanoparticles.The size of nanoparticles was increased with the EPI-loading content increasing.The release behavior of EPI from PA or FPA nanoparticles was studied in vitro by dialysis method and the results showed that total EPI release rate was controlled by the degree substitution of acetate(FPA＞PA1＞PA2＞PA3) and pH value of release medium (pH6.4＞pH7.0＞pH7.4).
The analysis of intracellular distribution of EPI was carried out in KB cells. Examination was done with inverted confocal laser scanning microscope.The results revealed that free EPI,PA/EPI and FPA/EPI nanoparticles gained access to the cell,but the route and the kinetics of uptake were difference apparently.Experiments tracking EPI fluorescence indicated that free EPI was rapidly internalized and localized in the nucleus,followed by the FPA/EPI nanoparticles and the last for PA/EPI nanoparticles. Cellular uptake extents of PA/EPI and FPA/EPI nanoparticles were evaluated using flow cytometry.Delivery of EPI by various EPI formulations to KB cells increased continuously with time of exposure.After lh incubation,fluorescence intensity in cells was:free EPI＞PA/EPI NPs＞FPA/EPI NPs＞FPA/EPI NPs + FA.By 4 h,the order of fluorescence intensity was:FPA/EPI NPs≥EPI＞PA/EPI NPs＞FPA/EPI NPs+FA.In addition,for FPA/EPI nanoparticles,more fluorescently labeled cells can be clearly visualized in the absence of folate in the medium than presence of 1mM folate, suggesting FPA/EPI nanoparticles were endocytosed in a folate receptor-mediated manner.
The blank PA and FPA nanoparticles showed no significant cytotoxicity in KB and L929 cells by MTT assay.Cytotoxicity of free EPI,EPI-loaded PA and FPA nanoparticles increased with the time of incubation,especially FPA/EPI nanoparticles. The cytotoxicity of FPA/EPI NPs against KB cells was inhibited by excess free folate, which suggested that free folate molecules prevented the cellular uptake of FPA nanoparticles by competitive binding to the folate receptors on the cell surface.The free EPI exhibited a higher cytotoxicity than the EPI loaded PA and FPA nanoparticles against L929 cells for the same concentration of EPI.
2.Study of deoxycholic acid-bearing chitosan and its folate conjugate as nano-drug delivery carriers
Folate(FA) modified deoxycholic acid-beating chitosan(FA-CS-DA) was synthesized by the reaction of conjugate carboxyl groups of FA and DA to the amino groups of chitosan.The structures were characterized by FTIR,~1H NMR and XRD.The degree of deoxycholic acid(DA) group substitution(DS) was determined by elemental analysis was 9.6,7.7 and 2.8,respectively.An extent of folate conjugation with deoxycholic acid-beating chitosan(FA-CS-DA1,2) measured by spectrophotometric was 170μmol/g polymer and 186μmol/g polymer,respectively.CS-DA and FA-CS-DA self-aggregated nanoparticles were prepared by dialysis method in physiological saline.The critical micelle concentration(CMC) of CS-DA conjugates depended on the DS of deoxycholic acid over a range of 0.015mg/ml～0.046 mg/ml,and that FA-CS-DA1 and FA-CS-DA2 conjugates were 0.028mg/ml and 0.049mg/ml,respectively.The mean diameters of CS-DA self-assembled nanoparticles were 115.7nm～196.5nm,and the mean diameters of FA-CS-DA were about 200 nm～300nm.All trans-retinoic acid(ATRA) efficiently loaded into CS-DA and FA-CS-DA nanoparticles up to 12 wt%using ultrasonication method.The size of diameter increased with the increasing of EPMoaded content.
Cell uptake studies were carried out in KB cells using fluorescein isothiocyanate labeled nanoparticles.The nanoparticles were taken up to the cells were increased with the time of incubation for 0.5～2h.The levels of FA-CS-DA nanoparticles were higher than those of CS-DA nanoparticles.The association of FA-CS-DA nanoparticles to KB cells was inhibited by an excess amount of folic acid,suggesting that the binding and/or uptake were mediated by the folate receptors.
In conclusion,these hydrophobized polysaccharides and their folate conjugates could form nanoparticles by self-aggregate manner.The methods of preparing nanoparticles were simple and feasible.The self-aggregate nanoparticles could be used as drug delivery carriers of both amphipathic and hydrophobic drugs,which could control release of drugs and protect them.The folate conjugate nanoparticles were taken up by KB cells mainly mediated by folic acid receptor,which indicated that folate conjugated nanoparticles offer considerable potential for employment as cancer-targeted carriers for the efficient delivery of anticancer drugs.
引文
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