基于主客体识别作用构筑的聚合物前药胶束及其药物控释性能研究
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摘要
研究制备了一种基于超分子聚合物的pH响应性前药胶束,其主体分子是β-环糊精-阿霉素前药分子,客体分子为偶氮苯封端的聚甲基丙烯酸N,N-二甲氨基乙酯.利用二维核磁NOESY谱鉴定了环糊精与偶氮苯之间的主客体包合作用,利用动态光散射和透射电子显微镜表征了超分子聚合物胶束的形貌和尺寸.结果表明超分子聚合物在水溶液中形成了球形纳米胶束,其粒径尺寸在80~100nm.超分子聚合物-前药胶束体外药物控释行为具有pH响应特性,分别在pH5.0和pH7.4下研究了其对药物的控释行为.利用荧光光谱法测定药物分子DOX的累计释放率,结果表明连接抗癌药物DOX分子的酰腙键对酸性环境极为敏感,可在短时间内被还原,实现抗癌药物的有效释放.
pH-sensitive supramolecular polymeric micelles were constructed by host-guest interactions betweenβ-CD-hydrazone-DOX and azobenzene terminated poly(2-(Dimethylamino)ethyl methacrylate)(Azo-PDMA).The host-guest interactions betweenβ-cyclodextrin and azobenzene were investigated by 2 D NOESY spectroscopy,and the morphology and size of supramolecular polymer micelles were investigated by dynamic light scattering(DLS)and transmission electron microscopy(TEM).On the basis of mentioned results,supramolecular micelles formed in the pure water possessed proper and uniform size(with diameters of 80~100 nm).Finally,the drug control release behavior of these micelles was analyzed in pH5.0 and pH7.4 phosphate buffer solution respectively.Then the concentration of released DOX was determined by fluorescence spectrometry.The results suggested that the hydrazine bond can be responsive in acid environment,leading to the release of DOX in a short time.
pH-sensitive supramolecular polymeric micelles were constructed by host-guest interactions betweenβ-CD-hydrazone-DOX and azobenzene terminated poly(2-(Dimethylamino)ethyl methacrylate)(Azo-PDMA).The host-guest interactions betweenβ-cyclodextrin and azobenzene were investigated by 2 D NOESY spectroscopy,and the morphology and size of supramolecular polymer micelles were investigated by dynamic light scattering(DLS)and transmission electron microscopy(TEM).On the basis of mentioned results,supramolecular micelles formed in the pure water possessed proper and uniform size(with diameters of 80~100 nm).Finally,the drug control release behavior of these micelles was analyzed in pH5.0 and pH7.4 phosphate buffer solution respectively.Then the concentration of released DOX was determined by fluorescence spectrometry.The results suggested that the hydrazine bond can be responsive in acid environment,leading to the release of DOX in a short time.
引文
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[2]Liu K,Kang Y,Wang Z,et al.Reversible and adaptive functional supramolecular materials:"Noncovalent interaction"materials[J].Adv Mater,2013,25(39):5 530-5 547.
[3]徐江飞,张希.中国超分子聚合物的研究与动态[J].高分子学报,2017(1):37-49.
[4]Yang L,Tan X,Wang Z,et al.Supramolecular polymers:History development,preparation,characterization,and functions[J].Chem Rev,2015,115(15):7 196-7 239.
[5]Hu J,Liu S.Engineering responsive polymer building blocks with host-guest molecular recognition for functional applications[J].Acc Chem Res,2014,47(7):2 084-2 095.
[6]Dong S,Zheng B,Wang F,et al.Supramolecular polymers constructed from macrocycle-based host-guest molecular recognition motifs[J].Acc Chem Res,2014,47(7):1 982-1994.
[7]Bai Y,Fan X,Tian W,et al.Morphology transitions of supramolecular hyperbranched polymers induced by double supramolecular driving forces[J].Polym Chem,2015,6(5):732-737.
[8]Bai Y,Fan X,Yao H,et al.Probing into the supramolecular driving force of an amphiphilicβ-cyclodextrin dimer in various solvents:Host-guest recognition or hydrophilic interaction[J].Journal of Phys Chem B,2015,119(35):11 839-11 899.
[9]Yan Q,Xin Y,Zhou R,et al.Light-controlled smart nanotubes based on the orthogonal assembly of two homopolymers[J].Chem Commun,2011,47(34):9 594-9 596.
[10]Chen Y,Liu Y.Construction and functions of cyclodextrin-based 1Dsupramolecular strand and their secondary assemblies[J].Adv Mater,2015,27(36):5 403-5 409.
[11]Peng L,Liu S,Feng A,et al.Polymeric nanocarriers based on cyclodextrins for drug delivery:Host-guest interaction as stimuli-responsive linker[J].Mol Pharmaceutics,2017,14(8):2 468-2 475.
[12]Chen Y,Wang Y,Wang H,et al.Zwitterionic supramolecular prodrug nanoparticles based on host-guest interactions for intracellular drug delivery[J].Polymer,2016,97(2):449-455.
[13]Susana M,Ana R,Angel C,et al.Supramolecular cyclodextrin-based drug nanocarriers[J].Chem Commun,2015,51(29):6 275-6 289.
[14]Dong R,Zhou Y,Lei Q,et al.Functional supramolecular polymers for biomedical applications[J].Adv Mater,2015,27(3):498-526.
[15]周应学,范晓东,任杰,等.环糊精-药物纳米复合粒子的制备及其控制释放研究进展[J].材料导报,2010,24(5):136-140.
[16]Peng L,Wang Z,Feng A,et al.Star amphiphilic supramolecular copolymer based on host-guest interaction for electrochemical controlled drug delivery[J].Polymer,2016,88:112-122.
[17]Peng L,Feng A,Zhang H,et al.Voltage-responsive micelles based on the assembly of two biocompatible homopolymers[J].Polym Chem,2014,5(5):1 751-1 759.
[18]Zhang H,Tian W,Suo R,et al.Photo-controlled hostguest interaction as a new strategy to improve the preparation of“breathing”hollow polymer nanospheres for controlled drug delivery[J].Jounal of Mater Chem B,2015,43(3):8 528-8 536.
[19]Brigger I,Dubernet C,Couvreur P.Nanoparticles in cancer therapy and diagnosis[J].Adv Drug Deliv Rev,2012,54(5):631-651.
[20]Jyotirmoy G,Joydeep D,Prasenjit M,et al.The protective role of arjunolic acid against doxorubicin induced intracellular ROS dependent JNK-p38and p53-mediated cardiac apoptosis[J].Biomaterials,2011,32(21):4 857-4 866.
[21]Yin Q,Shen J,Zhang Z,et al.Reversal of multidrug resistance by stimuli-responsive drug delivery systems for therapy of tumor[J].Adv Drug Deliv Rev,2013,65(13-14):1 699-1 715.
[22]Liu J,Zhao Y,Guo Q,et al.TAT-motified nanosilver for combating multidrug-resistant cancer[J].Biomaterials,2012,33(26):6 155-6 161.
[23]黎燕,黄卫,黄平,等.抗肿瘤药物输送体系[J].化学进展,2014,26(8):1 395-1 408.
[24]Danquah M,Zhang X,Mahato R,et al.Extravasation of polymeric nanomedicines across tumor[J].Adv Drug Deliv Rev,2011,63(8):623-639.
[25]Shi J,Votruba A,Farokhzad O,et al.Nanotechnology in drug delivery and tissue engineering:From discovery to applications[J].Nano Lett,2010,10(9):3 223-3 230.
[26]Elsabahy E,Wooley K.Design of polymeric nanoparticles for biomedical delivery applications[J].Chem Soc Rev,2012,41(7):2 545-2 561.
[27]于京,哈伟,师彦平.智能水凝胶双抗癌药物控释体系[J].化学进展,2015,27(11):1 640-1 648.
[28]Wang H,Xu F,Wang Y,et al.pH-responsive and biodegradable polymeric micells based on poly(β-amino ester)-graftphosphorylcholine for doxorubicin delivery[J].Polym Chem,2013,4(10):3 012-3 019.
[29]Fang J,Nakamura H,Maeda H,et al.The EPR effect:Unique features of tumor blood vessels for drug delivery,factors involved,and limitations and augmentation of the effect[J].Adv Drug Deliv Rev,2011,63(3):136-151.
[30]Cheng R,Feng F,Meng F,et al.Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug ang gene delivery[J].Journal of Control Release,2011,152(1):2-12.
[31]Cai T,Chen Y,Wang Y,et al.Functional 2-methylene-1,3-dioxepane terpolymer:A versatile platform to construct biodegradable polymeric prodrugs for intracellular drug delivery[J].Polym Chem,2014,5(13):4 016-4 068.
[32]Wang Y,Wang H,Chen J,et al.pH and hydrogen peroxide dual responsive supramolecular prodrug system for controlled release of bioactive molecules[J].Colloids and Surfaces B:Biointerfaces,2014,121(121):189-195.
[33]Liu T,Wang S,Song Y,et al.ABX-type amphiphilic macromonemer-based supramolecular hyperbranched polymers for controllable self-assembly[J].Polym Chem,2017,8(8):1306-1 314.