冬凌草甲素长循环脂质体的研究
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摘要
冬凌草甲素是从冬凌草中提取分离的一种四环二萜类化合物,而冬凌草是应用于临床最重要的中草药之一。半个多世纪以前,就已证实冬凌草甲素具有免疫调节、抗炎、抗病毒等作用,特别是对上呼吸道感染有很好的治疗作用。最近的实验室和临床研究表明,冬凌草甲素是有效的抗移植性肿瘤-前列腺癌、乳腺癌、大叶肺细胞癌等的药物。由于冬凌草甲素易氧化、水溶性差、生物半衰期短,限制了作为临床化疗药物的使用。论文旨在通过制备冬凌草甲素长循环脂质体,使药物在血液中滞留时间延长,浓度升高。论文对冬凌草甲素长循环脂质体制备工艺,冬凌草甲素长循环脂质体在小鼠血液和组织中的分布及冬凌草甲素长循环脂质体对荷H_22肝癌小鼠的抗肿瘤作用进行了研究。
首先研究了冬凌草中冬凌草甲素的提取纯化工艺。向冬凌草粉末中加入12倍量的95%乙醇,超声提取3次,每次30min。再向冬凌草乙醇提取液中加入冬凌草用量24%的活性炭超声脱色2次,每次20min。确定冬凌草甲素粗品的制备型高效液相色谱分离条件:色谱柱为μBondapack~(TM)C_(18)(80mm i.d×300mm,粒径25μm～40μm);柱温:40℃;流动相:甲醇-水(50/50,V/V);流速:60mL·min~(-1);检测波长:238nm;进样体积:10mL。将所收集的16min～23min的洗脱液经蒸发浓缩,真空干燥,得冬凌草甲素白色粉末,经高效液相检测纯度为99.0%,提取率65.4%。采用质谱、元素分析、紫外、红外、核磁共振和高效液相色谱鉴定和验证了提取物的化学结构。
研究冬凌草甲素长循环脂质体的制备工艺和建立测定冬凌草甲素含量的高效液相色谱法。以包封率和载药量为指标,考察了大豆卵磷脂、胆固醇、冬凌草甲素和聚乙二醇_(2000)-二硬脂酰磷脂酰乙醇胺(PEG_(2000)-DSPE)的用量,水化介质的种类和体积,对包封率和载药量的影响。通过试验设计优化了处方及制备工艺;选用LichrospherC_(18)柱(4.6 mmi.d×250mm,粒径5μm),柱温40℃,以甲醇-水(70/30,V/V)为流动相,检测波长238nm,在流速1.0mL·min~(-1)条件下进样10μL测定冬凌草甲素含量。最佳工艺为大豆卵磷脂0.26g,胆固醇0.14g,冬凌草甲素0.04g,PEG_(2000)-DSPE 0.5g,纯净水30mL,制得的冬凌草甲素脂质体粒径在100nm～200nm之间呈正态分布,平均粒径150nm,包封率达95.4%,载药量为4.24%。体外释放结果表明,脂质体中冬凌草甲素在96h释放基本完全。确定的处方较好,工艺可行,高效液相色谱法简便、准确、快速,有利于控制冬凌草甲素脂质体的质量。同法制备了冬凌草甲素普通脂质体(脂膜中不含PEG_(2000)-DSPE)。
制备的冬凌草甲素长循环脂质体和普通脂质体在5℃进行贮存试验,80d后各项指标保持稳定,包封率基本没有变化。结果表明,冬凌草甲素长循环脂质体和普通脂质体在5℃条件下贮存稳定性良好。
研究冬凌草甲素长循环脂质体和普通脂质体在小鼠体内的组织分布及药代动力学特性。采用高效液相色谱法测定小鼠血液和组织中冬凌草甲素的浓度。对冬凌草甲素长循环脂质体、冬凌草甲素普通脂质体和冬凌草甲素注射液在小鼠体内分布特点和药代动力学参数进行了比较。结果表明,冬凌草甲素长循环脂质体在肝、脾、肺、心及肾中的相对靶向率分别为2.10、1.95、1.34、2.39和0.84;冬凌草甲素普通脂质体在肝、脾、肺、心及肾中的相对靶向率分别为4.47、3.84、1.49、1.89和0.92。静脉注射冬凌草甲素长循环脂质体后药时曲线表明体内过程符合二室模型,各相半衰期分别为T_(1/2)~α＝3.18h,T_(1/2)~β＝98.36h,血药浓度.时间曲线下面积AUC_(0-48h)＝888.91 h·μg·mL~(-1),中心分布容V_c＝19.17 mL·Kg~(-1);静脉注射冬凌草甲素普通脂质体后药时曲线表明体内过程符合二室模型,各相半衰期分别为T_(1/2)~α＝2.54h,T_(1/2)~β＝33.98h,血药浓度.时间曲线下面积AUC_(0-48h)＝356.69 h·μg·mL~(-1),中心分布容V_c＝20.01mL·Kg~(-1);静脉注射冬凌草甲素注射液后药时曲线表明体内过程符合二室模型,各相半衰期分别为T_(1/2)~α＝0.63h,T_(1/2)β＝6.19h,血药浓度-时间曲线下面积AUC_(0-48h)＝156.07 h·μg·mL~(-1),中心分布容V_c＝10.66mL·Kg~(-1)。冬凌草甲素长循环脂质体延长了冬凌草甲素在小鼠体内的循环时间。
采用动物移植性肿瘤实验法,将H_22小鼠肝癌细胞接种于昆明小鼠皮下,进行体内抑瘤试验,考察冬凌草甲素长循环脂质体、冬凌草甲素普通脂质体和冬凌草甲素注射液给药后对实体瘤的抑瘤率。结果表明,冬凌草甲素长循环脂质体、冬凌草甲素普通脂质体和冬凌草甲素注射液均具有抗肿瘤效应,与冬凌草甲素普通脂质体和冬凌草甲素注射液相比,冬凌草甲素长循环脂质体显示更强的抑瘤性,给药剂量为3.35×10~(-2)g·Kg~(-1)·d~(-1)时三者抑瘤率分别为85.4%、71.4%和63.7%。
Oridonin,a complex diterpenoid derivative,is extracted from traditional chinese herbs, Rabdosia rubescens which is one of the most important traditional Chinese herbs commonly used in clinical treatment nowadays.More than half a century ago,oridonin was shown to have a variety of biological effects such as immunoregulatory and anti-inflammatory functions as well as antiviral functions especially in upper respiratory tract infections.Recent laboratory and clinical data suggest that oridonin is a very effective antitumor agent with profound effects on a number of malignant diseases such as prostate,breast,and non-small cell lung cancers.However,oridonin is unstable,easily oxidized and nonhydrophilic. Biological half life of oridonin is short.These disadvantages limited the clinical application of the chemotherapy medicine.In order to improve the detention time and concentration of oridonin in blood,long-circulating oridonin liposomes were prepared.The distribution of long-circulating oridonin liposomes in blood and tissues in mice were studied.The theraputic effects of long-circulating oridonin liposomes on H_(22) mousehepatoma carcinoma cells induced cancer mice were evaluted.
The extraction and purification processes of oridonin from Rabdosia rubescens were first studied.Rabdosia rubescens powder was ultrasonic extracted with 95%ethanol with a 12:1 ratio of solvent:Rabdosia rubescens for 30 minutes.Repeat the ultrasonic extraction for another 2 times.The combined ethanol extract was then ultrasonic decolorized with active carbon for 20 minutes.Repeat the ultrasonic decolorization one more time.The dosage of active carbon was 0.24g for 1g of Rabdosia rubescens used.The preparative high performance liquid chromatography separative conditions of crude oridonin were investigated. The decolorized oridonin was separated by a reverse phaseμBondapack~(TM)C_(18) column(80mm i.d×300mm,grain size 25μm～40μm).The temperature of the column was maintained at 40℃.The mobile phase was CH_3OH-H_2O(50/50,V/V).The flow rate was 60mL·min~(-1).The detective wave-length was set to 238nm and the injective volumn was 10mL.The eluted solution of 16min～23min was evaporated and vacuum dried.White powder of oridonin was obtained with 99.0%by HPLC.The extraction yield of oridonin was 65.4%based on analysed concentration of oridonin in Rabdosia rubescens.The structure of the final product separated was identified by LC-Ms,elemental analysis,UV,IR,HPLC and NMR spectrum.
To optimize preparing technique of long-circulating oridonin liposomes and establish HPLC method for determination of oridonin liposomes,the influence of various factors, including the dosage of lecithin,cholesterol,oridonin,PEG_(2000)-DSPE,hydrous medium and kinds of hydrous medium on the entrapment efficiency and ratio of loading drug were investigated,and the optimum formula was selected through orthogonal design test.The concentration of oridonin was determined by HPLC using a reverse phase Lichrospher C_(18) column(4.6mm i.d×250mm,grain size 5μm).The temperature of column was maintained at 40℃.The mobile phase was CH_3OH-H_2O(70/30,V/V).The flow rate was 1mL·min~(-1).The detective wave-length was set to 238nm and the injective volumn was 10μL.In the optimal process,0.26g lecithin,0.14g cholesterol,0.5g PEG_(2000)-DSPE,0.04g oridonin and 30mL pure water was used.The product had good size distribution from 100nm to 200nm.The mean particle size diameter was 150nm,entrapment efficiency was 95.4%and ratio of loading drug was 4.24%.The release time of oridonin from liposome was 96h.The preparative process of oridonin liposomes is feasible.The HPLC method is simple,rapid and the results is accurate and reliable.The regular oridonin liposomes was prepared in the same way without adding polyethylene glycol-distearoylphosphatidylethanolamine(PEG_(2000)-DSPE).
The long-circulating oridonin liposomes and regular oridonin liposomes were stored at 5℃for 80 days without visible change.Entrapment efficiency had no change.The result indicated that long-circulating oridonin liposomes and regular oridonin liposomes were stable at 5℃.
To study the biodistribution and pharmacokinetics of long-circulating oridonin liposomes and regular oridonin liposomes in mice,HPLC method was developed for the determination of the contents of oridonin in blood and tissues in mice.The long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin were tail iv administrated and results were compared.The relative targeting efficiency of long-circulating oridonin liposomes in the liver,spleen,lung,heart and kidney were 2.10,1.95,1.34,2.39 and 0.84;The relative targeting efficiency of regular oridonin liposomes in the liver,spleen,lung,heart and kidney were 4.47,3.84,1.49,1.89 and 0.92.The concentration-time curves of long-circulating oridonin liposomes was fitted to the two-compartment model with T_(1/2)~α＝3.18h,T_(1/2)~β＝98.36h, AUC_(0-48h)＝888.91 h·μg.mL~(-1),V_c＝19.17mL·Kg~(-1);The concentration-time curves of regular oridonin liposomes was fitted to the two-compartment model with T_(1/2)~α＝2.54h,T_(1/2)~β＝33.98h, AUC_(0-48h)＝356.69 h·μg·mL~(-1),V_c＝20.01mL·Kg~(-1);The concentration-time curves of free oridonin was fitted to the two-compartment model with T_(1/2)~α＝0.63h,T_(1/2)~β＝6.19h, AUC_(0-48h)＝156.07 h·μg·mL~(-1),V_c＝10.66mL·Kg~(-1).Long-circulating oridonin liposomes was found to reach a long circulation time.
For evaluation of the effect of long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin on tumor cells in vivo,H_(22) mousehepatoma carcinoma cells were transplanted subcutaneouly in mice to induce growth of solid tumors.Tumor weight inhibition rate was then detected after administration of the oridonin preparations. Long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin all showed antitumor effect.The long-circulating oridonin liposomes showed stronger antitumor effect than regular oridonin liposomes and free oridonin.The inhibitory rate of long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin was 85.4%, 71.4%,63.7%at a dose of 3.35×10~(-2) g·Kg~(-1)·d~(-1),respectively.
首先研究了冬凌草中冬凌草甲素的提取纯化工艺。向冬凌草粉末中加入12倍量的95%乙醇,超声提取3次,每次30min。再向冬凌草乙醇提取液中加入冬凌草用量24%的活性炭超声脱色2次,每次20min。确定冬凌草甲素粗品的制备型高效液相色谱分离条件:色谱柱为μBondapack~(TM)C_(18)(80mm i.d×300mm,粒径25μm～40μm);柱温:40℃;流动相:甲醇-水(50/50,V/V);流速:60mL·min~(-1);检测波长:238nm;进样体积:10mL。将所收集的16min～23min的洗脱液经蒸发浓缩,真空干燥,得冬凌草甲素白色粉末,经高效液相检测纯度为99.0%,提取率65.4%。采用质谱、元素分析、紫外、红外、核磁共振和高效液相色谱鉴定和验证了提取物的化学结构。
研究冬凌草甲素长循环脂质体的制备工艺和建立测定冬凌草甲素含量的高效液相色谱法。以包封率和载药量为指标,考察了大豆卵磷脂、胆固醇、冬凌草甲素和聚乙二醇_(2000)-二硬脂酰磷脂酰乙醇胺(PEG_(2000)-DSPE)的用量,水化介质的种类和体积,对包封率和载药量的影响。通过试验设计优化了处方及制备工艺;选用LichrospherC_(18)柱(4.6 mmi.d×250mm,粒径5μm),柱温40℃,以甲醇-水(70/30,V/V)为流动相,检测波长238nm,在流速1.0mL·min~(-1)条件下进样10μL测定冬凌草甲素含量。最佳工艺为大豆卵磷脂0.26g,胆固醇0.14g,冬凌草甲素0.04g,PEG_(2000)-DSPE 0.5g,纯净水30mL,制得的冬凌草甲素脂质体粒径在100nm～200nm之间呈正态分布,平均粒径150nm,包封率达95.4%,载药量为4.24%。体外释放结果表明,脂质体中冬凌草甲素在96h释放基本完全。确定的处方较好,工艺可行,高效液相色谱法简便、准确、快速,有利于控制冬凌草甲素脂质体的质量。同法制备了冬凌草甲素普通脂质体(脂膜中不含PEG_(2000)-DSPE)。
制备的冬凌草甲素长循环脂质体和普通脂质体在5℃进行贮存试验,80d后各项指标保持稳定,包封率基本没有变化。结果表明,冬凌草甲素长循环脂质体和普通脂质体在5℃条件下贮存稳定性良好。
研究冬凌草甲素长循环脂质体和普通脂质体在小鼠体内的组织分布及药代动力学特性。采用高效液相色谱法测定小鼠血液和组织中冬凌草甲素的浓度。对冬凌草甲素长循环脂质体、冬凌草甲素普通脂质体和冬凌草甲素注射液在小鼠体内分布特点和药代动力学参数进行了比较。结果表明,冬凌草甲素长循环脂质体在肝、脾、肺、心及肾中的相对靶向率分别为2.10、1.95、1.34、2.39和0.84;冬凌草甲素普通脂质体在肝、脾、肺、心及肾中的相对靶向率分别为4.47、3.84、1.49、1.89和0.92。静脉注射冬凌草甲素长循环脂质体后药时曲线表明体内过程符合二室模型,各相半衰期分别为T_(1/2)~α＝3.18h,T_(1/2)~β＝98.36h,血药浓度.时间曲线下面积AUC_(0-48h)＝888.91 h·μg·mL~(-1),中心分布容V_c＝19.17 mL·Kg~(-1);静脉注射冬凌草甲素普通脂质体后药时曲线表明体内过程符合二室模型,各相半衰期分别为T_(1/2)~α＝2.54h,T_(1/2)~β＝33.98h,血药浓度.时间曲线下面积AUC_(0-48h)＝356.69 h·μg·mL~(-1),中心分布容V_c＝20.01mL·Kg~(-1);静脉注射冬凌草甲素注射液后药时曲线表明体内过程符合二室模型,各相半衰期分别为T_(1/2)~α＝0.63h,T_(1/2)β＝6.19h,血药浓度-时间曲线下面积AUC_(0-48h)＝156.07 h·μg·mL~(-1),中心分布容V_c＝10.66mL·Kg~(-1)。冬凌草甲素长循环脂质体延长了冬凌草甲素在小鼠体内的循环时间。
采用动物移植性肿瘤实验法,将H_22小鼠肝癌细胞接种于昆明小鼠皮下,进行体内抑瘤试验,考察冬凌草甲素长循环脂质体、冬凌草甲素普通脂质体和冬凌草甲素注射液给药后对实体瘤的抑瘤率。结果表明,冬凌草甲素长循环脂质体、冬凌草甲素普通脂质体和冬凌草甲素注射液均具有抗肿瘤效应,与冬凌草甲素普通脂质体和冬凌草甲素注射液相比,冬凌草甲素长循环脂质体显示更强的抑瘤性,给药剂量为3.35×10~(-2)g·Kg~(-1)·d~(-1)时三者抑瘤率分别为85.4%、71.4%和63.7%。
Oridonin,a complex diterpenoid derivative,is extracted from traditional chinese herbs, Rabdosia rubescens which is one of the most important traditional Chinese herbs commonly used in clinical treatment nowadays.More than half a century ago,oridonin was shown to have a variety of biological effects such as immunoregulatory and anti-inflammatory functions as well as antiviral functions especially in upper respiratory tract infections.Recent laboratory and clinical data suggest that oridonin is a very effective antitumor agent with profound effects on a number of malignant diseases such as prostate,breast,and non-small cell lung cancers.However,oridonin is unstable,easily oxidized and nonhydrophilic. Biological half life of oridonin is short.These disadvantages limited the clinical application of the chemotherapy medicine.In order to improve the detention time and concentration of oridonin in blood,long-circulating oridonin liposomes were prepared.The distribution of long-circulating oridonin liposomes in blood and tissues in mice were studied.The theraputic effects of long-circulating oridonin liposomes on H_(22) mousehepatoma carcinoma cells induced cancer mice were evaluted.
The extraction and purification processes of oridonin from Rabdosia rubescens were first studied.Rabdosia rubescens powder was ultrasonic extracted with 95%ethanol with a 12:1 ratio of solvent:Rabdosia rubescens for 30 minutes.Repeat the ultrasonic extraction for another 2 times.The combined ethanol extract was then ultrasonic decolorized with active carbon for 20 minutes.Repeat the ultrasonic decolorization one more time.The dosage of active carbon was 0.24g for 1g of Rabdosia rubescens used.The preparative high performance liquid chromatography separative conditions of crude oridonin were investigated. The decolorized oridonin was separated by a reverse phaseμBondapack~(TM)C_(18) column(80mm i.d×300mm,grain size 25μm～40μm).The temperature of the column was maintained at 40℃.The mobile phase was CH_3OH-H_2O(50/50,V/V).The flow rate was 60mL·min~(-1).The detective wave-length was set to 238nm and the injective volumn was 10mL.The eluted solution of 16min～23min was evaporated and vacuum dried.White powder of oridonin was obtained with 99.0%by HPLC.The extraction yield of oridonin was 65.4%based on analysed concentration of oridonin in Rabdosia rubescens.The structure of the final product separated was identified by LC-Ms,elemental analysis,UV,IR,HPLC and NMR spectrum.
To optimize preparing technique of long-circulating oridonin liposomes and establish HPLC method for determination of oridonin liposomes,the influence of various factors, including the dosage of lecithin,cholesterol,oridonin,PEG_(2000)-DSPE,hydrous medium and kinds of hydrous medium on the entrapment efficiency and ratio of loading drug were investigated,and the optimum formula was selected through orthogonal design test.The concentration of oridonin was determined by HPLC using a reverse phase Lichrospher C_(18) column(4.6mm i.d×250mm,grain size 5μm).The temperature of column was maintained at 40℃.The mobile phase was CH_3OH-H_2O(70/30,V/V).The flow rate was 1mL·min~(-1).The detective wave-length was set to 238nm and the injective volumn was 10μL.In the optimal process,0.26g lecithin,0.14g cholesterol,0.5g PEG_(2000)-DSPE,0.04g oridonin and 30mL pure water was used.The product had good size distribution from 100nm to 200nm.The mean particle size diameter was 150nm,entrapment efficiency was 95.4%and ratio of loading drug was 4.24%.The release time of oridonin from liposome was 96h.The preparative process of oridonin liposomes is feasible.The HPLC method is simple,rapid and the results is accurate and reliable.The regular oridonin liposomes was prepared in the same way without adding polyethylene glycol-distearoylphosphatidylethanolamine(PEG_(2000)-DSPE).
The long-circulating oridonin liposomes and regular oridonin liposomes were stored at 5℃for 80 days without visible change.Entrapment efficiency had no change.The result indicated that long-circulating oridonin liposomes and regular oridonin liposomes were stable at 5℃.
To study the biodistribution and pharmacokinetics of long-circulating oridonin liposomes and regular oridonin liposomes in mice,HPLC method was developed for the determination of the contents of oridonin in blood and tissues in mice.The long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin were tail iv administrated and results were compared.The relative targeting efficiency of long-circulating oridonin liposomes in the liver,spleen,lung,heart and kidney were 2.10,1.95,1.34,2.39 and 0.84;The relative targeting efficiency of regular oridonin liposomes in the liver,spleen,lung,heart and kidney were 4.47,3.84,1.49,1.89 and 0.92.The concentration-time curves of long-circulating oridonin liposomes was fitted to the two-compartment model with T_(1/2)~α＝3.18h,T_(1/2)~β＝98.36h, AUC_(0-48h)＝888.91 h·μg.mL~(-1),V_c＝19.17mL·Kg~(-1);The concentration-time curves of regular oridonin liposomes was fitted to the two-compartment model with T_(1/2)~α＝2.54h,T_(1/2)~β＝33.98h, AUC_(0-48h)＝356.69 h·μg·mL~(-1),V_c＝20.01mL·Kg~(-1);The concentration-time curves of free oridonin was fitted to the two-compartment model with T_(1/2)~α＝0.63h,T_(1/2)~β＝6.19h, AUC_(0-48h)＝156.07 h·μg·mL~(-1),V_c＝10.66mL·Kg~(-1).Long-circulating oridonin liposomes was found to reach a long circulation time.
For evaluation of the effect of long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin on tumor cells in vivo,H_(22) mousehepatoma carcinoma cells were transplanted subcutaneouly in mice to induce growth of solid tumors.Tumor weight inhibition rate was then detected after administration of the oridonin preparations. Long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin all showed antitumor effect.The long-circulating oridonin liposomes showed stronger antitumor effect than regular oridonin liposomes and free oridonin.The inhibitory rate of long-circulating oridonin liposomes,regular oridonin liposomes and free oridonin was 85.4%, 71.4%,63.7%at a dose of 3.35×10~(-2) g·Kg~(-1)·d~(-1),respectively.
引文
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