生物可降解性药物缓释支架下肢缺血血运重建研究
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摘要
在缺血局部持续稳定的释放外源性生长因子,如重组人碱性成纤维细胞生长因子(rhbFGF)是治疗心肌缺血性疾病或下肢缺血性疾病的有效方法。rhbFGF稳定性差易失活,制备过程须严格控制以维持其活性。在本研究中,我们制备了双层支架,内层为螺旋镁(Mg),外层为包载rhbFGF的高分子聚合物聚乳酸-聚乙醇酸共聚物(PLGA)。我们研究了此双层支架在促进下肢缺血大鼠模型血管新生方面的作用。
牛血清白蛋白(BSA)被用作模拟药物,体外药物释放实验表明,BSA可以缓慢持续释放4周。在磷酸盐缓冲液(PBS)中孵育时间为4周时,Mg-PLGA支架中释放的BSA的量为75.29±1.33%,而PLGA支架中释放的BSA的量仅为54.73±2.89%。通过光谱法(紫外可见分光光谱UV-Vis,荧光光谱,圆二色谱CD)研究不同浓度的Mg2+对BSA结构、构型的影响,结果表明BSA的二级结构并未受到影响。同时,我们研究了支架体外降解行为,通过扫描电镜观察支架表面形貌的变化,分析了不同时间点支架的降解百分比以及腐蚀溶液pH值的变化。
体外细胞实验表明,与PLGA-rhbFGF支架相比,Mg-PLGA-rhbFGF支架对血管平滑肌细胞(SMC)有更低的毒性,更能促进细胞的增殖与迁移。在体内动物实验中,我们制备了大鼠下肢缺血模型,机械打孔后置入支架。术后2、4、6周,取支架周围组织进行分析。HE染色及CD31‘免疫组织化学染色显示：Mg-PLGA-rhbFGF支架中释放的rhbFGF更能促进下肢血管的新生。支架置入6周,Mg-PLGA-rhbFGF支架组的血管密度为85.3±10.1(number/mm2),明显高于PLGA-rhbFGF支架组(71.0±5.6)(number/mm2)和对照组(8.7±0.6)(number/mm2),p<0.01。Mg-PLGA-rhbFGF和PLGA-rhbFGF支架组的血流灌注恢复分别达到99.08±0.029%和80.68±0.032%,而对照组缺血下肢血流基本上未恢复。支架置入组大鼠体内Mg2+浓度在正常范围内,血常规及内脏病理学检测均正常,表明我们制备的支架具有良好的生物相容性。
葛根素是从豆科植物野葛或甘葛藤根中提取的一种异黄酮类化合物,被广泛应用于冠状动脉疾病,其在下肢缺血性疾病中的应用未曾见报道,且在以往的报道与研究中,葛根素的给药途径均局限为静脉注射、腹腔注射或灌胃。本研究中,我们将葛根素包载于高分子聚合物PLGA中,制得PLGA-葛根素支架,达到了缓释的效果,将其置入下肢缺血模型大鼠缺血下肢中,观察其促进血管新生的作用。此支架在大鼠缺血下肢血管新生及血流灌注方面均取得了良好的效果。我们对机制也进行了初步的探讨,结果发现,在支架置入组,骨骼肌中与血管新生密切相关的一氧化氮合酶(eNOs)、血管衍生生长因子-β(PDGF-β)、血管内皮生长因子(VEGF)mRNA均有着高表达量。支架置入组大鼠并未出现溶血反应,血常规及内脏病理学检测均正常,表明支架具有良好的生物相容性。之后我们将葛根素应用于创伤修复中,也取得了较好的效果。
综上所述,载rhbFGF的Mg-PLGA药物涂层支架及载葛根素的PLGA药物涂层支架可促进下肢缺血大鼠缺血骨骼肌血管新生,为危重症下肢缺血性疾病的治疗提供理论基础。
制备新型脑主动靶向抗体0X26耦联的超支化聚甘油接枝的聚乳酸-聚乙醇酸(hyperbranched polyglycerol-conjugated poly(lactic-co-glycolic acid), HPG-PLGA)纳米粒子。合成、表征聚合物HPG-PLGA,并通过复合乳液法制备纳米粒子,透射电镜显示纳米粒子平均粒径为170±20nm,X射线光电子能谱进行表面元素分析。内吗啡肽,作为模拟药物,被包载于纳米粒子中。体外药物释放实验表面内吗啡肽可以持续释放长达72h。细胞实验表明脑微血管内皮细胞对纳米离子的摄取作用是时间依赖性和浓度依赖性,摄取抑制实验表明这是一个caveolae相关的吸附介导的内吞过程。动物实验在慢性坐骨神经结扎大鼠模型上进行,0X26耦联的纳米粒子组与其他组相比,有较好的镇痛效果。因而,0X26耦联的HPG-PLGA纳米粒子是一个有广阔应用前景的脑靶向转运体。
Site-specific controlled release of exogenous, angiogenic growth factors such as recombinant human basic fibroblast growth factor (rhbFGF) has become a promising approach to improve ischemic heart disease or peripheral vascular disease. RhbFGF is unstable and the preparation process must be controlled strictively to maintain the bio-activity of rhbFGF. In the present study, we prepared a tubular stent composed by spiral magnesium (Mg) in the inner and a coating including a therapeutic agent rhbFGF and poly(lactic-co-glycolic acid)(PLGA) as matrix in the outer. We tested its effect on promoting angiogenesis in rat limb ischemic model.
In vitro release studies showed that the model protein bovine serum albumin (BSA) was released continuously for4weeks. BSA was released75.29±1.33%from Mg-PLGA stent and54.73±2.89%from PLGA stent4weeks after immersion in phosphate buffered saline (PBS). Influence of different concentrations of Mg2+on the structure of BSA was investigated by ultraviolet-visible (UV-Vis) spectra, fluorescence spectra and circular dichroism (CD) spectra. Results indicated that the secondary structure of BSA was not influenced by the addition of Mg2+. The in vitro degradation study was processed. The corrosion morphology was observed by scanning electron microscopy (SEM). The degradation percentage and the pH of the solution were tested at predetermined time points.
The in vitro cell experiments revealed that Mg-PLGA-rhbFGF stent had advantages over PLGA-rhbFGF stent on cytotoxicity, proliferation and migration. Rat limb ischemic model was build and stent was implanted into the adductor muscle after the creation of a mechanical channel.2,4and6weeks post stents implantation, muscle adjescent to the stent was retrieved for analysis. HE staining and CD31+immunostaining revealed that the controlled release of rhbFGF from Mg-PLGA-rhbFGF stent was superior in promoting angiogenesis to PLGA-rhbFGF stent.6weeks post stent implantation, the capillary density of Mg-PLGA-rhbFGF group was85.3±10.1(number/mm2), much higher to PLGA-rhbFGF group (71.0±5.6)(number/mm2) and control group (8.7±0.6)(number/mm2), p<0.01. What's more, the limb blood perfusion ratio of Mg-PLGA-rhbFGF and PLGA-rhbFGF group were dramatically increased, with data99.08±0.029%and80.68±0.032%, respectively, whereas the ischemia limb didn't recover in the control group. The concentrations of Mg2+were within normal range in the body fluid. Routine blood test and visceral pathology were conducted and no adverse effect was detected. The stents we prepared had good biocompatibility.
Puerarin is a major effective isoflavonoids extracted from the traditional Chinese medicine Ge-gen (Radix Puerariae, RP). Puerarin has been used to treat patients with coronary artery diseases (CAD). Limited data related to the effect of puerarin on PVD were seen. In the previous study, the routes of administration of puerarin were focused up on intravenous, intraperitoneal injection or gavage administration. In this study, puerarin was encapsulated in the copolymer PLGA and the role of PLGA-puerarin on angiogenesis in rat limb ischemic model was tested. It was found that PLGA-puerarin induced angiogenesis and increased blood perfusion ratio in the rat ischemic limb. The gene expression or activation of endothelial nitric oxide synthase (eNOS), platelet derived growth factor-β (PDGF-β) and vascular endothelial growth factor (VEGF) that correlated with angiogenesis were with high expression in the muscle adjescent to the implanted PLGA-puerarin stent. The stents we prepared didn't induce any hemolytic reaction. Routine blood test and visceral pathology were conducted and no adverse effect was detected. The stent we prepared had good biocompatibility. Wound healing study was conducted and results Indicated that puerarin had benefit effect on wound healing.
RhbFGF loaded Mg-PLGA stent and puerarin loaded PLGA stent could promote angiogenesis of rat limb ischemia, and they may provide a theoretical basis for the critical ill patients suffered from lower limb ischemic disease.
A novel nanoparticles (NPs)-based brain drug delivery system made of hyperbranched polyglycerol-conjugated poly (lactic-co-glycolic acid)(HPG-PLGA) which was surface functionalized with transferrin antibody (0X26) was prepared. HPG-PLGA was synthesized, characterized and applied to prepare NPs by means of double emulsion solvent evaporation technique. Transmission electron micrograph showed that NPs had a round and regular shape with a mean diameter of170±20nm. Surface chemical composition was detected by X-ray photoelectron spectroscopy. Endomorphins (EM), as a model drug, was encapsulated in the NPs. In vitro drug release study showed that EM was released continuously for72h. Cellular uptake study showed that the uptake of NPs by the brain microvascular endothelial cells was both time-and concentration-dependant. Further uptake inhibition study indicated that the uptake of NPs was via a caveolae-mediated endocytic pathway. In vivo EM brain delivery ability was evaluated based upon the rat model of chronic constriction injury of sciatic nerve.0X26modified NPs had achieved better analgesic effects, compared with other groups. Thus,0X26modified HPG-PLGA NPs may be a promising brain drug delivery carrier.
牛血清白蛋白(BSA)被用作模拟药物,体外药物释放实验表明,BSA可以缓慢持续释放4周。在磷酸盐缓冲液(PBS)中孵育时间为4周时,Mg-PLGA支架中释放的BSA的量为75.29±1.33%,而PLGA支架中释放的BSA的量仅为54.73±2.89%。通过光谱法(紫外可见分光光谱UV-Vis,荧光光谱,圆二色谱CD)研究不同浓度的Mg2+对BSA结构、构型的影响,结果表明BSA的二级结构并未受到影响。同时,我们研究了支架体外降解行为,通过扫描电镜观察支架表面形貌的变化,分析了不同时间点支架的降解百分比以及腐蚀溶液pH值的变化。
体外细胞实验表明,与PLGA-rhbFGF支架相比,Mg-PLGA-rhbFGF支架对血管平滑肌细胞(SMC)有更低的毒性,更能促进细胞的增殖与迁移。在体内动物实验中,我们制备了大鼠下肢缺血模型,机械打孔后置入支架。术后2、4、6周,取支架周围组织进行分析。HE染色及CD31‘免疫组织化学染色显示：Mg-PLGA-rhbFGF支架中释放的rhbFGF更能促进下肢血管的新生。支架置入6周,Mg-PLGA-rhbFGF支架组的血管密度为85.3±10.1(number/mm2),明显高于PLGA-rhbFGF支架组(71.0±5.6)(number/mm2)和对照组(8.7±0.6)(number/mm2),p<0.01。Mg-PLGA-rhbFGF和PLGA-rhbFGF支架组的血流灌注恢复分别达到99.08±0.029%和80.68±0.032%,而对照组缺血下肢血流基本上未恢复。支架置入组大鼠体内Mg2+浓度在正常范围内,血常规及内脏病理学检测均正常,表明我们制备的支架具有良好的生物相容性。
葛根素是从豆科植物野葛或甘葛藤根中提取的一种异黄酮类化合物,被广泛应用于冠状动脉疾病,其在下肢缺血性疾病中的应用未曾见报道,且在以往的报道与研究中,葛根素的给药途径均局限为静脉注射、腹腔注射或灌胃。本研究中,我们将葛根素包载于高分子聚合物PLGA中,制得PLGA-葛根素支架,达到了缓释的效果,将其置入下肢缺血模型大鼠缺血下肢中,观察其促进血管新生的作用。此支架在大鼠缺血下肢血管新生及血流灌注方面均取得了良好的效果。我们对机制也进行了初步的探讨,结果发现,在支架置入组,骨骼肌中与血管新生密切相关的一氧化氮合酶(eNOs)、血管衍生生长因子-β(PDGF-β)、血管内皮生长因子(VEGF)mRNA均有着高表达量。支架置入组大鼠并未出现溶血反应,血常规及内脏病理学检测均正常,表明支架具有良好的生物相容性。之后我们将葛根素应用于创伤修复中,也取得了较好的效果。
综上所述,载rhbFGF的Mg-PLGA药物涂层支架及载葛根素的PLGA药物涂层支架可促进下肢缺血大鼠缺血骨骼肌血管新生,为危重症下肢缺血性疾病的治疗提供理论基础。
制备新型脑主动靶向抗体0X26耦联的超支化聚甘油接枝的聚乳酸-聚乙醇酸(hyperbranched polyglycerol-conjugated poly(lactic-co-glycolic acid), HPG-PLGA)纳米粒子。合成、表征聚合物HPG-PLGA,并通过复合乳液法制备纳米粒子,透射电镜显示纳米粒子平均粒径为170±20nm,X射线光电子能谱进行表面元素分析。内吗啡肽,作为模拟药物,被包载于纳米粒子中。体外药物释放实验表面内吗啡肽可以持续释放长达72h。细胞实验表明脑微血管内皮细胞对纳米离子的摄取作用是时间依赖性和浓度依赖性,摄取抑制实验表明这是一个caveolae相关的吸附介导的内吞过程。动物实验在慢性坐骨神经结扎大鼠模型上进行,0X26耦联的纳米粒子组与其他组相比,有较好的镇痛效果。因而,0X26耦联的HPG-PLGA纳米粒子是一个有广阔应用前景的脑靶向转运体。
Site-specific controlled release of exogenous, angiogenic growth factors such as recombinant human basic fibroblast growth factor (rhbFGF) has become a promising approach to improve ischemic heart disease or peripheral vascular disease. RhbFGF is unstable and the preparation process must be controlled strictively to maintain the bio-activity of rhbFGF. In the present study, we prepared a tubular stent composed by spiral magnesium (Mg) in the inner and a coating including a therapeutic agent rhbFGF and poly(lactic-co-glycolic acid)(PLGA) as matrix in the outer. We tested its effect on promoting angiogenesis in rat limb ischemic model.
In vitro release studies showed that the model protein bovine serum albumin (BSA) was released continuously for4weeks. BSA was released75.29±1.33%from Mg-PLGA stent and54.73±2.89%from PLGA stent4weeks after immersion in phosphate buffered saline (PBS). Influence of different concentrations of Mg2+on the structure of BSA was investigated by ultraviolet-visible (UV-Vis) spectra, fluorescence spectra and circular dichroism (CD) spectra. Results indicated that the secondary structure of BSA was not influenced by the addition of Mg2+. The in vitro degradation study was processed. The corrosion morphology was observed by scanning electron microscopy (SEM). The degradation percentage and the pH of the solution were tested at predetermined time points.
The in vitro cell experiments revealed that Mg-PLGA-rhbFGF stent had advantages over PLGA-rhbFGF stent on cytotoxicity, proliferation and migration. Rat limb ischemic model was build and stent was implanted into the adductor muscle after the creation of a mechanical channel.2,4and6weeks post stents implantation, muscle adjescent to the stent was retrieved for analysis. HE staining and CD31+immunostaining revealed that the controlled release of rhbFGF from Mg-PLGA-rhbFGF stent was superior in promoting angiogenesis to PLGA-rhbFGF stent.6weeks post stent implantation, the capillary density of Mg-PLGA-rhbFGF group was85.3±10.1(number/mm2), much higher to PLGA-rhbFGF group (71.0±5.6)(number/mm2) and control group (8.7±0.6)(number/mm2), p<0.01. What's more, the limb blood perfusion ratio of Mg-PLGA-rhbFGF and PLGA-rhbFGF group were dramatically increased, with data99.08±0.029%and80.68±0.032%, respectively, whereas the ischemia limb didn't recover in the control group. The concentrations of Mg2+were within normal range in the body fluid. Routine blood test and visceral pathology were conducted and no adverse effect was detected. The stents we prepared had good biocompatibility.
Puerarin is a major effective isoflavonoids extracted from the traditional Chinese medicine Ge-gen (Radix Puerariae, RP). Puerarin has been used to treat patients with coronary artery diseases (CAD). Limited data related to the effect of puerarin on PVD were seen. In the previous study, the routes of administration of puerarin were focused up on intravenous, intraperitoneal injection or gavage administration. In this study, puerarin was encapsulated in the copolymer PLGA and the role of PLGA-puerarin on angiogenesis in rat limb ischemic model was tested. It was found that PLGA-puerarin induced angiogenesis and increased blood perfusion ratio in the rat ischemic limb. The gene expression or activation of endothelial nitric oxide synthase (eNOS), platelet derived growth factor-β (PDGF-β) and vascular endothelial growth factor (VEGF) that correlated with angiogenesis were with high expression in the muscle adjescent to the implanted PLGA-puerarin stent. The stents we prepared didn't induce any hemolytic reaction. Routine blood test and visceral pathology were conducted and no adverse effect was detected. The stent we prepared had good biocompatibility. Wound healing study was conducted and results Indicated that puerarin had benefit effect on wound healing.
RhbFGF loaded Mg-PLGA stent and puerarin loaded PLGA stent could promote angiogenesis of rat limb ischemia, and they may provide a theoretical basis for the critical ill patients suffered from lower limb ischemic disease.
A novel nanoparticles (NPs)-based brain drug delivery system made of hyperbranched polyglycerol-conjugated poly (lactic-co-glycolic acid)(HPG-PLGA) which was surface functionalized with transferrin antibody (0X26) was prepared. HPG-PLGA was synthesized, characterized and applied to prepare NPs by means of double emulsion solvent evaporation technique. Transmission electron micrograph showed that NPs had a round and regular shape with a mean diameter of170±20nm. Surface chemical composition was detected by X-ray photoelectron spectroscopy. Endomorphins (EM), as a model drug, was encapsulated in the NPs. In vitro drug release study showed that EM was released continuously for72h. Cellular uptake study showed that the uptake of NPs by the brain microvascular endothelial cells was both time-and concentration-dependant. Further uptake inhibition study indicated that the uptake of NPs was via a caveolae-mediated endocytic pathway. In vivo EM brain delivery ability was evaluated based upon the rat model of chronic constriction injury of sciatic nerve.0X26modified NPs had achieved better analgesic effects, compared with other groups. Thus,0X26modified HPG-PLGA NPs may be a promising brain drug delivery carrier.
引文
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