空心氧化铁载药磁纳米粒的制备及体外释放性能的实验研究
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摘要
目的：制备具有良好的磁靶向性、生物相容性且能携带化疗药物的空心磁性纳米粒,并对制备的空心磁性纳米粒的形貌、粒径及载药量、包封率、体外释放性能进行检测。
方法：采用改进的共沉淀法制备空心磁纳米粒子,采用正交实验法设计实验,以粒径大小、载药量和包封率3个指标考察压力、吸附时间、投药量三个主要影响因素,选用四因素三水平的正交表安排正交实验,从中选出最优组合,并以最优化组合重复实验,验证实验条件的稳定性以及实验可重复性。
结果：实验制备出平均粒径为90nm,粒度分布范围在70nm-110nm之间的空心磁性纳米粒,最佳制备条件下产物X射线粉末衍射表明：该产物为立方晶系结构的Fe3O4,并且该产物晶型单一,纯度高；由优化实验制得的载阿霉素磁性纳米粒粒径为300nm左右,载药量达到54.3%,包封率可达到95.7%。
结论：本研究所制备的磁性纳米粒具有空心结构,粒径小、分布均匀,具有长时间药物缓释效果,有望成为一种优良的靶向肿瘤药物载体。
Objective:To make hollow Fe3O4 magnetic nanoparticles which have good properties of magnetic targeting and biocompatibility.The prepared hollow Fe3O4 magnetic nanoparticles were characterized by telescope electron microscopy(TEM) for morphological properties,laser light scattering(LLS)for size and size distribution.The drug loading(DL), encapsulation efficiency (EE)and the drug release properties under in vitro conditions were also measured.
Methods:We used modified coprecipitation method in producing magnetic nanoparticles. Designing the experiment using the method of orthogonal design,through evaluating the nanoparticles from size of nanoparticles,drug loading and encapsulation efficiency,observe effection of adsorption pressure,adsorption time and dosage on the three level in the course of preparing hollow Fe3O4 drug-loaded magnetic NPs.From the three level,we choose the best one,and repeat experiment to verify repeatable and stabilities of this experimental condition.
Results:By analyzing particle size and TEM indicates that the average diameter of hollow Fe3O4 NPs is 90nm, the average size of particle ranged from 70 to 110-nm. The X-ray diffraction indicate that the prepared power is pure cubic Fe3O4. The size of hollow Fe3O4 drug-loaded magnetic NPs produced by optimizational experiment were about 300nm, the drug loading and encapsulation efficiency were 54.3% and 95.7% respectively.
Conclusions:The hollow Fe3O4 drug-loaded magnetic NPs which made in this study can be used as anexcellent kind of drug carrier targeting tumor for its property of delayed releasing.
方法：采用改进的共沉淀法制备空心磁纳米粒子,采用正交实验法设计实验,以粒径大小、载药量和包封率3个指标考察压力、吸附时间、投药量三个主要影响因素,选用四因素三水平的正交表安排正交实验,从中选出最优组合,并以最优化组合重复实验,验证实验条件的稳定性以及实验可重复性。
结果：实验制备出平均粒径为90nm,粒度分布范围在70nm-110nm之间的空心磁性纳米粒,最佳制备条件下产物X射线粉末衍射表明：该产物为立方晶系结构的Fe3O4,并且该产物晶型单一,纯度高；由优化实验制得的载阿霉素磁性纳米粒粒径为300nm左右,载药量达到54.3%,包封率可达到95.7%。
结论：本研究所制备的磁性纳米粒具有空心结构,粒径小、分布均匀,具有长时间药物缓释效果,有望成为一种优良的靶向肿瘤药物载体。
Objective:To make hollow Fe3O4 magnetic nanoparticles which have good properties of magnetic targeting and biocompatibility.The prepared hollow Fe3O4 magnetic nanoparticles were characterized by telescope electron microscopy(TEM) for morphological properties,laser light scattering(LLS)for size and size distribution.The drug loading(DL), encapsulation efficiency (EE)and the drug release properties under in vitro conditions were also measured.
Methods:We used modified coprecipitation method in producing magnetic nanoparticles. Designing the experiment using the method of orthogonal design,through evaluating the nanoparticles from size of nanoparticles,drug loading and encapsulation efficiency,observe effection of adsorption pressure,adsorption time and dosage on the three level in the course of preparing hollow Fe3O4 drug-loaded magnetic NPs.From the three level,we choose the best one,and repeat experiment to verify repeatable and stabilities of this experimental condition.
Results:By analyzing particle size and TEM indicates that the average diameter of hollow Fe3O4 NPs is 90nm, the average size of particle ranged from 70 to 110-nm. The X-ray diffraction indicate that the prepared power is pure cubic Fe3O4. The size of hollow Fe3O4 drug-loaded magnetic NPs produced by optimizational experiment were about 300nm, the drug loading and encapsulation efficiency were 54.3% and 95.7% respectively.
Conclusions:The hollow Fe3O4 drug-loaded magnetic NPs which made in this study can be used as anexcellent kind of drug carrier targeting tumor for its property of delayed releasing.
引文
[1]A.S.Lubbe,C.Alexion,C.Bergemann.Clinical application of magnetic drug targeting[J].J.Surg.Res.,2001,95(2):200-206.
[2]Widder KJ,Senyei AE, Scarpelli DG, et al. Cis Diammine-Dicholroplatinum (Ⅱ)-resistant Sublines derived from two human Ovarian tumor cell lines. Cancer Res,1988;48:3355
[3]陆彬编著,药物新剂型与技术.北京：人民卫生出版社.1998,154.
[4]吴传斌,魏树礼.磁性药物微球研究进展.中国药学杂志,1993；28(6)：330-334.
[5]黄佳英.邱祖民.阿霉素磁性靶向药物研究进展,2008,(6)：23~25.
[6]沈海霞.阿霉素磁毫微粒的制备、表征及体外释放性能的研究.福州大学硕士论文,2004,6.
[7]K.J.Widder,A.E.Senyei,D.G.Scarpelli,et al..Magnetic microspheres:A model system for site specific drug delivery in vivo.Proc.Soc. Exp.Bio.lMed.,1978,58: 141～145.
[8]A.E.Senyei,S.D.Reich,C.Goczy,et al..In vivo kinetics of magnetically targeted low-dose doxorubicin.J.Pharm Sci.,1981,70(4):389～391.
[9]陈骐,孙淑英,顾学裘等.磁性微球载体—抗癌药复尿嘧啶新剂型.中国药理学报,1983；4(4)：273
[10]吴传斌,魏树礼,卢炜等.磁性微球的磁响应性及狗肾动脉栓塞实验研究.药学学报,1994,2994)：311
[11]张阳德,龚连生.磁性阿霉素白蛋白纳米粒的研制.中国现代医学杂志2001,11(3)：1-3
[12]张赞.Fe3O4纳米颗粒及其靶向药物研究,国防科技大学硕士论文,2002(11).
[13]MARTIN V M, SIEWERT C, SCHARL A, et al. Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS[J]. Exp Hematol,1998,26:252—264.
[14]HAWKINS T. DNA purification and isolation using magneticparticles[P]. US Patent,5705628.1998 05 16.
[15]MORIMOTO Y, NATSUME H. Targeting technology utilizing magnetic microparticulate system for cancer therapy[J].Jpn J Clin Med Med,1998,56: 649—656.
[16]高娃.[J].化学教学,2001,8：46.
[17]GUPTA P K, HUNG C T, RAO N S. Ultrastructural disposition of adriamycin associated magnetic albumin microspheres in rat [J]. J Pharm Sci,1989,78: 290—294.
[18]TADAHIKO K, TA KASHI S, SHOJ I S, et al. Targeted delivery of anticancer drugs with intravenously administed magnetic liposomes in osteosarcoma 2bearing hamster[J]. Cancer Res,2000,17:309-315.
[19]CHRISTOPH A, WOL FGANG A, ROSWITHA J, et al. Locoregional cancer treatment with magnetic drug targeting[J]. Cancer Res,2000,60:641-648.
[20]Caruso F,Caruso R A et al.Science,1998,282:1111-1114.
[21]Caruso F, Chem. Eur J,2000.6:413—419.
[22]Alexandridis P,Hatton T A.Colloids and Surfaces A,1995,96:1-46.
[23]赵剑曦,林翠英,等.功能分子学报,2000.13(2)：177-181
[24],马文哲,等.空心超顺磁性Fe3O4磁性纳米微球的制备和表征[J].无机材料学报(Journal of Inorganic Materials),2004,19(6):1407-1409
[25]中华人民共和国药典,药典注释[M].北京：化学工业出版社,1990：963-967.
[26]沈海霞.阿霉素磁性毫微粒的制备、表征及其体外释放性能的研究.福州大学硕士论文,2004(5).
[27]刘安琪,等.空心多孔纳米载体负载药物的药量分布研究[J].高校化学工程学报,2007,21(5)：832～836.
[28]相秉仁编著.计算药学.中国医药科技出版社,1990.
[1]Torchilin VP. Drug Targeting [J]. Eur J Pharm Sci,2000, (11Suppl 2):s81-91.
[2]常津,刘海峰,姚康德.医用纳米控释系统的研究进展.中国生物医学工程学报,2000,12(4)：423～431.
[3]Votairas P A Hydrodynamics of magnetic drug targeting[J].Biomech,2002, 35(6):813-821.
[4]王平康,袁青禄,刘岐山,等.磁性抗癌药物载体研制[J].中国医院药学杂志,1990,10(1)：2-4.
[5]A Gedanken,Ultra,Using sonochemistry for the fabrication of nanomaterials, Sonochem.,2004,11:47～55
[6]Deng J G, Ding X B,Zhang W C,et al.Magnetic and conducting Fe3O4-cross-linked polyaniline nanoparticles with core-shell structure[J]. Polymer, 2002,43(8):2179-2184.
[7]P.Luo,T.G.Nieh.Preparing hydroxyapatite powders with controlled morphology, Biomaterials,1996,17(20):1959～1964.
[8]Widder KJ, Senyei AE, Rannay DF. In vitro release of biOlOgically activeadriamycin by magnetically responsive albumin microspheres[J]. Cancer RES,1980,4o(10):3512-3517.
[9]Widder KJ, Marino PA, Moms RM, et al. Selective targeting ofmagnetic albumin microspheres to the Yoshida sarcoma:ultrastmctural evaluation of microsphere disposition[J]. Eur J Cancer Clin Oncol,1983,19(1):141-147.
[10]Widder K J,Senyei AE, Scarpelli DG,et al. Magnetic microspheres:A model system for site specific drug delivery in vivo. Proc Soc Exp Biol Med,1978,58; 141-145.
[11]Ibrahim A,Couvreur P,Roland M,et al.New magnetic drug carrier.J Pharm Pharmcaol,1983,35:59-61.
[12]陈道达,艾时斌,马建华等.磁液载附阿霉素靶向定位治疗消化系肿瘤.中华实验外科杂志,1996,13(1)；1～2.
[13]Gupta PK, Hung CT. Comparative disposition of adriamycin delivered via magnetic albumin mi crospheres in presence and absence of magnetic field in rats[J]. Life Science.1990,46(7):471-479.
[14]于育红,张宁呆,叶胜龙,等.丝裂霉素C白蛋白磁性微球用于裸鼠人肝癌模型疗效观察[J].中国肿瘤临床,1998,25(9)：675-677.
[15]吕凤娇,陈晓耕,等.阿霉素纳米粒的制备与模拟体外释放行为[J],2008,25(2)：148～150.
[2]Widder KJ,Senyei AE, Scarpelli DG, et al. Cis Diammine-Dicholroplatinum (Ⅱ)-resistant Sublines derived from two human Ovarian tumor cell lines. Cancer Res,1988;48:3355
[3]陆彬编著,药物新剂型与技术.北京：人民卫生出版社.1998,154.
[4]吴传斌,魏树礼.磁性药物微球研究进展.中国药学杂志,1993；28(6)：330-334.
[5]黄佳英.邱祖民.阿霉素磁性靶向药物研究进展,2008,(6)：23~25.
[6]沈海霞.阿霉素磁毫微粒的制备、表征及体外释放性能的研究.福州大学硕士论文,2004,6.
[7]K.J.Widder,A.E.Senyei,D.G.Scarpelli,et al..Magnetic microspheres:A model system for site specific drug delivery in vivo.Proc.Soc. Exp.Bio.lMed.,1978,58: 141～145.
[8]A.E.Senyei,S.D.Reich,C.Goczy,et al..In vivo kinetics of magnetically targeted low-dose doxorubicin.J.Pharm Sci.,1981,70(4):389～391.
[9]陈骐,孙淑英,顾学裘等.磁性微球载体—抗癌药复尿嘧啶新剂型.中国药理学报,1983；4(4)：273
[10]吴传斌,魏树礼,卢炜等.磁性微球的磁响应性及狗肾动脉栓塞实验研究.药学学报,1994,2994)：311
[11]张阳德,龚连生.磁性阿霉素白蛋白纳米粒的研制.中国现代医学杂志2001,11(3)：1-3
[12]张赞.Fe3O4纳米颗粒及其靶向药物研究,国防科技大学硕士论文,2002(11).
[13]MARTIN V M, SIEWERT C, SCHARL A, et al. Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS[J]. Exp Hematol,1998,26:252—264.
[14]HAWKINS T. DNA purification and isolation using magneticparticles[P]. US Patent,5705628.1998 05 16.
[15]MORIMOTO Y, NATSUME H. Targeting technology utilizing magnetic microparticulate system for cancer therapy[J].Jpn J Clin Med Med,1998,56: 649—656.
[16]高娃.[J].化学教学,2001,8：46.
[17]GUPTA P K, HUNG C T, RAO N S. Ultrastructural disposition of adriamycin associated magnetic albumin microspheres in rat [J]. J Pharm Sci,1989,78: 290—294.
[18]TADAHIKO K, TA KASHI S, SHOJ I S, et al. Targeted delivery of anticancer drugs with intravenously administed magnetic liposomes in osteosarcoma 2bearing hamster[J]. Cancer Res,2000,17:309-315.
[19]CHRISTOPH A, WOL FGANG A, ROSWITHA J, et al. Locoregional cancer treatment with magnetic drug targeting[J]. Cancer Res,2000,60:641-648.
[20]Caruso F,Caruso R A et al.Science,1998,282:1111-1114.
[21]Caruso F, Chem. Eur J,2000.6:413—419.
[22]Alexandridis P,Hatton T A.Colloids and Surfaces A,1995,96:1-46.
[23]赵剑曦,林翠英,等.功能分子学报,2000.13(2)：177-181
[24],马文哲,等.空心超顺磁性Fe3O4磁性纳米微球的制备和表征[J].无机材料学报(Journal of Inorganic Materials),2004,19(6):1407-1409
[25]中华人民共和国药典,药典注释[M].北京：化学工业出版社,1990：963-967.
[26]沈海霞.阿霉素磁性毫微粒的制备、表征及其体外释放性能的研究.福州大学硕士论文,2004(5).
[27]刘安琪,等.空心多孔纳米载体负载药物的药量分布研究[J].高校化学工程学报,2007,21(5)：832～836.
[28]相秉仁编著.计算药学.中国医药科技出版社,1990.
[1]Torchilin VP. Drug Targeting [J]. Eur J Pharm Sci,2000, (11Suppl 2):s81-91.
[2]常津,刘海峰,姚康德.医用纳米控释系统的研究进展.中国生物医学工程学报,2000,12(4)：423～431.
[3]Votairas P A Hydrodynamics of magnetic drug targeting[J].Biomech,2002, 35(6):813-821.
[4]王平康,袁青禄,刘岐山,等.磁性抗癌药物载体研制[J].中国医院药学杂志,1990,10(1)：2-4.
[5]A Gedanken,Ultra,Using sonochemistry for the fabrication of nanomaterials, Sonochem.,2004,11:47～55
[6]Deng J G, Ding X B,Zhang W C,et al.Magnetic and conducting Fe3O4-cross-linked polyaniline nanoparticles with core-shell structure[J]. Polymer, 2002,43(8):2179-2184.
[7]P.Luo,T.G.Nieh.Preparing hydroxyapatite powders with controlled morphology, Biomaterials,1996,17(20):1959～1964.
[8]Widder KJ, Senyei AE, Rannay DF. In vitro release of biOlOgically activeadriamycin by magnetically responsive albumin microspheres[J]. Cancer RES,1980,4o(10):3512-3517.
[9]Widder KJ, Marino PA, Moms RM, et al. Selective targeting ofmagnetic albumin microspheres to the Yoshida sarcoma:ultrastmctural evaluation of microsphere disposition[J]. Eur J Cancer Clin Oncol,1983,19(1):141-147.
[10]Widder K J,Senyei AE, Scarpelli DG,et al. Magnetic microspheres:A model system for site specific drug delivery in vivo. Proc Soc Exp Biol Med,1978,58; 141-145.
[11]Ibrahim A,Couvreur P,Roland M,et al.New magnetic drug carrier.J Pharm Pharmcaol,1983,35:59-61.
[12]陈道达,艾时斌,马建华等.磁液载附阿霉素靶向定位治疗消化系肿瘤.中华实验外科杂志,1996,13(1)；1～2.
[13]Gupta PK, Hung CT. Comparative disposition of adriamycin delivered via magnetic albumin mi crospheres in presence and absence of magnetic field in rats[J]. Life Science.1990,46(7):471-479.
[14]于育红,张宁呆,叶胜龙,等.丝裂霉素C白蛋白磁性微球用于裸鼠人肝癌模型疗效观察[J].中国肿瘤临床,1998,25(9)：675-677.
[15]吕凤娇,陈晓耕,等.阿霉素纳米粒的制备与模拟体外释放行为[J],2008,25(2)：148～150.