胃癌血管靶向肽GX1介导的载紫杉醇纳米脂质载体的制备及表征
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摘要
目的:制备胃癌血管靶向肽GX1介导的载紫杉醇靶向纳米脂质载体(GX1-PTX-NLCs),并对其制剂学性质、体外释放及稳定性进行考察。方法:采用乳化溶剂挥发法制备纳米脂质载体,并以粒径、Zeta电位、包封率、载药量等评价指标筛选出最佳制备处方,通过透射电镜对纳米脂质载体进行形态学考察,在2~8℃条件下观察纳米粒8 d内的稳定性,并考察了其体外释放情况。结果:采用最佳制备处方得到的GX1-PTX-NLCs粒径小而均匀,平均粒径(198.6±3.13)nm,Zeta电位值为(-11.9±1.08)mV,包封率达到80%以上,载药量为(0.4±0.013)%;GX1-PTX-NLCs在透射电镜下呈球形,包载药物清晰可见;8 d内PTXNLCs与GX1-PTX-NLCs稳定性良好,包封率和载药量无显著变化;体外释放实验GX1-PTX-NLCs在16 h全部释放完毕,与原药相比缓释效果明显。结论:胃癌血管靶向肽GX1介导的载紫杉醇靶向纳米脂质载体包封率高,稳定性良好,是一种潜在的高效靶向制剂。
Objective: To prepare gastric cancer vasculature targeted peptide GX1 mediated nanostructured lipid carriers( NLCs) loaded with paclitaxel( GX1-PTX-NLCs),and investigate their characteristics,in vitro release and stability. Methods: In the present work,the paclitaxel-loaded nanostructured lipid carriers( PTXNLCs) were prepared by emulsion solvent evaporation technique. Optimization of the preparation formulation of NLCs was accomplished using particle size,Zeta potential,entrapment efficiency( EE) and drug loading( DL) as evaluation indexes. Transmission electron microscope( TEM) was used to characterize the morphology of NLCs.The in vitro release and stability of NLCs in 8 days were performed at 2 ~ 8 ℃. Results: The particle sizes of the prepared NLCs were small and well-distributed. The particle size,Zeta potential,entrapment efficiency and drug loading of GX1-PTX-NLCs were( 198. 6 ± 3. 13) nm,( 11. 9 ± 1. 08) mV,above 80%,and( 0. 4 ± 0. 013) %,respectively. The TEM micrographs showed that the GX1-PTX-NLCs were spherical in shape and the loaded-drug was clearly visible. The results of stability test verified that there were no significant changes in the EE and DL of PTX-NLCs and GX1-PTX-NLCs in 8 days. The in vitro release study demonstrated that the GX1-PTX-NLCs were almost all released in 16 h,the slow-release effect of GX1-PTX-NLCs were more obvious than paclitaxel solution.Conclusion: The gastric cancer vasculature targeted peptide GX1 mediated nanostructured lipid carriers loadedwith paclitaxel were proved to be of high entrapment efficiency and good stability,which could be a potentially effective targeted preparation.
Objective: To prepare gastric cancer vasculature targeted peptide GX1 mediated nanostructured lipid carriers( NLCs) loaded with paclitaxel( GX1-PTX-NLCs),and investigate their characteristics,in vitro release and stability. Methods: In the present work,the paclitaxel-loaded nanostructured lipid carriers( PTXNLCs) were prepared by emulsion solvent evaporation technique. Optimization of the preparation formulation of NLCs was accomplished using particle size,Zeta potential,entrapment efficiency( EE) and drug loading( DL) as evaluation indexes. Transmission electron microscope( TEM) was used to characterize the morphology of NLCs.The in vitro release and stability of NLCs in 8 days were performed at 2 ~ 8 ℃. Results: The particle sizes of the prepared NLCs were small and well-distributed. The particle size,Zeta potential,entrapment efficiency and drug loading of GX1-PTX-NLCs were( 198. 6 ± 3. 13) nm,( 11. 9 ± 1. 08) mV,above 80%,and( 0. 4 ± 0. 013) %,respectively. The TEM micrographs showed that the GX1-PTX-NLCs were spherical in shape and the loaded-drug was clearly visible. The results of stability test verified that there were no significant changes in the EE and DL of PTX-NLCs and GX1-PTX-NLCs in 8 days. The in vitro release study demonstrated that the GX1-PTX-NLCs were almost all released in 16 h,the slow-release effect of GX1-PTX-NLCs were more obvious than paclitaxel solution.Conclusion: The gastric cancer vasculature targeted peptide GX1 mediated nanostructured lipid carriers loadedwith paclitaxel were proved to be of high entrapment efficiency and good stability,which could be a potentially effective targeted preparation.
引文
[1]JAYAVELU ND,BAR NS.Metabolomic studies of human gastric cancer:review[J].World J Gastroenterol,2014,20(25):8092.
[2]MADEN CH,GOMES J,SCHWARZ Q,et al.NRP-1 and NRP-2cooperate to regulate gangliogenesis,axon guidance and target innervation in the sympathetic nervous system[J].Developmental Bio,2012,369(2):277-285.
[4]HOLLEB AI,FOLKMAN J.Tumor angiogenesis[J].CA Cancer J Clin,1972,22(4):226-229.
[5]FOLKMAN J.Tumor angiogenesis:therapeutic implications[J].N Engl J Med,1971,285(21):1182-1186.
[6]DU Y,ZHANG Q,JING LJ,et al.GX1-conjugated poly(lacticacid)nanoparticles encapsulating endostar for improved in vivoanticolorectal cancer treatment[J].Int J Nanomedicine,2015,10(1):3791-3802.
[7]XIONG D,LIU ZB,BIAN TR,et al.GX1-mediated anionic liposomes carrying adenoviral vectors for enhanced inhibition of gastric cancer vascular endothelial cell[J].Int J Pharm,2015,496(2):699-708.
[8]WU AW,YUAN P,LI ZY,et al.Capecitabine plus paclitaxel induction treatment in gastric cancer patients with liver metastasis:a prospective,uncontrolled,open-label Phase II clinical study[J].Future Oncol,2016,12(18):2107-2116.
[9]毋海兰,马智宇,张淑秋.紫杉醇不同剂型对大鼠血浆中游离药物浓度的影响[J].中国医药工业杂志,2016,47(11):1430-1435.
[10]蒲俊勇,吴酮,李勤耕.水溶性紫杉醇前体药物的合成及其药动学、药效学[J].光谱实验室,2013,30(2):995-999.
[11]付寒,胡关莲,何勤,等.细胞穿膜肽TAT和可断裂PEG共修饰载紫杉醇脂质体的制备及体外促细胞凋亡作用[J].药学学报,2014,49(7):1054-1061.
[12]郭盼,李淑娟,于世慧,等.血管内皮生长因子受体靶向的紫杉醇胶束的制备及其缓释效果[J].中国科技论文,2014,9(6):720-724.
[13]金光明,尹学哲,金明姬,等.聚乙二醇化多西他赛白蛋白纳米粒的制备及其体内外抗肺癌作用的研究[J].中国新药杂志,2016,25(23):2750-2755.
[14]于欢.人参皂苷Rg3脂质体研究[D].长春:吉林大学,2013.
[15]WU LB,DING JD.In vitro degradation of three-dimensional porous poly(D,L-lactide-co-glycolide)scaffolds for tissue engineering[J].Biomaterials,2004,25(27):5821-5830.
[16]RAZA K,SHAREEF MA,SINGAL P,et al.Lipid-based capsaicin-loaded nano-colloidal biocompatible topical carriers with enhanced analgesic potential and decreased dermal irritation[J].J Liposome Res,2014,24(4):290-296.
[17]张兰,李彦辉,王彩霞,等.紫杉醇脂质体的制备及初步毒性、药效学研究[J].中国药学杂志,2013,48(3):446-449.
[18]ZHAO C,FAN T,YANG Y,et al.Preparation,macrophages targeting delivery and anti-inflammatory study of pentapeptide grafted nanostructured lipid carriers[J].Int J Pharm,2013,450(1-2):11-20.
[19]CHAFER V,VON BRIESEN H,ANDREESEN R,et al.Phagocytosis of nanoparticles by human immunodeficiency virus(HIV)-infected macrophages:a possibility for antiviral drug targeting[J].Pharm Res,1992,9(4):541-546.
[20]郭海燕,莫穗林.脂质体物理稳定性与包封率的影响因素[J].中国新药杂志,2004,13(6):498-501.
[2]MADEN CH,GOMES J,SCHWARZ Q,et al.NRP-1 and NRP-2cooperate to regulate gangliogenesis,axon guidance and target innervation in the sympathetic nervous system[J].Developmental Bio,2012,369(2):277-285.
[4]HOLLEB AI,FOLKMAN J.Tumor angiogenesis[J].CA Cancer J Clin,1972,22(4):226-229.
[5]FOLKMAN J.Tumor angiogenesis:therapeutic implications[J].N Engl J Med,1971,285(21):1182-1186.
[6]DU Y,ZHANG Q,JING LJ,et al.GX1-conjugated poly(lacticacid)nanoparticles encapsulating endostar for improved in vivoanticolorectal cancer treatment[J].Int J Nanomedicine,2015,10(1):3791-3802.
[7]XIONG D,LIU ZB,BIAN TR,et al.GX1-mediated anionic liposomes carrying adenoviral vectors for enhanced inhibition of gastric cancer vascular endothelial cell[J].Int J Pharm,2015,496(2):699-708.
[8]WU AW,YUAN P,LI ZY,et al.Capecitabine plus paclitaxel induction treatment in gastric cancer patients with liver metastasis:a prospective,uncontrolled,open-label Phase II clinical study[J].Future Oncol,2016,12(18):2107-2116.
[9]毋海兰,马智宇,张淑秋.紫杉醇不同剂型对大鼠血浆中游离药物浓度的影响[J].中国医药工业杂志,2016,47(11):1430-1435.
[10]蒲俊勇,吴酮,李勤耕.水溶性紫杉醇前体药物的合成及其药动学、药效学[J].光谱实验室,2013,30(2):995-999.
[11]付寒,胡关莲,何勤,等.细胞穿膜肽TAT和可断裂PEG共修饰载紫杉醇脂质体的制备及体外促细胞凋亡作用[J].药学学报,2014,49(7):1054-1061.
[12]郭盼,李淑娟,于世慧,等.血管内皮生长因子受体靶向的紫杉醇胶束的制备及其缓释效果[J].中国科技论文,2014,9(6):720-724.
[13]金光明,尹学哲,金明姬,等.聚乙二醇化多西他赛白蛋白纳米粒的制备及其体内外抗肺癌作用的研究[J].中国新药杂志,2016,25(23):2750-2755.
[14]于欢.人参皂苷Rg3脂质体研究[D].长春:吉林大学,2013.
[15]WU LB,DING JD.In vitro degradation of three-dimensional porous poly(D,L-lactide-co-glycolide)scaffolds for tissue engineering[J].Biomaterials,2004,25(27):5821-5830.
[16]RAZA K,SHAREEF MA,SINGAL P,et al.Lipid-based capsaicin-loaded nano-colloidal biocompatible topical carriers with enhanced analgesic potential and decreased dermal irritation[J].J Liposome Res,2014,24(4):290-296.
[17]张兰,李彦辉,王彩霞,等.紫杉醇脂质体的制备及初步毒性、药效学研究[J].中国药学杂志,2013,48(3):446-449.
[18]ZHAO C,FAN T,YANG Y,et al.Preparation,macrophages targeting delivery and anti-inflammatory study of pentapeptide grafted nanostructured lipid carriers[J].Int J Pharm,2013,450(1-2):11-20.
[19]CHAFER V,VON BRIESEN H,ANDREESEN R,et al.Phagocytosis of nanoparticles by human immunodeficiency virus(HIV)-infected macrophages:a possibility for antiviral drug targeting[J].Pharm Res,1992,9(4):541-546.
[20]郭海燕,莫穗林.脂质体物理稳定性与包封率的影响因素[J].中国新药杂志,2004,13(6):498-501.