载羟基喜树碱聚乳酸羟基乙酸微球的制备及抑制肝癌栓塞后血管生成的实验研究
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摘要
1载羟基喜树碱的聚乳酸羟基乙酸微球的制备及表征
目的：通过乳液溶剂挥发法制备可以用于动脉栓塞研究的PLGA空白微球及载有HCPT的PLGA载药微球,并且对微球的特性进行表征。
材料与方法：采用O/W乳液乳剂挥发法制备PLGA微球,通过比较有机溶剂二氯甲烷与二甲基甲酰胺比例、投药比、聚合物浓度、乳化时间、乳化转速等对微球的形态、载药量及粒径分布情况的影响,筛选出制备微球的最佳方案。根据筛选出的处方制备空白PLGA微球及载药PLGA微球,评价制备方案的稳定性。通过荧光显微镜、电镜等进行微球的形态表征,激光粒度仪测定粒径分布。使用恒温摇床研究载药37℃下在PBS中缓释药物的情况,HPLC法检测不同时间点的取样浓度,计算累计释药量,绘制微球的药物缓释曲线。
结果：使用乳液溶剂挥发法制备了粒径为85±37μm的载HCPT的PLGA微球,载药量0.4%,包封率64%,制备了粒径为90±41μm的空白PLGA微球。荧光显微镜下可观察到HCPT在微球内分布均匀,扫描电子显微镜下微球表面光整。体外药物释放实验表面微球的缓释作用良好,在第25天时微球累计释放了载药量的29.2%。
结论：乳液溶剂挥发法可以制备适合进行栓塞治疗使用的PLGA载药微球。
2PLGA微球栓塞兔VX2种植性肝癌模型的实验研究
目的：研究PLGA空白微球进行兔VX2种植性肝癌模型栓塞的可行性,通过与临床中常用栓塞剂PVA颗粒栓塞效果的对比,研究PLGA微球栓塞对肿瘤生长的影响。
材料与方法：制备兔VX2种植性肝癌模型30只,MR检查确定肝癌模型成功建立后将30只实验动物分为三组进行肝动脉栓塞治疗：A组进行生理盐水假栓塞,B组使用150-250μm的PVA颗粒栓塞剂进行栓塞,C组使用实验第一部分制备的空白的PLGA微球进行栓塞。栓塞后的第7天处死实验动物。计算栓塞前后肿瘤的坏死率及肿瘤生长率,比较不同栓塞方法对肿瘤生长的影响。
结果:PLGA微球可以经过2.7F微导管顺利进行栓塞治疗。三组肿瘤的生长率分别为：A组372.5±80.1%,B组175.3±80.9%,C组164.1±57.2%,A组与B组及C组间肿瘤生长率有统计学差异(P<0.05),B组肿瘤生长率虽然大于C组,但是无统计学差异(P>0.05)。肿瘤坏死率在A组肿瘤坏死率与B组和C组存在统计学差异(P<0.05),但是B组与C组间肿瘤坏死率无统计学差异(P>0.05)。
结论：PLGA微球可以作为肝癌动物模型中栓塞剂进行实验研究。
3载HCPT的PLGA微球抑制栓塞后残存肿瘤新生血管形成的实验研究
目的：研究载HCPT的微球抑制肝癌栓塞治疗后残存肿瘤组织内新生血管.
材料与方法：制备兔VX2肝癌模型40只,将40只荷瘤兔随机分为四组：A组接受生理盐水假栓塞,B组使用PLGA微球进行栓塞,C组使用载HCPT的PLGA微球进行栓塞,D组使用HCPT与碘油乳剂灌注肝动脉后再以150-250μm PVA颗粒栓塞供血动脉。在栓塞后第1天及第5天分别处死各组实验动物5只,4%多聚甲醛固定,石蜡包埋后切片,免疫组化染色分别检测HIF-1α、VEGF及MVD的表达情况。
结果：所有实验动物均成功进行了栓塞治疗并存活到实验观察终点。栓塞治疗后肿瘤组织内均可见肿瘤细胞的大片坏死,坏死区间点片状残存的肿瘤组织。免疫组织化学染色显示HIF-1α在残存肿瘤细胞的细胞核及胞浆内均有表达,正常肝脏组织及靠近肝脏的肿瘤组织内未见明显的HIF-1α表达。VEGF表达以坏死区旁边残存肿瘤细胞及血管内皮细胞中表达为主,正常肝脏组织及与之相邻的肿瘤组织也存在不同程度的表达。新生血管再肿瘤组织散在分布,在肿瘤组织边缘微血管密度较其他部位高。统计学分析发现进行PLGA栓塞的实验动物残存肿瘤组织HIF-1α和VEGF的表达以及MVD明显高于其他的实验组(P<0.05),而接受生理盐水假栓塞、载药微球及HCPT乳剂栓塞的实验组肿瘤组织内HIF-1α和VEGF的表达无明显的差别(P>0.05)
结论：载HCPT的PLGA微球可能通过缓慢释放HCPT抑制残存肿瘤组织新生血管的形成,增强栓塞治疗的效果。
Part I Preparation and Characterization of the HCPT Loaded PLGA microspheres
Objective:To prepare the HCPT loaded PLGA microspheres and blank PLGA microspheres with the emulsion solvent evaporation method. The microspheres were characterized after the preparations.
Materials and methods:The microspheres were prepared with O/W emulsion solvent evaporation method. The factors affecting the formation of microspheres including organic solvent ratio of dichloromethane and dimethylformamide, polymer concentration, emulsification time, stirring rate were screened to get suitable programs for the best parameter to control the microsphere morphology, drug loading and particle size distribution. The blank microspheres and drug loaded microspheres were prepared with the screened method. The microspheres were characterized with the fluorescence microscopy to detect the loaded HCPT, electron microscopy to observe the morphology, laser particle size analyzer determination of particle size distribution. In vitro drug release was performed within the dialysis bag in a constant temperature shaker with PBS at37℃. The concentration of samples at different time points were calculated the cumulative amount of drug release to create a release curve.
Results: The blank PLGA microspheres and HCPT loaded microspheres were successfully prepared with the emulsion solvent evaporation method. The average diameter of the PLGA loading HCPT microspheres was85±37μm (mean±standard deviation), and average diameter the blank PLGA microspheres was90±41μm (mean±standard deviation). The drug loading rate was0.4%and the encapsulation rate was65%. HCPT distributed uniformly in the microspheres with green fluorescence in the fluorescent microscope. The microspheres showed smart surface in the scanning electron microscope. HCPT were sustained released form the microsphere and29.2%drugs were released from the microspheres in the25th days in the vitro release system.
Conclusion:The emulsion solvent evaporation method can be used to prepared PLGA drug-loading microspheres that were suitable for the transcatheter arterial embolization.
Part II Experimental Evaluation of the PLGA microspheres for Embolization in the Rabbit VX2Liver Tumor Model
Objective:To investigate the feasibility of blank PLGA microspheres in the rabbit VX2implanted liver tumor model embolism. Compare the embolic effect of the PLGA microspheres with PVA particles which is commonly used in clinic as embolic agent by evaluating the tumor growth rate.
Materials and mthods:Thirty tumor-bearing rabbits which were conformed with MRI were divided into threes groups randomly (10in each group). The rabbits in the group A were treated with false embolization with saline. The transcatheter arterial embolizaton was performed in the group B with blank PLGA microspheres. The rabbits in the group C received transcatheter arterial embolizaion with PVA particles (150-250μm). The rabbits were humanly sacrificed in seventh days after the embolization and the liver scan was performed with MRI before the sacrifice. The tumor growth rate was calculated by comparing the tumor volume before and after the embolic therapy.
Results:PLGA microspheres can be subjected to2.7F micro-catheter to perform embolization. Three groups of tumor growth rates were372.5±80.1%,175.3±80.9%and164.1±57.2%in group A, group B and group C, respectively. There was statistically significant difference among groups (P<0.05). Although tumor growth rate in group B was greater than that in group C, there was no significant difference (P>0.05). Ther was sigfificant difference among groups for the tumor necrosis rate, but there was no significant difference between group B and group C.
Conclusion:PLGA microspheres can be used as the embolic agent in liver cancer animal models for experimental research.
Part III Experimental evaluation the inhibition of angiogenesis in residual tumor after embolization with HCPT loaded PLGA microspheres
Objective:To investigate the inhibition of angiogenesis in the residual tumor after embolization with HCPT loaded PLGA microspheres.
Materials and methods:A total of40tumor bearing rabbits of VX2carcinoma was divided into4groups randomly (10in each group). The rabbits in group A received saline false embolism. The rabbits in group B were embolized with PLGA microspheres. The rabbits in group C were treated with PLGA microspheres containing HCPT. For the animals in group D, emulsion containing HCPT and Lipiodol was infused to the hepatic artery and then the150-250μm PVA particles were used to embolize the tumor feeding arteries. Five animals were sacrificed in1st or5th days after embolization with sodium pentobarbital (100mg/kg). The tumor samples were harvested and fixed in4%paraformaldehyde. Then the samples were embedded in paraffin and sliced for immunohistochemical staining to detect the expression of HIF-1α and VEGF and MVD.
Results:The interventional therapy was successfully performed in all animals. And the animals survived to the end of the experimental observation. Large area necrosis was found in the animals slice that receiving emblolic therapy and residual tumor cells scattered in the tumor. Immunohistochemical staining showed that HIF-1expression in both the nucleus and cytoplasm in the residual tumor cells but not in the liver tissue and tumor cells near the normal liver tissues. VEGF staining was mainly found in the residual tumor cells and vascular endothelial cells of the residual tumor tissues, and a few in normal liver tissue and adjacent tumor tissue. The neovascularization localized in the tumor edge predominantly. There was significant difference for the expression of HIF-la and VEGF and MVD respectively (P<0.05). The expression of HIF-1α and VEGF and MVD in the animals treated with PLGA microspheres was significantly higher than the experimental group in the residual tumor tissues. There was no significant difference for the expression of HIF-1α and VEGF and MVD in group1,3and4(P>0.05).
Conclusion:HCPT loaded PLGA microspheres showed the inhibition of angiogenesis in the residual tumor by inhibiting the HIF-1α with the HCPT released from the microspheres, therefore enhancing the effect of embolization.
目的：通过乳液溶剂挥发法制备可以用于动脉栓塞研究的PLGA空白微球及载有HCPT的PLGA载药微球,并且对微球的特性进行表征。
材料与方法：采用O/W乳液乳剂挥发法制备PLGA微球,通过比较有机溶剂二氯甲烷与二甲基甲酰胺比例、投药比、聚合物浓度、乳化时间、乳化转速等对微球的形态、载药量及粒径分布情况的影响,筛选出制备微球的最佳方案。根据筛选出的处方制备空白PLGA微球及载药PLGA微球,评价制备方案的稳定性。通过荧光显微镜、电镜等进行微球的形态表征,激光粒度仪测定粒径分布。使用恒温摇床研究载药37℃下在PBS中缓释药物的情况,HPLC法检测不同时间点的取样浓度,计算累计释药量,绘制微球的药物缓释曲线。
结果：使用乳液溶剂挥发法制备了粒径为85±37μm的载HCPT的PLGA微球,载药量0.4%,包封率64%,制备了粒径为90±41μm的空白PLGA微球。荧光显微镜下可观察到HCPT在微球内分布均匀,扫描电子显微镜下微球表面光整。体外药物释放实验表面微球的缓释作用良好,在第25天时微球累计释放了载药量的29.2%。
结论：乳液溶剂挥发法可以制备适合进行栓塞治疗使用的PLGA载药微球。
2PLGA微球栓塞兔VX2种植性肝癌模型的实验研究
目的：研究PLGA空白微球进行兔VX2种植性肝癌模型栓塞的可行性,通过与临床中常用栓塞剂PVA颗粒栓塞效果的对比,研究PLGA微球栓塞对肿瘤生长的影响。
材料与方法：制备兔VX2种植性肝癌模型30只,MR检查确定肝癌模型成功建立后将30只实验动物分为三组进行肝动脉栓塞治疗：A组进行生理盐水假栓塞,B组使用150-250μm的PVA颗粒栓塞剂进行栓塞,C组使用实验第一部分制备的空白的PLGA微球进行栓塞。栓塞后的第7天处死实验动物。计算栓塞前后肿瘤的坏死率及肿瘤生长率,比较不同栓塞方法对肿瘤生长的影响。
结果:PLGA微球可以经过2.7F微导管顺利进行栓塞治疗。三组肿瘤的生长率分别为：A组372.5±80.1%,B组175.3±80.9%,C组164.1±57.2%,A组与B组及C组间肿瘤生长率有统计学差异(P<0.05),B组肿瘤生长率虽然大于C组,但是无统计学差异(P>0.05)。肿瘤坏死率在A组肿瘤坏死率与B组和C组存在统计学差异(P<0.05),但是B组与C组间肿瘤坏死率无统计学差异(P>0.05)。
结论：PLGA微球可以作为肝癌动物模型中栓塞剂进行实验研究。
3载HCPT的PLGA微球抑制栓塞后残存肿瘤新生血管形成的实验研究
目的：研究载HCPT的微球抑制肝癌栓塞治疗后残存肿瘤组织内新生血管.
材料与方法：制备兔VX2肝癌模型40只,将40只荷瘤兔随机分为四组：A组接受生理盐水假栓塞,B组使用PLGA微球进行栓塞,C组使用载HCPT的PLGA微球进行栓塞,D组使用HCPT与碘油乳剂灌注肝动脉后再以150-250μm PVA颗粒栓塞供血动脉。在栓塞后第1天及第5天分别处死各组实验动物5只,4%多聚甲醛固定,石蜡包埋后切片,免疫组化染色分别检测HIF-1α、VEGF及MVD的表达情况。
结果：所有实验动物均成功进行了栓塞治疗并存活到实验观察终点。栓塞治疗后肿瘤组织内均可见肿瘤细胞的大片坏死,坏死区间点片状残存的肿瘤组织。免疫组织化学染色显示HIF-1α在残存肿瘤细胞的细胞核及胞浆内均有表达,正常肝脏组织及靠近肝脏的肿瘤组织内未见明显的HIF-1α表达。VEGF表达以坏死区旁边残存肿瘤细胞及血管内皮细胞中表达为主,正常肝脏组织及与之相邻的肿瘤组织也存在不同程度的表达。新生血管再肿瘤组织散在分布,在肿瘤组织边缘微血管密度较其他部位高。统计学分析发现进行PLGA栓塞的实验动物残存肿瘤组织HIF-1α和VEGF的表达以及MVD明显高于其他的实验组(P<0.05),而接受生理盐水假栓塞、载药微球及HCPT乳剂栓塞的实验组肿瘤组织内HIF-1α和VEGF的表达无明显的差别(P>0.05)
结论：载HCPT的PLGA微球可能通过缓慢释放HCPT抑制残存肿瘤组织新生血管的形成,增强栓塞治疗的效果。
Part I Preparation and Characterization of the HCPT Loaded PLGA microspheres
Objective:To prepare the HCPT loaded PLGA microspheres and blank PLGA microspheres with the emulsion solvent evaporation method. The microspheres were characterized after the preparations.
Materials and methods:The microspheres were prepared with O/W emulsion solvent evaporation method. The factors affecting the formation of microspheres including organic solvent ratio of dichloromethane and dimethylformamide, polymer concentration, emulsification time, stirring rate were screened to get suitable programs for the best parameter to control the microsphere morphology, drug loading and particle size distribution. The blank microspheres and drug loaded microspheres were prepared with the screened method. The microspheres were characterized with the fluorescence microscopy to detect the loaded HCPT, electron microscopy to observe the morphology, laser particle size analyzer determination of particle size distribution. In vitro drug release was performed within the dialysis bag in a constant temperature shaker with PBS at37℃. The concentration of samples at different time points were calculated the cumulative amount of drug release to create a release curve.
Results: The blank PLGA microspheres and HCPT loaded microspheres were successfully prepared with the emulsion solvent evaporation method. The average diameter of the PLGA loading HCPT microspheres was85±37μm (mean±standard deviation), and average diameter the blank PLGA microspheres was90±41μm (mean±standard deviation). The drug loading rate was0.4%and the encapsulation rate was65%. HCPT distributed uniformly in the microspheres with green fluorescence in the fluorescent microscope. The microspheres showed smart surface in the scanning electron microscope. HCPT were sustained released form the microsphere and29.2%drugs were released from the microspheres in the25th days in the vitro release system.
Conclusion:The emulsion solvent evaporation method can be used to prepared PLGA drug-loading microspheres that were suitable for the transcatheter arterial embolization.
Part II Experimental Evaluation of the PLGA microspheres for Embolization in the Rabbit VX2Liver Tumor Model
Objective:To investigate the feasibility of blank PLGA microspheres in the rabbit VX2implanted liver tumor model embolism. Compare the embolic effect of the PLGA microspheres with PVA particles which is commonly used in clinic as embolic agent by evaluating the tumor growth rate.
Materials and mthods:Thirty tumor-bearing rabbits which were conformed with MRI were divided into threes groups randomly (10in each group). The rabbits in the group A were treated with false embolization with saline. The transcatheter arterial embolizaton was performed in the group B with blank PLGA microspheres. The rabbits in the group C received transcatheter arterial embolizaion with PVA particles (150-250μm). The rabbits were humanly sacrificed in seventh days after the embolization and the liver scan was performed with MRI before the sacrifice. The tumor growth rate was calculated by comparing the tumor volume before and after the embolic therapy.
Results:PLGA microspheres can be subjected to2.7F micro-catheter to perform embolization. Three groups of tumor growth rates were372.5±80.1%,175.3±80.9%and164.1±57.2%in group A, group B and group C, respectively. There was statistically significant difference among groups (P<0.05). Although tumor growth rate in group B was greater than that in group C, there was no significant difference (P>0.05). Ther was sigfificant difference among groups for the tumor necrosis rate, but there was no significant difference between group B and group C.
Conclusion:PLGA microspheres can be used as the embolic agent in liver cancer animal models for experimental research.
Part III Experimental evaluation the inhibition of angiogenesis in residual tumor after embolization with HCPT loaded PLGA microspheres
Objective:To investigate the inhibition of angiogenesis in the residual tumor after embolization with HCPT loaded PLGA microspheres.
Materials and methods:A total of40tumor bearing rabbits of VX2carcinoma was divided into4groups randomly (10in each group). The rabbits in group A received saline false embolism. The rabbits in group B were embolized with PLGA microspheres. The rabbits in group C were treated with PLGA microspheres containing HCPT. For the animals in group D, emulsion containing HCPT and Lipiodol was infused to the hepatic artery and then the150-250μm PVA particles were used to embolize the tumor feeding arteries. Five animals were sacrificed in1st or5th days after embolization with sodium pentobarbital (100mg/kg). The tumor samples were harvested and fixed in4%paraformaldehyde. Then the samples were embedded in paraffin and sliced for immunohistochemical staining to detect the expression of HIF-1α and VEGF and MVD.
Results:The interventional therapy was successfully performed in all animals. And the animals survived to the end of the experimental observation. Large area necrosis was found in the animals slice that receiving emblolic therapy and residual tumor cells scattered in the tumor. Immunohistochemical staining showed that HIF-1expression in both the nucleus and cytoplasm in the residual tumor cells but not in the liver tissue and tumor cells near the normal liver tissues. VEGF staining was mainly found in the residual tumor cells and vascular endothelial cells of the residual tumor tissues, and a few in normal liver tissue and adjacent tumor tissue. The neovascularization localized in the tumor edge predominantly. There was significant difference for the expression of HIF-la and VEGF and MVD respectively (P<0.05). The expression of HIF-1α and VEGF and MVD in the animals treated with PLGA microspheres was significantly higher than the experimental group in the residual tumor tissues. There was no significant difference for the expression of HIF-1α and VEGF and MVD in group1,3and4(P>0.05).
Conclusion:HCPT loaded PLGA microspheres showed the inhibition of angiogenesis in the residual tumor by inhibiting the HIF-1α with the HCPT released from the microspheres, therefore enhancing the effect of embolization.
引文
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