功能性巯基化聚合物胶束口服药物传递系统的构建与评价
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摘要
目前,肿瘤的主要治疗手段为化学疗法。化疗药物由于溶解度低、膜透性差、体内分布选择性不好,易降解等问题,使得临床使用的大部分化疗制剂为注射剂型。但是注射给药刺激性大,患者顺应性差,因此开发口服化疗药物传递系统对肿瘤的治疗具有重要意义。
本文设计并构建了功能性巯基化聚合物胶束,其具有增溶化疗药物、抑制P-gp、生物粘附及促进渗透等多功能性,能显著提高化疗药物的口服吸收。本文以紫杉醇(PTX)为模型药物,以自合成的功能性两亲性共聚物为载体材料,制备紫杉醇纳米胶束。在对功能性聚合物进行合成、结构确证及性质研究的基础上,对紫杉醇纳米胶束及相应制剂学性质、生物粘附性质、小肠吸收情况、吸收机制及体内药动学进行了考察,同时对紫杉醇纳米胶束的细胞水平转运机制进行了研究。
以维生素E琥珀酸酯(VES)为疏水内核,以壳聚糖(CS)为亲水主链,以N-乙酰半胱氨酸(NAC)为表面修饰基团,合成了不同巯基取代度的两亲性巯基化共聚物CS-VES-NAC-1,-2,-3和未巯基化两亲性共聚物CS-VES。采用IR、1H-NMR、TGA、EDS等手段对共聚物进行了结构确证。使用Ellman's试剂法测定了CS-VES-NAC系列共聚物的游离巯基含量分别为182.6、275.5、451.5μmol/g,溶胀性性良好。稳定性试验结果表明CS-VES-NAC共聚物中游离巯基在不同温度(4℃、室温及37℃)和不同pH环境中(pH1.2HCl溶液、pH5.4PBS溶液及pH6.8PBS溶液)均具有较好的稳定性,可用于载药胶束的制备。
以巯基聚合物CS-VES-NAC为载体,采用探头超声法制备纳米胶束。随着巯基取代度的增加,CS-VES-NAC-1,-2,-3空白纳米胶束粒径逐渐降低,分别为240.0、228.2、192.2nm, Zeta电位也逐渐降低,分别为+59.4、+58.4、+51.9mv。以紫杉醇为模型药物制备载药胶束,考察不同载药量对粒径、Zeta电位的影响。载药胶束粒径范围为180nm～250nm,包封率约为60%-80%,zeta电位均在+40mv以上。同时,巯基取代度对胶束的粒径及zeta电位也有影响,随着巯基取代度的增加,粒径及zeta电位均有下降趋势。透射电镜图显示载药胶束呈球形,外观圆整,粒径分布均匀,有清晰的核-壳结构,平均粒径约为200nm,与动态光散射的测定结果基本一致。DSC、X-射线结果表明紫杉醇以无定型状态存在于胶束内核中。体外释放研究表明载药胶束缓释作用明显,可保证在生理状态下紫杉醇在胶束内核中稳定存在,避免药物提前泄漏。
以Ⅲ型粘蛋白为肠黏膜的体外模型,对纳米胶束的生物粘附能力进行考察。结果表明,CS-VES-NAC聚合物胶束能以二硫键共价结合的方式与粘蛋白进行相互作用,明显提高粘附性。采用原位单向在体肠灌流试验考察了胶束制剂的在体肠吸收情况。结果表明,胶束制剂的吸收速率常数Ka要高于紫杉醇溶液剂,其中吸收最好的是CS-VES-NAC-1胶束,在十二指肠段的吸收速率(Ka)是溶液剂的4.51倍。同时,在十二指肠、空肠、回肠段,CS-VES-NAC系列胶束组的表观渗透系数(Papp)也均高于溶液剂(p<0.05)。CS-VES-NAC-1胶束在十二指肠段的Papp值是溶液剂的4.64倍。肠段摄取机制结果表明,网格蛋白途径、小窝蛋白途径、巨胞饮及非网格蛋白非小窝蛋白途径均参与对纳米粒的摄取。激光共聚焦显微镜结果表明,巯基化胶束经口服给药后,小肠膜渗透性比游离药物组、CS-VES组均有提高,小肠中吸收最好部位是十二指肠段。
采用UPLC-MS/MS方法研究了PTX溶液剂及各胶束制剂的体内药动学。各组制剂以十二指肠给药的方式进行,同时以PTX溶液剂静脉注射为对照计算绝对生物利用度。结果表明,PTX溶液剂,CS-VES胶束及CS-VES-NAC-1,-2,-3胶束的绝对生物利用度分别为3.21%、3.39%、13.65%、13.33%、7.68%；CS-VES胶束及CS-VES-NAC-1,-2,-3胶束组的AUC0-24h分别是PTX-Sol对照组(十二指肠给药)的1.06、4.25、4.15和2.39倍,t1/2分别是PTX-Sol对照组(十二指肠给药)的1.33、4.31、1.78和1.25倍。药动学结果表明紫杉醇巯基化聚合物胶束能够提高紫杉醇的血药浓度,增加生物利用度,同时延长其在血液中的循环时间。
以人结肠癌细胞Caco-2为肠吸收细胞模型,对纳米胶束的细胞水平生物学机制进行了研究。结果表明,空白胶束的细胞毒性较低,载体材料安全性良好。CS-VES-NAC胶束通过生物粘附作用和促进内吞的方式增加PTX的细胞摄取。另外,CS-VES-NAC-1胶束能显著增加PTX肠腔侧到基底侧的渗透性,并降低反方向的外排,将PTX的外排比率降低10倍(外排率为2.13)。聚合物胶束以能量依赖性的方式进行跨细胞转运,其中网格蛋白途和小窝蛋白途径均有参与。细胞摄取试验表明CS-VES和CS-VES-NAC-1载体材料具有P-gp的抑制作用,可以显著降低细胞对PTX的外排。此外,CS-VES-NAC-1载体材料还可打开细胞间紧密连接,增加细胞旁路转运,使PTX溶液剂的膜渗透性提高了19.46倍,外排比率降低为0.75。表明CS-VES-NAC聚合物纳米胶束可作为化疗药物的有效传递系统。
To date, chemotherapy is the major treatment for cancer therapy. Injection is the most widely used dosage form in clinical application, due to the inappropriate characteristics of anticancer drugs, including low solubility, poor membrane permeability, lack of selectivity in distribution, and easy degradation. However, severe side effects limit their application. Therefore, the development of the oral chemotherapy delivery system has important implications for tumor treatment.
This research designed and established the functional thiolated polymeric micelle system, which can increase the solubility of chemotherapeutic drugs, inhibit P-gp protein, bioadhere, promote penetration and improve the oral absorption of hydrophobic chemotherapeutic drugs. Drug-loaded micelles were prepared, using paclitaxel (PTX) as model drug, synthetic functional amphiphilic copolymer as carrier material. The main contents of this study include synthesis, characterization and property study of the polymer, preparation drug-loaded micelles, and evaluation of bioadhesion, intestinal absorption, endocytosis mechanisms, in vivo pharmacokinetics. Moreover, mechanisms at celluar level of PTX-loaded micelles were also investigated.
Three kinds of thiolated amphiphilic copolymer of chitosan-vitamin E succinate-N-acetylcysteine (CS-VES-NAC) was synthesized by using chitosan as hydrophilic backbone, vitamin E succinate as hydrophobic core, N-acetylcysteine as functional groups. The chemical structure of the copolymer was identified by IR,1H-NMR, TGA and EDS. Free thiol groups of CS-VES-NAC-1,-2,-3copolymers examined by Ellman's method were182.6,275.5and451.5μmol/g, respectively, which render the copolymer has good swellaing behavior. Stability test results indicate that free sulfhydryl groups have good stability at the conditions of4℃, room temperature,37℃, and in pH1.2,5.4,6.8buffer solutions, which can meet the preparation requirements.
The micelles were prepared by probe ultrasonication method. With the increase of sulfhydrylation substitution, mean diameters of blank CS-VES-NAC-1,-2,-3micelles were240.0,228.2and192.2nm, respectively. Zeta potential was+59.4,+58.4and+51.9mv, respectively. PTX was used as model drug to prepare the drug-loaded micelles. The effects of drug loading ratio on particle size and zeta potential were investigated. The particle size of drug-loaded micelles ranged from180nm to250nm, the encapsulation efficiency was about60%-80%, and the zeta potentials were all above+40mv. Moreover, sulfhydrylation substitution degree also has an effect on particle size and zeta potential. The images of drug-loaded micelles were spherical and round, with a narrow size distribution and a clear core-shell structure. Average particle size was about200nm, which was consistent with the measurement results of dynamic light scattering. DSC, X-ray results showed that PTX was in an amorphous form in the micellar core. Drug-loaded micelles showed a sustained release profile, which can maintain the stability of PTX and avoid drug leakage in physiological state.
Mucin (type Ⅲ) was used as experimental model to study the biological adhesion. The results showed that CS-VES-NAC copolymer micelles could interact with mucin by covalent disulfide bonds, which can improve the adhesion significantly. Intestinal absorption of nanomicelles was investigated by in situ intestinal perfusion method. The results indicated that the absorption rate (Ka) of nanomicelles was higher than that of PTX solution, wherein CS-VES-NAC-1nanomicelles showed the most preferable absorption. The absorption rate was4.51times of PTX solution in duodenum segment. Besides, the apparent permeability (Papp) of CS-VES-NAC nanomicelles was also higher than that of PTX solution in duodenum, jejunum and ileum segments. The value of CS-VES-NAC-1nanomicelles was4.64times of pacllitaxel solution in duodenum segment. Intestinal absorption mechanisms showed that clathrin-dependent pathway, caveolin-dependent pathway, macropinocytosis, non-clathrin, non-caveolin-dependent pathway were all involved in the endocytosis process of CS-VES-NAC nanomicelles. Confocal laser scanning microscopy showed that after oral administration, thiolated micelles showed better permeability than that of free drug and CS-VES micelles.
UPLC-MS/MS method was used to study the pharmacokinetics of PTX solution and PTX-loaded micelles. The experiment was conducted by duodenum administration, while PTX solution was intravenously administrated as control to obtain absolute bioavailability. The results showed that the relative bioavailability of PTX solution, CS-VES micelles, and CS-VES-NAC-1,-2,-3micelles was3.21%,3.39%,13.65%,13.33%and7.68%, respectively. AUC0-24h of CS-VES and CS-VES-NAC-1,-2,-3micelles was1.06,4.25,5.15and2.39fold higher than that of PTX solution, and the values of t1/2were1.33,4.31,1.78and1.25times higher than PTX solution. These indicated that thiolated polymeric micelles could increase the blood concentration of paclitaxel, increase bioavailability and prolong the systemic circulation.
Human colon cancer cells (Caco-2) was applied to investigate the cellular biological mechanism of nanomicelles. Blank nanomicelles showed low cytotoxicity, suggesting good safety of the copolymer. Paclitaxel-loaded CS-VES-NAC nanomicelles could increase the cellular uptake due to bioadhesive interaction. Further, CS-VES-NAC-1nanomicelles could increase the permeation of PTX from apical side to basolateral side and decrease the efflux ratio of PTX by10-fold from the opposite direction (efflux ratio=2.13). The transcellular transport of micelles was energy-dependent, in which clathrin-dependent and caveolin-dependent pathway was both involved. Cellular uptake experiment also indicated that the P-gp inhibition effect of CS-VES and CS-VES-NAC-1copolymer could increase PTX cellular content. In addition, CS-VES-NAC-1copolymer could open the tight junctions between cells, increase paracellular transport, enhance the permeability of PTX solution by19.46-fold, and decrease the efflux ratio to0.75.
本文设计并构建了功能性巯基化聚合物胶束,其具有增溶化疗药物、抑制P-gp、生物粘附及促进渗透等多功能性,能显著提高化疗药物的口服吸收。本文以紫杉醇(PTX)为模型药物,以自合成的功能性两亲性共聚物为载体材料,制备紫杉醇纳米胶束。在对功能性聚合物进行合成、结构确证及性质研究的基础上,对紫杉醇纳米胶束及相应制剂学性质、生物粘附性质、小肠吸收情况、吸收机制及体内药动学进行了考察,同时对紫杉醇纳米胶束的细胞水平转运机制进行了研究。
以维生素E琥珀酸酯(VES)为疏水内核,以壳聚糖(CS)为亲水主链,以N-乙酰半胱氨酸(NAC)为表面修饰基团,合成了不同巯基取代度的两亲性巯基化共聚物CS-VES-NAC-1,-2,-3和未巯基化两亲性共聚物CS-VES。采用IR、1H-NMR、TGA、EDS等手段对共聚物进行了结构确证。使用Ellman's试剂法测定了CS-VES-NAC系列共聚物的游离巯基含量分别为182.6、275.5、451.5μmol/g,溶胀性性良好。稳定性试验结果表明CS-VES-NAC共聚物中游离巯基在不同温度(4℃、室温及37℃)和不同pH环境中(pH1.2HCl溶液、pH5.4PBS溶液及pH6.8PBS溶液)均具有较好的稳定性,可用于载药胶束的制备。
以巯基聚合物CS-VES-NAC为载体,采用探头超声法制备纳米胶束。随着巯基取代度的增加,CS-VES-NAC-1,-2,-3空白纳米胶束粒径逐渐降低,分别为240.0、228.2、192.2nm, Zeta电位也逐渐降低,分别为+59.4、+58.4、+51.9mv。以紫杉醇为模型药物制备载药胶束,考察不同载药量对粒径、Zeta电位的影响。载药胶束粒径范围为180nm～250nm,包封率约为60%-80%,zeta电位均在+40mv以上。同时,巯基取代度对胶束的粒径及zeta电位也有影响,随着巯基取代度的增加,粒径及zeta电位均有下降趋势。透射电镜图显示载药胶束呈球形,外观圆整,粒径分布均匀,有清晰的核-壳结构,平均粒径约为200nm,与动态光散射的测定结果基本一致。DSC、X-射线结果表明紫杉醇以无定型状态存在于胶束内核中。体外释放研究表明载药胶束缓释作用明显,可保证在生理状态下紫杉醇在胶束内核中稳定存在,避免药物提前泄漏。
以Ⅲ型粘蛋白为肠黏膜的体外模型,对纳米胶束的生物粘附能力进行考察。结果表明,CS-VES-NAC聚合物胶束能以二硫键共价结合的方式与粘蛋白进行相互作用,明显提高粘附性。采用原位单向在体肠灌流试验考察了胶束制剂的在体肠吸收情况。结果表明,胶束制剂的吸收速率常数Ka要高于紫杉醇溶液剂,其中吸收最好的是CS-VES-NAC-1胶束,在十二指肠段的吸收速率(Ka)是溶液剂的4.51倍。同时,在十二指肠、空肠、回肠段,CS-VES-NAC系列胶束组的表观渗透系数(Papp)也均高于溶液剂(p<0.05)。CS-VES-NAC-1胶束在十二指肠段的Papp值是溶液剂的4.64倍。肠段摄取机制结果表明,网格蛋白途径、小窝蛋白途径、巨胞饮及非网格蛋白非小窝蛋白途径均参与对纳米粒的摄取。激光共聚焦显微镜结果表明,巯基化胶束经口服给药后,小肠膜渗透性比游离药物组、CS-VES组均有提高,小肠中吸收最好部位是十二指肠段。
采用UPLC-MS/MS方法研究了PTX溶液剂及各胶束制剂的体内药动学。各组制剂以十二指肠给药的方式进行,同时以PTX溶液剂静脉注射为对照计算绝对生物利用度。结果表明,PTX溶液剂,CS-VES胶束及CS-VES-NAC-1,-2,-3胶束的绝对生物利用度分别为3.21%、3.39%、13.65%、13.33%、7.68%；CS-VES胶束及CS-VES-NAC-1,-2,-3胶束组的AUC0-24h分别是PTX-Sol对照组(十二指肠给药)的1.06、4.25、4.15和2.39倍,t1/2分别是PTX-Sol对照组(十二指肠给药)的1.33、4.31、1.78和1.25倍。药动学结果表明紫杉醇巯基化聚合物胶束能够提高紫杉醇的血药浓度,增加生物利用度,同时延长其在血液中的循环时间。
以人结肠癌细胞Caco-2为肠吸收细胞模型,对纳米胶束的细胞水平生物学机制进行了研究。结果表明,空白胶束的细胞毒性较低,载体材料安全性良好。CS-VES-NAC胶束通过生物粘附作用和促进内吞的方式增加PTX的细胞摄取。另外,CS-VES-NAC-1胶束能显著增加PTX肠腔侧到基底侧的渗透性,并降低反方向的外排,将PTX的外排比率降低10倍(外排率为2.13)。聚合物胶束以能量依赖性的方式进行跨细胞转运,其中网格蛋白途和小窝蛋白途径均有参与。细胞摄取试验表明CS-VES和CS-VES-NAC-1载体材料具有P-gp的抑制作用,可以显著降低细胞对PTX的外排。此外,CS-VES-NAC-1载体材料还可打开细胞间紧密连接,增加细胞旁路转运,使PTX溶液剂的膜渗透性提高了19.46倍,外排比率降低为0.75。表明CS-VES-NAC聚合物纳米胶束可作为化疗药物的有效传递系统。
To date, chemotherapy is the major treatment for cancer therapy. Injection is the most widely used dosage form in clinical application, due to the inappropriate characteristics of anticancer drugs, including low solubility, poor membrane permeability, lack of selectivity in distribution, and easy degradation. However, severe side effects limit their application. Therefore, the development of the oral chemotherapy delivery system has important implications for tumor treatment.
This research designed and established the functional thiolated polymeric micelle system, which can increase the solubility of chemotherapeutic drugs, inhibit P-gp protein, bioadhere, promote penetration and improve the oral absorption of hydrophobic chemotherapeutic drugs. Drug-loaded micelles were prepared, using paclitaxel (PTX) as model drug, synthetic functional amphiphilic copolymer as carrier material. The main contents of this study include synthesis, characterization and property study of the polymer, preparation drug-loaded micelles, and evaluation of bioadhesion, intestinal absorption, endocytosis mechanisms, in vivo pharmacokinetics. Moreover, mechanisms at celluar level of PTX-loaded micelles were also investigated.
Three kinds of thiolated amphiphilic copolymer of chitosan-vitamin E succinate-N-acetylcysteine (CS-VES-NAC) was synthesized by using chitosan as hydrophilic backbone, vitamin E succinate as hydrophobic core, N-acetylcysteine as functional groups. The chemical structure of the copolymer was identified by IR,1H-NMR, TGA and EDS. Free thiol groups of CS-VES-NAC-1,-2,-3copolymers examined by Ellman's method were182.6,275.5and451.5μmol/g, respectively, which render the copolymer has good swellaing behavior. Stability test results indicate that free sulfhydryl groups have good stability at the conditions of4℃, room temperature,37℃, and in pH1.2,5.4,6.8buffer solutions, which can meet the preparation requirements.
The micelles were prepared by probe ultrasonication method. With the increase of sulfhydrylation substitution, mean diameters of blank CS-VES-NAC-1,-2,-3micelles were240.0,228.2and192.2nm, respectively. Zeta potential was+59.4,+58.4and+51.9mv, respectively. PTX was used as model drug to prepare the drug-loaded micelles. The effects of drug loading ratio on particle size and zeta potential were investigated. The particle size of drug-loaded micelles ranged from180nm to250nm, the encapsulation efficiency was about60%-80%, and the zeta potentials were all above+40mv. Moreover, sulfhydrylation substitution degree also has an effect on particle size and zeta potential. The images of drug-loaded micelles were spherical and round, with a narrow size distribution and a clear core-shell structure. Average particle size was about200nm, which was consistent with the measurement results of dynamic light scattering. DSC, X-ray results showed that PTX was in an amorphous form in the micellar core. Drug-loaded micelles showed a sustained release profile, which can maintain the stability of PTX and avoid drug leakage in physiological state.
Mucin (type Ⅲ) was used as experimental model to study the biological adhesion. The results showed that CS-VES-NAC copolymer micelles could interact with mucin by covalent disulfide bonds, which can improve the adhesion significantly. Intestinal absorption of nanomicelles was investigated by in situ intestinal perfusion method. The results indicated that the absorption rate (Ka) of nanomicelles was higher than that of PTX solution, wherein CS-VES-NAC-1nanomicelles showed the most preferable absorption. The absorption rate was4.51times of PTX solution in duodenum segment. Besides, the apparent permeability (Papp) of CS-VES-NAC nanomicelles was also higher than that of PTX solution in duodenum, jejunum and ileum segments. The value of CS-VES-NAC-1nanomicelles was4.64times of pacllitaxel solution in duodenum segment. Intestinal absorption mechanisms showed that clathrin-dependent pathway, caveolin-dependent pathway, macropinocytosis, non-clathrin, non-caveolin-dependent pathway were all involved in the endocytosis process of CS-VES-NAC nanomicelles. Confocal laser scanning microscopy showed that after oral administration, thiolated micelles showed better permeability than that of free drug and CS-VES micelles.
UPLC-MS/MS method was used to study the pharmacokinetics of PTX solution and PTX-loaded micelles. The experiment was conducted by duodenum administration, while PTX solution was intravenously administrated as control to obtain absolute bioavailability. The results showed that the relative bioavailability of PTX solution, CS-VES micelles, and CS-VES-NAC-1,-2,-3micelles was3.21%,3.39%,13.65%,13.33%and7.68%, respectively. AUC0-24h of CS-VES and CS-VES-NAC-1,-2,-3micelles was1.06,4.25,5.15and2.39fold higher than that of PTX solution, and the values of t1/2were1.33,4.31,1.78and1.25times higher than PTX solution. These indicated that thiolated polymeric micelles could increase the blood concentration of paclitaxel, increase bioavailability and prolong the systemic circulation.
Human colon cancer cells (Caco-2) was applied to investigate the cellular biological mechanism of nanomicelles. Blank nanomicelles showed low cytotoxicity, suggesting good safety of the copolymer. Paclitaxel-loaded CS-VES-NAC nanomicelles could increase the cellular uptake due to bioadhesive interaction. Further, CS-VES-NAC-1nanomicelles could increase the permeation of PTX from apical side to basolateral side and decrease the efflux ratio of PTX by10-fold from the opposite direction (efflux ratio=2.13). The transcellular transport of micelles was energy-dependent, in which clathrin-dependent and caveolin-dependent pathway was both involved. Cellular uptake experiment also indicated that the P-gp inhibition effect of CS-VES and CS-VES-NAC-1copolymer could increase PTX cellular content. In addition, CS-VES-NAC-1copolymer could open the tight junctions between cells, increase paracellular transport, enhance the permeability of PTX solution by19.46-fold, and decrease the efflux ratio to0.75.
引文
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