长循环靶向性载药胶束的构建及其细胞水平评价
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摘要
聚合物胶束是当前药物传输领域研究的热点,在用作药物载体时具有多个优点,如对疏水性或难溶性药物的增溶作用,聚合物亲水链由一定长度的聚乙二醇等组成时可具备长循环性,而在聚合物胶束的表面修饰以靶识别分子可使其具备主动靶向性。本文制备了载香豆素6和米托蒽琨的聚合物胶束,并研究了地塞米松处理对Hela细胞摄取叶酸偶联载香豆素6胶束的影响。
首先,以双氨基PEG (PEG-bis-amine)、叶酸(folate)、磷脂酰乙醇胺(1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, DSPE)为原料合成了叶酸-PEG-磷脂酰乙醇胺(folate-PEG-DSPE),并利用傅立叶红外波谱仪和核磁共振谱仪对终产物进行了结构表征,结果证实所得到的终产物为目标化合物；还利用高效液相色谱法对得到的终产物进行了含量分析；然后,以甲氧基聚乙二醇-磷脂酰乙醇胺(mPEG-DSPE)和合成的叶酸-PEG-磷脂酰乙醇胺(folate-PEG-DSPE)为材料,通过膜水化法制备出载香豆素6(coumarin6)的普通胶束(plain micelles)和叶酸偶联胶束(folate-conjugated micelles)。分别采用透射电镜和激光粒度分析仪对胶束的形态和粒径分布进行了检测,发现透射电镜下的干燥胶束粒径约50-60nm,而溶液状态下的胶束平均粒径约100nm;还利用高效液相色谱法分别检测了胶束溶液的香豆素6浓度,并计算出了聚合物胶束的载药量和包封率分别约为0.8%和15.4%；此外,还利用高效液相色谱法检测了叶酸偶联胶束中的folate-PEG-DSPE,实验结果表明,膜水化法是制备载药聚合物胶束的适宜方法,所制备的叶酸偶联胶束含有folate-PEG-DSPE.实验结果还表明,聚合物胶束对于疏水性小分子药物具有显著的增溶作用；
其次,以甲氧基聚乙二醇一磷脂酰乙醇胺为材料,利用膜水化法制备包载水溶性较好的蒽环类抗肿瘤药米托蒽醌盐酸盐(mitoxantrone hydrochloride)的聚合物胶束,考察了磷脂酰乙醇胺对米托蒽琨包封率和载药量的影响。动态光散射法考察了胶束的粒径分布,其平均粒径约10nm；发现磷脂酰乙醇胺的添加可以使聚合物胶束对米托蒽醌的包封率和载药量增加达23%左右；
然后,考察了叶酸受体α阳性的Hela细胞对载香豆素6的普通胶束和叶酸偶联胶束的体外摄取实验,利用荧光显微镜和流式细胞仪考察Hela细胞对于叶酸偶联胶束的摄取作用,发现Hela细胞对于叶酸偶联胶束的摄取明显高于普通胶束,证明通过叶酸小分子与细胞表面的叶酸受体a的特异性识别和结合作用,可以促进细胞对于叶酸偶联载药胶束的摄取；
最后,研究了地塞米松处理对于Hela细胞摄取载香豆素6的叶酸偶联胶束的影响。利用多个剂量(5nM,50nM,100nM)的地塞米松处理Hela细胞96h,并用实时定量PCR技术和流式细胞技术分别检测了处理后Hela细胞的mRNA水平和细胞表面FRa水平,发现地塞米松处理后的Hela细胞的mRNA水平增加了近3倍,而Hela细胞表面FRa水平增加了1倍多；在5nM地塞米松处理96h的Hela细胞中加入叶酸偶联胶束,以未经处理的Hela细胞为对照,采用荧光显微镜和流式细胞仪考察细胞摄取量,发现地塞米松处理的Hela细胞对叶酸偶联胶束的摄取增加了近1倍,也即说明通过上调细胞表面FRa水平可以增强叶酸偶联胶束在肿瘤细胞的内吞。
本研究成功制备了载香豆素6的普通胶束和叶酸偶联胶束,动态光散射法检测的平均粒径约100nm；此外,还制备了载米托蒽醌的聚合物胶束,平均粒径约10nm,磷脂酰乙醇胺可以增加聚合物胶束对于米托蒽醌的载药量和包封率;在细胞水平证实了通过地塞米松可以上调Hela细胞的FRα表达水平,继而促进其对叶酸偶联载药胶束的摄取。
Polymeric micelles as interests of current drug delivery research have several advantages, such as solubilization for hydrophobic or unsoluble drugs, longevity in blood circulation and active targeting by attaching ligand molecules to the surface of micelles which could specifically initiate ligand-receptor binding-based endocytosis. In this dissertation, folate-conjugated micelles were prepared and evaluated in folate receptor a(FR a)-positive Hela cells. The dissertation consists of five chapters, and is shown as follows.
Firstly, folate-PEG-DSPE was synthesized by three-step synthesis method, from PEG-bis-amine,folate and phosphatidylethanolamine, and confirmed structurally by FT-IR and1H NMR.In addition, high performance liquid chromatography (HPLC) was utilized to quantify folate-PEG-DSPE.
Secondly, polymeric micelles were prepared by thin-film rehydration method, fluorescent dyes coumarin6as model of hydrophobic drugs.The micelles containing folate-PEG-DSPE were called folate-conjugated micelles(FM) and those containing no folate-PEG-DSPE were called plain micelles(PM).The surface morphology of FM and PM were observed by transmission electron microscope (TEM), the particle size were also examined by dynamic light scattering(DLS), the drug loading and encapsulation efficiency were assayed by HPLC. In TEM pictures, FM and PM were spherical and uniform-sized particles,with diameter about50-60nm.In micelles solution, the mean particle size of FM and PM were about100nm.The drug loading and encapsulation efficiency of FM and PM were about0.8%and15.4%, respectively.
Thirdly, polymeric micelles loading mitoxantrone(MTO) were prepared by thin-film rehydration method, effect of DSPE as additive on the MTO loading and encapsulation efficiency was examined. The particle size distribution were examined by dynamic light scattering(DLS), and drug loading and encapsulation efficiency were determined by HPLC.The mean size of MTO-loaded polymeric micelles with or without DSPE was about10nm, but the drug loading and encapsulation efficiency were enhanced by DSPE.
Fourthly, FRa positive Hela cells were co-incubated with FM or PM, the endocytosis of micelles were examined by fluorescence microscope and flow cytometer(FCM). The fluorescent images and FCM histogram showed that the endocytosis of FM was more than PM. This results demonstrated the endocytosis of FRa(+) cells could be enhanced by the specific binding of folate on the micelles and FRa on the cells membrane.
Finally, Hela cells were treated with dexamethasone(dex,5nM,5OnM,100nM) for96hours in order to upregulating FRa level. And FRa mRNA and membrane FRa level were examined by real-time quantitative polymerase chain reaction (RT-PCR) and FCM. The results showed the mRNA level and FRa level of Hela cells were nearly tripled and doubled by dex treatment, respectively. After Hela cells were treated with dex for96h, folate-conjugated micelles were added to the culture plate and co-incubated for2hours, Hela cells without dex treatment as control, then the endocytosis of micelles were examined by fluorescence microscope and FCM. The results showed that the endocytosis of micelles in Hela cells with dex treatment were more than those without dex treatment.
In conclusion, the drug loading and encapsulation efficiency of polymeric micelles for MTO could be increased by DSPE. The endocytosis of foalte-conjugated micelles in Hela cells could be enhanced by upregulating FRa level with dex treatment, and this is a promising strategy for facilitating FRa-based targeting and further research is nessesary.
首先,以双氨基PEG (PEG-bis-amine)、叶酸(folate)、磷脂酰乙醇胺(1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, DSPE)为原料合成了叶酸-PEG-磷脂酰乙醇胺(folate-PEG-DSPE),并利用傅立叶红外波谱仪和核磁共振谱仪对终产物进行了结构表征,结果证实所得到的终产物为目标化合物；还利用高效液相色谱法对得到的终产物进行了含量分析；然后,以甲氧基聚乙二醇-磷脂酰乙醇胺(mPEG-DSPE)和合成的叶酸-PEG-磷脂酰乙醇胺(folate-PEG-DSPE)为材料,通过膜水化法制备出载香豆素6(coumarin6)的普通胶束(plain micelles)和叶酸偶联胶束(folate-conjugated micelles)。分别采用透射电镜和激光粒度分析仪对胶束的形态和粒径分布进行了检测,发现透射电镜下的干燥胶束粒径约50-60nm,而溶液状态下的胶束平均粒径约100nm;还利用高效液相色谱法分别检测了胶束溶液的香豆素6浓度,并计算出了聚合物胶束的载药量和包封率分别约为0.8%和15.4%；此外,还利用高效液相色谱法检测了叶酸偶联胶束中的folate-PEG-DSPE,实验结果表明,膜水化法是制备载药聚合物胶束的适宜方法,所制备的叶酸偶联胶束含有folate-PEG-DSPE.实验结果还表明,聚合物胶束对于疏水性小分子药物具有显著的增溶作用；
其次,以甲氧基聚乙二醇一磷脂酰乙醇胺为材料,利用膜水化法制备包载水溶性较好的蒽环类抗肿瘤药米托蒽醌盐酸盐(mitoxantrone hydrochloride)的聚合物胶束,考察了磷脂酰乙醇胺对米托蒽琨包封率和载药量的影响。动态光散射法考察了胶束的粒径分布,其平均粒径约10nm；发现磷脂酰乙醇胺的添加可以使聚合物胶束对米托蒽醌的包封率和载药量增加达23%左右；
然后,考察了叶酸受体α阳性的Hela细胞对载香豆素6的普通胶束和叶酸偶联胶束的体外摄取实验,利用荧光显微镜和流式细胞仪考察Hela细胞对于叶酸偶联胶束的摄取作用,发现Hela细胞对于叶酸偶联胶束的摄取明显高于普通胶束,证明通过叶酸小分子与细胞表面的叶酸受体a的特异性识别和结合作用,可以促进细胞对于叶酸偶联载药胶束的摄取；
最后,研究了地塞米松处理对于Hela细胞摄取载香豆素6的叶酸偶联胶束的影响。利用多个剂量(5nM,50nM,100nM)的地塞米松处理Hela细胞96h,并用实时定量PCR技术和流式细胞技术分别检测了处理后Hela细胞的mRNA水平和细胞表面FRa水平,发现地塞米松处理后的Hela细胞的mRNA水平增加了近3倍,而Hela细胞表面FRa水平增加了1倍多；在5nM地塞米松处理96h的Hela细胞中加入叶酸偶联胶束,以未经处理的Hela细胞为对照,采用荧光显微镜和流式细胞仪考察细胞摄取量,发现地塞米松处理的Hela细胞对叶酸偶联胶束的摄取增加了近1倍,也即说明通过上调细胞表面FRa水平可以增强叶酸偶联胶束在肿瘤细胞的内吞。
本研究成功制备了载香豆素6的普通胶束和叶酸偶联胶束,动态光散射法检测的平均粒径约100nm；此外,还制备了载米托蒽醌的聚合物胶束,平均粒径约10nm,磷脂酰乙醇胺可以增加聚合物胶束对于米托蒽醌的载药量和包封率;在细胞水平证实了通过地塞米松可以上调Hela细胞的FRα表达水平,继而促进其对叶酸偶联载药胶束的摄取。
Polymeric micelles as interests of current drug delivery research have several advantages, such as solubilization for hydrophobic or unsoluble drugs, longevity in blood circulation and active targeting by attaching ligand molecules to the surface of micelles which could specifically initiate ligand-receptor binding-based endocytosis. In this dissertation, folate-conjugated micelles were prepared and evaluated in folate receptor a(FR a)-positive Hela cells. The dissertation consists of five chapters, and is shown as follows.
Firstly, folate-PEG-DSPE was synthesized by three-step synthesis method, from PEG-bis-amine,folate and phosphatidylethanolamine, and confirmed structurally by FT-IR and1H NMR.In addition, high performance liquid chromatography (HPLC) was utilized to quantify folate-PEG-DSPE.
Secondly, polymeric micelles were prepared by thin-film rehydration method, fluorescent dyes coumarin6as model of hydrophobic drugs.The micelles containing folate-PEG-DSPE were called folate-conjugated micelles(FM) and those containing no folate-PEG-DSPE were called plain micelles(PM).The surface morphology of FM and PM were observed by transmission electron microscope (TEM), the particle size were also examined by dynamic light scattering(DLS), the drug loading and encapsulation efficiency were assayed by HPLC. In TEM pictures, FM and PM were spherical and uniform-sized particles,with diameter about50-60nm.In micelles solution, the mean particle size of FM and PM were about100nm.The drug loading and encapsulation efficiency of FM and PM were about0.8%and15.4%, respectively.
Thirdly, polymeric micelles loading mitoxantrone(MTO) were prepared by thin-film rehydration method, effect of DSPE as additive on the MTO loading and encapsulation efficiency was examined. The particle size distribution were examined by dynamic light scattering(DLS), and drug loading and encapsulation efficiency were determined by HPLC.The mean size of MTO-loaded polymeric micelles with or without DSPE was about10nm, but the drug loading and encapsulation efficiency were enhanced by DSPE.
Fourthly, FRa positive Hela cells were co-incubated with FM or PM, the endocytosis of micelles were examined by fluorescence microscope and flow cytometer(FCM). The fluorescent images and FCM histogram showed that the endocytosis of FM was more than PM. This results demonstrated the endocytosis of FRa(+) cells could be enhanced by the specific binding of folate on the micelles and FRa on the cells membrane.
Finally, Hela cells were treated with dexamethasone(dex,5nM,5OnM,100nM) for96hours in order to upregulating FRa level. And FRa mRNA and membrane FRa level were examined by real-time quantitative polymerase chain reaction (RT-PCR) and FCM. The results showed the mRNA level and FRa level of Hela cells were nearly tripled and doubled by dex treatment, respectively. After Hela cells were treated with dex for96h, folate-conjugated micelles were added to the culture plate and co-incubated for2hours, Hela cells without dex treatment as control, then the endocytosis of micelles were examined by fluorescence microscope and FCM. The results showed that the endocytosis of micelles in Hela cells with dex treatment were more than those without dex treatment.
In conclusion, the drug loading and encapsulation efficiency of polymeric micelles for MTO could be increased by DSPE. The endocytosis of foalte-conjugated micelles in Hela cells could be enhanced by upregulating FRa level with dex treatment, and this is a promising strategy for facilitating FRa-based targeting and further research is nessesary.
引文
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