Poloxamer188~W/O乳液电纺卡铂聚L-乳酸纤维的制备和表征
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摘要
目的制备一种能够缓释卡铂的局部化疗用纤维膜。方法药物的水溶液为水相,聚L-乳酸的二氯甲烷溶液为油相,Poloxamer188~为乳化剂,探头超声制备W/O乳液后静电纺丝将体系拉制成纤维。采用扫描电子显微镜观察纤维形态,采用广角-X射线衍射扫描法观察纤维表面有无药物结晶析出,采用差示热分析和傅立叶变换红外光谱评价药物在高分子纤维中的结合状态。碘-碘化钾络合显色法测定Poloxamer188~的释放,采用原子吸收分光光度法测定卡铂的释放,绘制释放曲线并回归。采用MTT法测试释放药物的抗He La细胞活性。结果扫描电子显微镜观察制备得到直径较为均一的纤维膜,乳液静电纺丝所得纤维直径大于均相溶液纺丝,乳液纺丝所得纤维表面有微小孔状结构。广角X-射线衍射结果表明纤维表面无药物结晶析出,差示热分析结果表明卡铂在纤维亦为非结晶状态存在,傅立叶变换红外光谱发现卡铂与纤维材料良好复合。各样品中卡铂突释明显,随着Poloxamer188~添加量的增多,其本身和卡铂均从纤维中的突释量逐渐增大,纤维中药物释放速率加快。当Poloxamer188~的复合量为10%、20%和30%时,缓释超过10 h。Poloxamer188~释放曲线复合Freundlich方程式,卡铂释放曲线符合0级释放动力学。结论 W/O乳液静电纺丝法能够制备得到对卡铂有缓释作用的抗He La细胞纤维膜。
Objective To load carboplatin in poly L-lactic acid electrospun fibrous films and investigate the incorporation and release. Methods W/O emulsions were prepared first by using carboplatin water solution was used as internal phase,poly L-lactic acid dichloromethane solution as external phase,and Poloxamer188~of 10%,20%,30%,40%,50% mass ratio to poly L-lactic acid as emulsifier. Then fibers were prepared by electrospinning those emulsions and characterized by scanning electron microscopy for morphological characterization,by X-ray diffraction and differential thermal analysis to investigate the incorporating status. Atomic absorption spectrophotometry and complexing coloration spectrometry were used to detect the released carboplatin and Poloxamer188~for drawing the release curves of them,respectively.The antitumor activities of the carboplatin released from fibers against HeLa cells was evaluated by M TT method. Results M icro-scale fibers could be obtained after emulsion electrospinning. As the amount of complexed Poloxamer188~increased,the fibers diameter decreased and morphology was improved. There was no Poloxamer188~existing on the fibers surfaces,but seperated aggregates of Poloxamer188~may exist in the inner position of the fiber matrix. Poloxamer188~presented burst release. Carboplatin presented more than 10 h when the Poloxamer188~complexing amount was 10%,20%,30% and the release curve could be fitted as 0 order equation while release curves of Poloxamer188~fitted Frendlich 's equation. Released carboplatin reserved the anti-HeLa cell activity. Conclusion By W/O emuslion electrospinning with Poloxamer188~as emulsifier,carboplatin could be incorporated within the poly L-lactic acid fibrous films of acceptable morphology and desirable release behavior with anti HeLa cell activity.
Objective To load carboplatin in poly L-lactic acid electrospun fibrous films and investigate the incorporation and release. Methods W/O emulsions were prepared first by using carboplatin water solution was used as internal phase,poly L-lactic acid dichloromethane solution as external phase,and Poloxamer188~of 10%,20%,30%,40%,50% mass ratio to poly L-lactic acid as emulsifier. Then fibers were prepared by electrospinning those emulsions and characterized by scanning electron microscopy for morphological characterization,by X-ray diffraction and differential thermal analysis to investigate the incorporating status. Atomic absorption spectrophotometry and complexing coloration spectrometry were used to detect the released carboplatin and Poloxamer188~for drawing the release curves of them,respectively.The antitumor activities of the carboplatin released from fibers against HeLa cells was evaluated by M TT method. Results M icro-scale fibers could be obtained after emulsion electrospinning. As the amount of complexed Poloxamer188~increased,the fibers diameter decreased and morphology was improved. There was no Poloxamer188~existing on the fibers surfaces,but seperated aggregates of Poloxamer188~may exist in the inner position of the fiber matrix. Poloxamer188~presented burst release. Carboplatin presented more than 10 h when the Poloxamer188~complexing amount was 10%,20%,30% and the release curve could be fitted as 0 order equation while release curves of Poloxamer188~fitted Frendlich 's equation. Released carboplatin reserved the anti-HeLa cell activity. Conclusion By W/O emuslion electrospinning with Poloxamer188~as emulsifier,carboplatin could be incorporated within the poly L-lactic acid fibrous films of acceptable morphology and desirable release behavior with anti HeLa cell activity.
引文
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[10]ALEX AT,JOSEPH A,SHAVI G,et al.Development and evaluation of carboplatin-loaded PCL nanoparticles for intranasal delivery[J].Drug Delivery,2016,23(7):2144-2153.
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[15]YAN F,ZHANG C,ZHENG Y,et al.The effect of poloxamer 188 on nanoparticle morphology,size,cancer cell uptake,and cytotoxicity[J].Nanomedicine-Nanotechnology Biology and M edicine,2010,6(1):170-178.
[16]XU X,YANG L,XU X,et al.Ultrafine medicated fibers electrospun from W/O emulsions[J].Journal of Controlled Release,2005,108(1):33-42.
[17]XU X,CHEN X,MA P,et al.The release behavior of doxorubicin hydrochloride from medicated fibers prepared by emulsion-electrospinning[J].European Journal of Pharmaceutics&Biopharm,2008,70(1):165-170.
[18]WANG C,WANG L,MIN W.Evolution of core-shell structure:from emulsion to ultrafine emulsion electrospun fibers[J].M aterials Letters,2014,124(6):192-196.
[19]王浩,邓英杰,焦自学,等.聚L-乳酸与聚乙二醇-b-聚L-乳酸电纺纤维中布洛芬的释放[J].沈阳药科大学学报,2010,27(9):686-694.
[20]WANG H,LI Y Q,JIA Y H.Vesicle-formation of hexadecyl phosphatidyl choline released from polyε-caprolactone electrospun fibrous mats:preparation and characterization[J].Colloid&Polymer Science,2013,291(10):2475-2479.
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[22]CHANG J H,OHNO M,ESUMI K,et al.Interaction of lodine w ith nonionic surfactant and polyethylene glycol in aqueous potassium lodide solution[J].Journal of the American Oil Chemists’Society,1988,65(10):1664-1668.
[23]HU L A,CHATELUT E,ROYER B,et al.Level of evidence for therapeutic drug monitoring of carboplatin[J].Therapie,2010,65(3):157-162.
[24]NIKOLOFF N,PONZINIBBIO M V,PADULA G,et al.Folic acid enhances the apoptotic and genotoxic activity of carboplatin in He La cell line[J].Toxicology in Vitro,2016,37:142-147.
[25]WANG S S,ZHANG HY,CHENG L A,et al.Analysis of the cytotoxic activity of carboplatin and gemcitabine combination[J].Anticancer Research,2010,30(11):4573-4578.
[26]WANG H,SONG H,CHEN X,et al.Ibuprofen release from PEG-PLLA electrospun fibers containing PEGblocked polyα-hydroxyl octanoic acid as an additive[J].Journal of Applied Polymer Science,2010,67(3):417-425.
[27]王浩,康卫民,张亚秋,等.壬苯醇醚聚ε-己内酯电纺纤维的表征和释放[J].沈阳药科大学学报,2015,32(4):249-255.
[28]IGNATIOUS F,SUN L,LEE C P,et al.Electrospun nanofibers in oral drug delivery[J].Pharmaceutical Research,2010,27(4):576-588.
[29]XU X,CHEN X,XU X,et al.BCNU-loaded PEG-PL-LA ultrafine fibers and their in vitro antitumor activity against Glioma C6 cells[J].Journal of Controlled Release,2006,114(3):307-316.
[30]MALEKI M,AMANI-TEHRAN M,LATIFI M,et al.Drug release profile in core-shell nanofibrous structures:a study on peppas equation and artificial neural netw ork modeling[J].Computer M ethods&Programs in Biomedicine,2014,113(1):92-100.
[31]YANG Y,LI X,CUI W,et al.Structural stability and release profiles of proteins from core-shell poly(DL-lactide)ultrafine fibers prepared by emulsion electrospinning[J].Journal of Biomedical M aterials Research(Part A),2008,26 A(2):374-385.
[32]ZHANG H,ZHAO C G,ZHAO Y H,et al.Electrospinning of ultrafine core/shell fibers for biomedical applications[J].Science China Chemistry,2010,53(6):1246-1254.
[33]YARIN A L.Coaxial electrospinning and emulsion electrospinning of core-shell fibers[J].Polymers for Advanced Technologies,2011,22(3):310-317.
[2]MEINEL A J,GERMERSHAUS O,LUHMANN T,et al.Electrospun matrices for localized drug delivery:current technologies and selected biomedical applications[J].European Journal of Pharmaceutics&Biopharm,2012,81(1):1-13.
[3]KENAWY E R,ABDEL-HAY E,WNEK G E.Processing of nanofibers through electrospinning as drug delivery system[J].M aterials Chemistry&Physics,2009,113(1):296-302.
[4]DILRUBA S,KALAYDA G V.Platium-based drugs:past,present and future[J].Cancer Chemotherapy and Pharmacology,2016,77(6):1103-1124.
[5]GABANO E,RAVERA M,OSELLA D.The drug targeting and delivery approach applied to Pt-antitumour complexes.A coordination point of view[J].Current M edicinal Chemistry,2009,16(34):4544-4580.
[6]SADHUKHA T,PRABHA S.Encapsulation in nanoparticles improves anti-cancer efficay of carboplatin[J].AAPS Pharmscitech,2014,15(4):1029-1038.
[8]HAXTON K J,BURT H M.Polymeric drug delivery of platinum-based anticancer agents[J].Journal of Pharmaceutical Sciences,2009,98(7):2299-2316.
[9]WANG X,WANG J,WU W B,et al.Vaginal delivery of carboplatin-loaded thermosensitive hydrogel to prevent local cervical cancer recurrence in mice[J].Drug Delivery,2016,23(9):3544-3551.
[10]ALEX AT,JOSEPH A,SHAVI G,et al.Development and evaluation of carboplatin-loaded PCL nanoparticles for intranasal delivery[J].Drug Delivery,2016,23(7):2144-2153.
[11]LI S,TENON M,GARRCAU H.Enzymatic degradation of stereocopolymers derived from L-,DL-and meso-lactides[J].Polym Degrad Stabil,2000,67(1):85-90.
[12]LAO L L,VENKATRAMAN,PEPPAS N A.Modeling of drug release from biodegradable polymer blends[J].European Journal of Pharmaceutics&Biopharm,2008,70(4):796-803.
[13]MCDONALD P F,LYONS J G,GEEVER L M.In vitro degradation and drug release from polymer blends based on poly(dl-lactide),poly(l-lactide-glycolide)and poly(epsilon-caprolactone)[J].Journal of M aterials Science,2010,45(5):1284-1292.
[14]YORDANOV G,SKROBANSKA R,PETKOVA M.Poly(butyl cyanoacrylate)nanoparticles stabilised w ith poloxamer 188:particle size control and cytotoxic effects in cervical carcinoma(He La)cells[J].Chamical Papers,2015,70(3):365-374.
[15]YAN F,ZHANG C,ZHENG Y,et al.The effect of poloxamer 188 on nanoparticle morphology,size,cancer cell uptake,and cytotoxicity[J].Nanomedicine-Nanotechnology Biology and M edicine,2010,6(1):170-178.
[16]XU X,YANG L,XU X,et al.Ultrafine medicated fibers electrospun from W/O emulsions[J].Journal of Controlled Release,2005,108(1):33-42.
[17]XU X,CHEN X,MA P,et al.The release behavior of doxorubicin hydrochloride from medicated fibers prepared by emulsion-electrospinning[J].European Journal of Pharmaceutics&Biopharm,2008,70(1):165-170.
[18]WANG C,WANG L,MIN W.Evolution of core-shell structure:from emulsion to ultrafine emulsion electrospun fibers[J].M aterials Letters,2014,124(6):192-196.
[19]王浩,邓英杰,焦自学,等.聚L-乳酸与聚乙二醇-b-聚L-乳酸电纺纤维中布洛芬的释放[J].沈阳药科大学学报,2010,27(9):686-694.
[20]WANG H,LI Y Q,JIA Y H.Vesicle-formation of hexadecyl phosphatidyl choline released from polyε-caprolactone electrospun fibrous mats:preparation and characterization[J].Colloid&Polymer Science,2013,291(10):2475-2479.
[21]ROSS S,OLIVIER J P.A new method for the determination of critical micelle concentrations of un-ionized associations colloids in aqueous or in non-aqueous solution[J].Journal of Physical Chemistry,1959,63(10):1671-1674
[22]CHANG J H,OHNO M,ESUMI K,et al.Interaction of lodine w ith nonionic surfactant and polyethylene glycol in aqueous potassium lodide solution[J].Journal of the American Oil Chemists’Society,1988,65(10):1664-1668.
[23]HU L A,CHATELUT E,ROYER B,et al.Level of evidence for therapeutic drug monitoring of carboplatin[J].Therapie,2010,65(3):157-162.
[24]NIKOLOFF N,PONZINIBBIO M V,PADULA G,et al.Folic acid enhances the apoptotic and genotoxic activity of carboplatin in He La cell line[J].Toxicology in Vitro,2016,37:142-147.
[25]WANG S S,ZHANG HY,CHENG L A,et al.Analysis of the cytotoxic activity of carboplatin and gemcitabine combination[J].Anticancer Research,2010,30(11):4573-4578.
[26]WANG H,SONG H,CHEN X,et al.Ibuprofen release from PEG-PLLA electrospun fibers containing PEGblocked polyα-hydroxyl octanoic acid as an additive[J].Journal of Applied Polymer Science,2010,67(3):417-425.
[27]王浩,康卫民,张亚秋,等.壬苯醇醚聚ε-己内酯电纺纤维的表征和释放[J].沈阳药科大学学报,2015,32(4):249-255.
[28]IGNATIOUS F,SUN L,LEE C P,et al.Electrospun nanofibers in oral drug delivery[J].Pharmaceutical Research,2010,27(4):576-588.
[29]XU X,CHEN X,XU X,et al.BCNU-loaded PEG-PL-LA ultrafine fibers and their in vitro antitumor activity against Glioma C6 cells[J].Journal of Controlled Release,2006,114(3):307-316.
[30]MALEKI M,AMANI-TEHRAN M,LATIFI M,et al.Drug release profile in core-shell nanofibrous structures:a study on peppas equation and artificial neural netw ork modeling[J].Computer M ethods&Programs in Biomedicine,2014,113(1):92-100.
[31]YANG Y,LI X,CUI W,et al.Structural stability and release profiles of proteins from core-shell poly(DL-lactide)ultrafine fibers prepared by emulsion electrospinning[J].Journal of Biomedical M aterials Research(Part A),2008,26 A(2):374-385.
[32]ZHANG H,ZHAO C G,ZHAO Y H,et al.Electrospinning of ultrafine core/shell fibers for biomedical applications[J].Science China Chemistry,2010,53(6):1246-1254.
[33]YARIN A L.Coaxial electrospinning and emulsion electrospinning of core-shell fibers[J].Polymers for Advanced Technologies,2011,22(3):310-317.