一种还原响应性紫杉醇胶束的制备与性能
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摘要
首先,以甲氧基聚乙二醇(mPEG)为大分子引发剂,以辛酸亚锡为催化剂使D,L-丙交酯开环聚合,得到共聚物甲氧基聚乙二醇-聚乳酸(mPEG-PLA);然后,在该共聚物的末尾端进行羟基树枝化并接枝硫辛酸(LA),制备了可交联聚合物mPEG-PLA-(LA)4。采用核磁共振氢谱(1 H-NMR)和凝胶渗透色谱(GPC)对聚合物的结构和分子量进行了表征。进一步采用薄膜水化法制备了包载紫杉醇的交联共聚物胶束,并利用动态光散射(DLS)和透射电镜(TEM)对胶束结构进行了表征,采用动物实验评价了载药胶束的抑瘤效果。结果表明:胶束的平均粒径为34.0nm,结构规整。相比于未交联胶束,交联胶束具有更好的稳定性与还原响应性,抑瘤效果提高显著。
A novel disulfide cross-linked redox-sensitive lipoic acid dendronized methoxy polyethylene glycol-polylactide block copolymer(mPEG-PLA-(LA)4)was successfully prepared.Firstly,methoxy polyethylene glycol-polylactide(mPEG-PLA)was synthesized by a ring opening polymerization of D,Llactide using methoxy polyethylene glycol(mPEG)as a macroinitiator and stannous octoate(Sn(Oct)2)as the catalyst.Then,mPEG-PLA-(OH)4was obtained by reaction of mPEG-PLA with acetonide-2,2-dimethylol propanoic anhydride(Ac-DMPA)and deprotection of the terminal acetonide groups.Finally,lipoic acid terminated methoxy polyethylene glycol-polylactide block copolymer(mPEG-PLA-(LA)4)was synthesized and paclitaxel-loaded mPEG-PLA-(LA)4micelles were prepared by solid dispersion-thin film hydration method.The structures and molecular weights of the polymers were characterized by nuclear magnetic hydrogen spectrum(1 H-NMR)and gel permeation chromatography(GPC).Transmission electron microscope(TEM)and dynamic light scattering(DLS)were used to investigate the morphology and size distribution of the micelles.The results show that mPEG-PLA-(LA)4micelles have spherical structure with average diameter of 34.0nm.Besides,the in vitro release behavior of paclitaxel-loaded mPEG-PLA-(LA)4micelles was determined by a modified dialysis method.Compared with mPEG-PLA micelles,mPEG-PLA-(LA)4micelles have better stability and redox-responsive.The in vivo results reveal that mPEG-PLA-(LA)4micelles reduce the acute toxicity in mice and show improved anti-tumor efficacy compared with mPEG-PLA micelles.All these indicate that mPEG-PLA-(LA)4micelles are highly promising drug delivery system for clinical application.
A novel disulfide cross-linked redox-sensitive lipoic acid dendronized methoxy polyethylene glycol-polylactide block copolymer(mPEG-PLA-(LA)4)was successfully prepared.Firstly,methoxy polyethylene glycol-polylactide(mPEG-PLA)was synthesized by a ring opening polymerization of D,Llactide using methoxy polyethylene glycol(mPEG)as a macroinitiator and stannous octoate(Sn(Oct)2)as the catalyst.Then,mPEG-PLA-(OH)4was obtained by reaction of mPEG-PLA with acetonide-2,2-dimethylol propanoic anhydride(Ac-DMPA)and deprotection of the terminal acetonide groups.Finally,lipoic acid terminated methoxy polyethylene glycol-polylactide block copolymer(mPEG-PLA-(LA)4)was synthesized and paclitaxel-loaded mPEG-PLA-(LA)4micelles were prepared by solid dispersion-thin film hydration method.The structures and molecular weights of the polymers were characterized by nuclear magnetic hydrogen spectrum(1 H-NMR)and gel permeation chromatography(GPC).Transmission electron microscope(TEM)and dynamic light scattering(DLS)were used to investigate the morphology and size distribution of the micelles.The results show that mPEG-PLA-(LA)4micelles have spherical structure with average diameter of 34.0nm.Besides,the in vitro release behavior of paclitaxel-loaded mPEG-PLA-(LA)4micelles was determined by a modified dialysis method.Compared with mPEG-PLA micelles,mPEG-PLA-(LA)4micelles have better stability and redox-responsive.The in vivo results reveal that mPEG-PLA-(LA)4micelles reduce the acute toxicity in mice and show improved anti-tumor efficacy compared with mPEG-PLA micelles.All these indicate that mPEG-PLA-(LA)4micelles are highly promising drug delivery system for clinical application.
引文
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[2]ZHUANG B,DU L,XU H X,et al.Self-assembled micelle loading cabazitaxel for therapy of lung cancer[J].International Journal of Pharmaceutics,2016,499(2):146-155.
[3]XUE P,LIU D,WANG J,et al.Redox-sensitive citronellol cabazitaxel conjugate:Maintained in vitro cytotoxicity and self-assembled as multifunctional nanomedicine[J].Bioconjugate Chemistry,2016,27(5):1360-1372.
[4]XIE C,ZHANG P,ZHANG Z K,et al.Drug-loaded pseudo-block copolymer micelles with a multi-armed star polymer as the micellar exterior[J].Nanoscale,2015,7(29):12572-12580.
[5]张建,马明煊,闫强.基于生物刺激源的响应性聚合物及其可控自组装[J].功能高分子学报,2016,29(2):115-133.
[6]HAN X X,CHEN D,SUN J,et al.A novel cabazitaxel-loaded polymeric micelle system with superior in vitro stability and long blood circulation time[J].Journal of Biomaterials Science:Polymer Edition,2016,27(7):626-642.
[7]WANG H,TANG L,TU C L,et al.Redox-responsive,core-cross-linked micelles capable of ondemand,concurrent drug release and structure disassembly[J].Biomacromolecules,2013,14(10):3706-3712.
[8]SHUAI X T,THOMAS M,XI F,et al.Core-cross-linked polymeric micelles as paclitaxel carriers[J].Bioconjugate Chemistry,2004,15(3):441-448.
[9]KOO A N,LEE H J,KIM S E,et al.Disulfide-cross-linked PEG-poly(amino acid)s copolymer micelles for glutathionemediated intracellular drug delivery[J].Chemical Communications,2008,2008(48):6570-6572.
[10]MENG F H,WIM E H,ZHONG Z Y.Reduction-sensitive polymers and bioconjugates for biomedical applications[J].2009,30(12):2180-2198.
[11]CAJOT S,LAUTRAM N,PASSIRANI C,et al.Design of reversibly core cross-linked micelles sensitive to reductive environment[J].Journal of Controlled Release,2011,152(1):30-36.
[12]向存程,季金苟,刘月华,等.mPEG-PLA共聚物胶束对DHA的增溶及光保护作用[J].功能高分子学报,2017,30(2):221-226.
[13]MICHAEL M,EVA M,ANDERS H.Rapid and efficient synthesis of aliphatic ester dendrons and dendrimers[J].Macromolecules,2002,35(22):8307-8314.
[14]李晨晨,龚飞荣,程树军,等.姜黄素缓释胶束的制备、表征及其抗细胞毒类药物的多药耐药性评价[J].华东理工大学学报(自然科学版),2014,40(5):562-567.