载药聚氰基丙烯酸正丁酯纳米粒的制备
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摘要
目的:优化工艺制备吐温80和(或)PEG20000双重修饰的聚氰基丙烯酸正丁酯纳米载体,进一步制备包载福莫司汀、替莫唑胺的聚氰基丙烯酸正丁酯纳米粒。
方法:(1)选择α-氰基丙烯酸正丁酯为载体材料,吐温80和(或)PEG20000为表面修饰材料,用乳液聚合法制备双重修饰的聚氰基丙烯酸正丁酯纳米载体。在单因素试验基础上,进行均匀设计,并优化制备工艺。(2)进一步制备包载福莫司汀、替莫唑胺的聚氰基丙烯酸正丁酯纳米粒,通过考察粒径大小和包封率两个指标,优化制备工艺。
结果:(1)优化条件下制备的双重修饰的聚氰基丙烯酸正丁酯纳米载体(PBCA-NP)为乳白色胶体溶液,透射电镜观察纳米载体呈圆形,无粘连。粒度分析仪测定平均粒径约137.7nm,粒子分散度(PDI)为0.190。(2)优化条件下制备的包载福莫司汀的聚氰基丙烯酸正丁酯纳米粒(FCNU-PBCA-NP)为乳白色胶体溶液,透射电镜观察纳米粒呈圆形,无粘连。粒度分析仪测定平均粒径为(124.6±5.2)nm,粒子分散度(PDI)范围为0.07-0.16,平均包封率ER为(64.12±2.36)%。(3)优化条件下制备的包载替莫唑胺的聚氰基丙烯酸正丁酯纳米粒(TMZ-PBCA-NP)为乳白色胶体溶液,透射电镜观察纳米载体呈圆形,无粘连。粒度分析仪测定纳米粒平均粒径约125.1nm,粒子分散度(PDI)为0.098,替莫唑胺包封率(ER)约83.02%。
结论:首次以α-氰基丙烯酸正丁酯为载体材料,吐温80和(或)PEG20000为表面修饰材料,用乳液聚合法制备双重修饰的聚氰基丙烯酸正丁酯纳米载体,并经优化筛选出最佳制备工艺,并进一步成功制备包载福莫司汀、替莫唑胺的聚氰基丙烯酸正丁酯纳米粒,对拓展福莫司汀、替莫唑胺临床给药新剂型提供一定的参考,并对进一步研究其缓释性和脑靶向性奠定基础。目前国内外未见报道。
Objective:To prepare polybutylcyanoacrylate(PBCA) nanocarriers with optimized process,double-located with Tween80 and(or) polyethylene glycol(PEG)20000,to further prepare fotemustine polybutylcyanoacrylate nanoparticles(FCNU-PBCA-NP) and temozolomide polybutylcyanoacrylate nanoparticles(TMZ-PBCA-NP).
Method:(1)Double-coated PBCA nanocarries was prepared by emulsion polymerization method with butylα-cyanoacrylate(BCA) as carrier materials, Tween80 and(or) PEG20000 as surfactants,and the procedure was optimized by both single factor test and uniform design test.(2) To further prepare fotemustine polybutylcyanoacrylate nanoparticles(FCNU-PBCA-NP) and temozolomide polybutylcyanoacrylate nanoparticles(TMZ-PBCA-NP),and optimize the preparing technology according to the particle size and the embedding ration(ER).
Results:(1) The solution of double-coated PBAC-NP under optimum conditions was milk-white colloidal solution and the nanocarriers were circular and non-adhesion through transmission electronic microscopy.The average particle size was about 137.7nm and particle density index(PDI)was about 0.190.(2) The solution of fotemustine polybutylcyanoacrylate nanoparticles(FCNU-PBCA-NP) under optimum conditions was milk-white colloidal solution and the nanocarriers were circular and non-adhesion through transmission electronic microscopy.The average particle size was about(124.6±5.2)nm and particle density index(PDI) was about 0.07～0.16.the average embedding ration(ER) was about(64.12±2.36)%.(3)The solution of temozolomide polybutylcyanoacrylate nanoparticles(TMZ-PBCA-NP) under optimum conditions was milk-white colloidal solution and the nanocarriers were circular and non-adhesion through transmission electronic microscopy.The average particle size was about 125.1nm and particle density index(PDI) was about 0.098.the average embedding ration(ER) was about 83.02%.
Conclusion:Double-coated PBCA nanocarries was prepared by emulsion polymerization method with butylα-cyanoacrylate(BCA) as carrier materials, Tween80 and(or) PEG20000 as surfactants for the first time,and the procedure was optimized by uniform design test.fotemustine polybutylcyanoacrylate nanoparticles (FCNU-PBCA-NP) and temozolomide polybutylcyanoacrylate nanoparticles (TMZ-PBCA-NP) were successfully prepared On this basis.They have provided a new direction for fotemutine and temozolomide dosage forms,and laid the foundation for Research for Sustained release and targeting of brain.They have not been reported at home and abroad at present.
方法:(1)选择α-氰基丙烯酸正丁酯为载体材料,吐温80和(或)PEG20000为表面修饰材料,用乳液聚合法制备双重修饰的聚氰基丙烯酸正丁酯纳米载体。在单因素试验基础上,进行均匀设计,并优化制备工艺。(2)进一步制备包载福莫司汀、替莫唑胺的聚氰基丙烯酸正丁酯纳米粒,通过考察粒径大小和包封率两个指标,优化制备工艺。
结果:(1)优化条件下制备的双重修饰的聚氰基丙烯酸正丁酯纳米载体(PBCA-NP)为乳白色胶体溶液,透射电镜观察纳米载体呈圆形,无粘连。粒度分析仪测定平均粒径约137.7nm,粒子分散度(PDI)为0.190。(2)优化条件下制备的包载福莫司汀的聚氰基丙烯酸正丁酯纳米粒(FCNU-PBCA-NP)为乳白色胶体溶液,透射电镜观察纳米粒呈圆形,无粘连。粒度分析仪测定平均粒径为(124.6±5.2)nm,粒子分散度(PDI)范围为0.07-0.16,平均包封率ER为(64.12±2.36)%。(3)优化条件下制备的包载替莫唑胺的聚氰基丙烯酸正丁酯纳米粒(TMZ-PBCA-NP)为乳白色胶体溶液,透射电镜观察纳米载体呈圆形,无粘连。粒度分析仪测定纳米粒平均粒径约125.1nm,粒子分散度(PDI)为0.098,替莫唑胺包封率(ER)约83.02%。
结论:首次以α-氰基丙烯酸正丁酯为载体材料,吐温80和(或)PEG20000为表面修饰材料,用乳液聚合法制备双重修饰的聚氰基丙烯酸正丁酯纳米载体,并经优化筛选出最佳制备工艺,并进一步成功制备包载福莫司汀、替莫唑胺的聚氰基丙烯酸正丁酯纳米粒,对拓展福莫司汀、替莫唑胺临床给药新剂型提供一定的参考,并对进一步研究其缓释性和脑靶向性奠定基础。目前国内外未见报道。
Objective:To prepare polybutylcyanoacrylate(PBCA) nanocarriers with optimized process,double-located with Tween80 and(or) polyethylene glycol(PEG)20000,to further prepare fotemustine polybutylcyanoacrylate nanoparticles(FCNU-PBCA-NP) and temozolomide polybutylcyanoacrylate nanoparticles(TMZ-PBCA-NP).
Method:(1)Double-coated PBCA nanocarries was prepared by emulsion polymerization method with butylα-cyanoacrylate(BCA) as carrier materials, Tween80 and(or) PEG20000 as surfactants,and the procedure was optimized by both single factor test and uniform design test.(2) To further prepare fotemustine polybutylcyanoacrylate nanoparticles(FCNU-PBCA-NP) and temozolomide polybutylcyanoacrylate nanoparticles(TMZ-PBCA-NP),and optimize the preparing technology according to the particle size and the embedding ration(ER).
Results:(1) The solution of double-coated PBAC-NP under optimum conditions was milk-white colloidal solution and the nanocarriers were circular and non-adhesion through transmission electronic microscopy.The average particle size was about 137.7nm and particle density index(PDI)was about 0.190.(2) The solution of fotemustine polybutylcyanoacrylate nanoparticles(FCNU-PBCA-NP) under optimum conditions was milk-white colloidal solution and the nanocarriers were circular and non-adhesion through transmission electronic microscopy.The average particle size was about(124.6±5.2)nm and particle density index(PDI) was about 0.07～0.16.the average embedding ration(ER) was about(64.12±2.36)%.(3)The solution of temozolomide polybutylcyanoacrylate nanoparticles(TMZ-PBCA-NP) under optimum conditions was milk-white colloidal solution and the nanocarriers were circular and non-adhesion through transmission electronic microscopy.The average particle size was about 125.1nm and particle density index(PDI) was about 0.098.the average embedding ration(ER) was about 83.02%.
Conclusion:Double-coated PBCA nanocarries was prepared by emulsion polymerization method with butylα-cyanoacrylate(BCA) as carrier materials, Tween80 and(or) PEG20000 as surfactants for the first time,and the procedure was optimized by uniform design test.fotemustine polybutylcyanoacrylate nanoparticles (FCNU-PBCA-NP) and temozolomide polybutylcyanoacrylate nanoparticles (TMZ-PBCA-NP) were successfully prepared On this basis.They have provided a new direction for fotemutine and temozolomide dosage forms,and laid the foundation for Research for Sustained release and targeting of brain.They have not been reported at home and abroad at present.
引文
[1]尹震.恶性脑胶质瘤局部控缓释药物间质化疗的研究进展[J].中华神经外科学杂志,2000,16(6):399-401.
[2]Kreuter J,Petrov VE,Kharkevich DA,et al.Influence of the type of surfactanat on the analgesic effects induced by the Peptide dalargin after its delivery across the blood-brain Barrier using surfactant-coated nanoparticles.[J].J Control.Release,1997,49(1):81-87.
[3]Ramge P,Unger R.E,Oltrogge J.B,et al.Polysorbate-80 coatingenhances uptake of Polybutylcyanoacrylate(PBCA)-nanoparticles by human and bovine Primary brain capillary endothelial cells.Eur.J.Neuroscience.2000,12(6):1931.
[4]Alyaudtin RN,Reichel A,Lobenberg R,et al.interaction of poly(butylcyanoacrylate)nanoparticles with the blood-brain barrier in vivo and in vitro[J].J.Drug Target.2001,9:209.
[5]Pilar Calvoa,Bruno Gouritinb,Irene Brigger,et al.PEGylated polycyanoacrylate Nanoparticles as vector for durg delivery in Prion diseases[J].Journal of Neuroscinece Methods,2001,111(2):151-155.
[6]Fontana G,Licciardi M,Mansueto S,et al.Amoxicillin-loaded polyethylcyanoacrylate nanoparticles:influence of PEG coating on the particle size,drug release rate and phagocytic uptake[J].Biomaterials,2001,22(21):2857-2865.
[7]Kim HR,Gil S,K Andrieux,et al.Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells.Cell Mol Life Sci.2007;64(3):356-364.
[8]徐辉碧.纳米医药[M].北京:清华大学出版社.2004:136-139.
[9]De Rossi A,Rossi L,Laudisi A,et al.Focus on Fotemustine[J].J Exp Clin Cancer Res.2006,25(4):461-468.
[1]Kreuter J,Petrov VE,Kharkevich DA,et al.Influence of the type of surfactanat on the analgesic effects induced by the Peptide dalargin after its delivery across the blood-brain Barrier using surfactant-coated nanoparticles.[J].J Control.Release,1997,49(1):81-87.
[2]Ramge P,Unger R.E,Oltrogge J.B,et al.Polysorbate-80 coatingenhances uptake of Polybutylcyanoacrylate(PBCA)-nanoparticles by human and bovine Primary brain capillary endothelial cells.Eur.J.Neuroscience.2000,12(6):1931
[3]Alyaudtin RN,Reichel A,Lobenberg R,et al.interaction of poly(butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro[J].J.Drug Target.2001,9:209
[4]Pilar Calvoa,Bruno Gouritinb,Irene Brigger,et al.PEGylated polycyanoacrylate Nanoparticles as vector for durg delivery in Prion diseases[J].Journal of Neuroscinece Methods,2001,111(2):151-155
[5]Fontana G, Licciardi M, Mansueto S, et al.Amoxicillin-loaded polyethylcyanoacrylate nanoparticles:influence of PEG coating on the particle size,drug release rate and phagocytic uptake[J].Biomaterials,2001,22(21):2857-2865.
[6]Kim HR,Gil S,K Andrieux,et al.Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells.Cell Mol Life Sci.2007;64(3):356-364
[7]Douglas SJ,Ilium L,Davis SS,et al.Particle size and size distribution of poly(butyl-2-cyanoacrylate) nanoparticles.J Colloid Inter Sci.1985,103:154.
[1]De Rossi A,Rossi L,Laudisi A,et al.Focus on Fotemustine[J].J Exp Clin Cancer Res.2006,25(4):461-468.
[2]Kreuter J.Nanoparticulate systems for brain delivery of drugs[J].Adv Drug Deliv Rev.2001,47(1):65-81.
[3]Lu W,Zhang Y,Tan YZ,et al.Cationic albumin-conjugated pegylated nanoparticles as novel drug carrier for brain delivery[J].J Control Release.2005,107(3):428-448.
[4]Lu W,Wan J,She Z,et al.Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle[J].J Control Release.2007,118(1):38-53.
[5]Liu L,Guo K,Lu J,et al.Biologically active core/shell nanoparticles self-assembled from cholesterol-terminated PEG-TAT for drug delivery across the blood-brain barrier[J].Biomaterials.2008.29(10):1509-1517.
[6]徐辉碧.纳米医药[M].北京:清华大学出版社.2004:136-139.
[7]Peracchia MT,Vauthier C,Puisieux F,et al.Development of sterically stabilized poly(isobutyl 2-cyanoacrylate) nanoparticles by chemical coupling of poly(ethylene glycol)[J].J Biomed Mater Res.1997,34(3):317-326.
[8]Das D,Lin S.Double-coated poly(butylcynanoacrylate) nanoparticulate delivery systems for brain targeting of dalargin via oral administration[J].J Pharm Sci.2005,94(6):1343-1353.
[9]张阳德,丁诚,张宗久,等.优化工艺制备表阿霉素α-聚氰基丙烯酸正丁酯纳米粒[J].中华实验外科杂志,2006,23(10):1191-1193.
[10]黄乐松,王春霞,陈志良,等.吉西他滨聚氰基丙烯酸正丁酯纳米粒的制备工艺[J].南方医科大学学报,2007,27(11):1653-1656.
[11]刘海燕,陈劲春,陈兴罔.吲哚美辛聚氰基丙烯酸正丁酯纳米粒的制备[J].北京化工大学学报,2008,35(4):73-76.
[1]Kreuter J,Petrov VE,Kharkevich DA,et al.Influence of the type of surfactanat on the analgesic effects induced by the Peptide dalargin after its delivery across the blood-brain Barrier using surfactant-coated nanoparticles.[J].J Control.Release,1997,49(1):81-87。
[2]Ramge P,Unger R.E,Oltrogge J.B,et al.Polysorbate-80 coatingenhances uptake of Polybutylcyanoacrylate(PBCA)-nanoparticles by human and bovine Primary brain capillary endothelial cells.Eur.J.Neuroscience.2000,12(6):1931
[3]Alyaudtin RN,Reichel A,Lobenberg R,et al.interaction of poly(butylcyanoacrylate)nanoparticles with the blood-brain barrier in vivo and in vitro[J].J.Drug Target.2001,9:209
[4]Pilar Calvoa,Bruno Gouritinb,Irene Brigger,et al.PEGylated polycyanoacrylate Nanoparticles as vector for durg delivery in Prion diseases[J].Journal of Neuroscinece Methods,2001,111(2):151-155
[5]Fontana G, Licciardi M, Mansueto S, et al.Amoxicillin-loaded polyethylcyanoacrylate nanoparticles:influence of PEG coating on the particle size,drug release rate and phagocytic uptake[J].Biomaterials,2001,22(21):2857-2865.
[6]Kim HR,Gil S,K Andrieux,et al.Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells.Cell Mol Life Sci.2007;64(3):356-364.
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[17]Das D,Lin S.Double-coated poly(butylcynanoacrylate) nanoparticulate delivery systems for brain targeting of dalargin via oral administration.J Pharm Sci,2005,94(6):1343-135
[2]Kreuter J,Petrov VE,Kharkevich DA,et al.Influence of the type of surfactanat on the analgesic effects induced by the Peptide dalargin after its delivery across the blood-brain Barrier using surfactant-coated nanoparticles.[J].J Control.Release,1997,49(1):81-87.
[3]Ramge P,Unger R.E,Oltrogge J.B,et al.Polysorbate-80 coatingenhances uptake of Polybutylcyanoacrylate(PBCA)-nanoparticles by human and bovine Primary brain capillary endothelial cells.Eur.J.Neuroscience.2000,12(6):1931.
[4]Alyaudtin RN,Reichel A,Lobenberg R,et al.interaction of poly(butylcyanoacrylate)nanoparticles with the blood-brain barrier in vivo and in vitro[J].J.Drug Target.2001,9:209.
[5]Pilar Calvoa,Bruno Gouritinb,Irene Brigger,et al.PEGylated polycyanoacrylate Nanoparticles as vector for durg delivery in Prion diseases[J].Journal of Neuroscinece Methods,2001,111(2):151-155.
[6]Fontana G,Licciardi M,Mansueto S,et al.Amoxicillin-loaded polyethylcyanoacrylate nanoparticles:influence of PEG coating on the particle size,drug release rate and phagocytic uptake[J].Biomaterials,2001,22(21):2857-2865.
[7]Kim HR,Gil S,K Andrieux,et al.Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells.Cell Mol Life Sci.2007;64(3):356-364.
[8]徐辉碧.纳米医药[M].北京:清华大学出版社.2004:136-139.
[9]De Rossi A,Rossi L,Laudisi A,et al.Focus on Fotemustine[J].J Exp Clin Cancer Res.2006,25(4):461-468.
[1]Kreuter J,Petrov VE,Kharkevich DA,et al.Influence of the type of surfactanat on the analgesic effects induced by the Peptide dalargin after its delivery across the blood-brain Barrier using surfactant-coated nanoparticles.[J].J Control.Release,1997,49(1):81-87.
[2]Ramge P,Unger R.E,Oltrogge J.B,et al.Polysorbate-80 coatingenhances uptake of Polybutylcyanoacrylate(PBCA)-nanoparticles by human and bovine Primary brain capillary endothelial cells.Eur.J.Neuroscience.2000,12(6):1931
[3]Alyaudtin RN,Reichel A,Lobenberg R,et al.interaction of poly(butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro[J].J.Drug Target.2001,9:209
[4]Pilar Calvoa,Bruno Gouritinb,Irene Brigger,et al.PEGylated polycyanoacrylate Nanoparticles as vector for durg delivery in Prion diseases[J].Journal of Neuroscinece Methods,2001,111(2):151-155
[5]Fontana G, Licciardi M, Mansueto S, et al.Amoxicillin-loaded polyethylcyanoacrylate nanoparticles:influence of PEG coating on the particle size,drug release rate and phagocytic uptake[J].Biomaterials,2001,22(21):2857-2865.
[6]Kim HR,Gil S,K Andrieux,et al.Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells.Cell Mol Life Sci.2007;64(3):356-364
[7]Douglas SJ,Ilium L,Davis SS,et al.Particle size and size distribution of poly(butyl-2-cyanoacrylate) nanoparticles.J Colloid Inter Sci.1985,103:154.
[1]De Rossi A,Rossi L,Laudisi A,et al.Focus on Fotemustine[J].J Exp Clin Cancer Res.2006,25(4):461-468.
[2]Kreuter J.Nanoparticulate systems for brain delivery of drugs[J].Adv Drug Deliv Rev.2001,47(1):65-81.
[3]Lu W,Zhang Y,Tan YZ,et al.Cationic albumin-conjugated pegylated nanoparticles as novel drug carrier for brain delivery[J].J Control Release.2005,107(3):428-448.
[4]Lu W,Wan J,She Z,et al.Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle[J].J Control Release.2007,118(1):38-53.
[5]Liu L,Guo K,Lu J,et al.Biologically active core/shell nanoparticles self-assembled from cholesterol-terminated PEG-TAT for drug delivery across the blood-brain barrier[J].Biomaterials.2008.29(10):1509-1517.
[6]徐辉碧.纳米医药[M].北京:清华大学出版社.2004:136-139.
[7]Peracchia MT,Vauthier C,Puisieux F,et al.Development of sterically stabilized poly(isobutyl 2-cyanoacrylate) nanoparticles by chemical coupling of poly(ethylene glycol)[J].J Biomed Mater Res.1997,34(3):317-326.
[8]Das D,Lin S.Double-coated poly(butylcynanoacrylate) nanoparticulate delivery systems for brain targeting of dalargin via oral administration[J].J Pharm Sci.2005,94(6):1343-1353.
[9]张阳德,丁诚,张宗久,等.优化工艺制备表阿霉素α-聚氰基丙烯酸正丁酯纳米粒[J].中华实验外科杂志,2006,23(10):1191-1193.
[10]黄乐松,王春霞,陈志良,等.吉西他滨聚氰基丙烯酸正丁酯纳米粒的制备工艺[J].南方医科大学学报,2007,27(11):1653-1656.
[11]刘海燕,陈劲春,陈兴罔.吲哚美辛聚氰基丙烯酸正丁酯纳米粒的制备[J].北京化工大学学报,2008,35(4):73-76.
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