双硒葡聚糖水凝胶的合成及其药物释放行为
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摘要
首先,通过双硒化钠(Na2Se2)与11-溴-1-十一醇的亲核取代反应合成了一种二羟基二硒化物;然后,通过该二硒化物与异佛尔酮二异氰酸酯(IPDI)反应合成了一种异氰酸根封端的双硒交联剂;最后,通过葡聚糖与该交联剂的反应合成了一种含双硒键的葡聚糖水凝胶。采用核磁共振氢谱(~1H-NMR)、傅里叶红外光谱(FT-IR)、凝胶渗透色谱(GPC)、拉曼光谱(Raman)、旋转流变仪(Rheology)、紫外-可见分光光度计(UV-Vis)等表征方法研究了产物的结构、溶胀性能、氧化响应行为、流变性能和体外药物释放行为。结果表明:含双硒键的葡聚糖水凝胶具有氧化响应能力;在没有氧化刺激条件下,该水凝胶24h的累积药物释放量为45%左右,而在氧化刺激条件下(w(H_2O_2)=0.2),只需14h便可释放90%的负载药物。
The reactive oxygen species(ROS),like hydrogen peroxide(H_2O_2),generated commonly during metabolism,and the increased level of H_2O_2 in tumor cells could be up to 0.5nmol/(104 cells·h)in comparison with that in normal cells,which provided a possibility for the usage of oxidation-responsive hydrogels in biomedical field.Herein,di-(1-hydroxylundecyl)diselenide was prepared by the nucleophilic substitution reaction between sodium diselenide(Na2Se2) and 11-bromoundecanol,and then reacted with isophorone diisocyanate(IPDI)into an isocyanate-terminated diselenide crosslinker.Finally,a diselenide dextran hydrogel was synthesized by crosslinking dextran with the diselenide agent.The structure,swelling profile,oxidation-responsive capability,rheology property,and in vitro drug release behavior of the diselenide dextran hydrogel were characterized by proton nuclear magnetic resonance(1 H-NMR)spectrum,Fourier-transform infrared(FT-IR)spectra,gel permeation chromatography(GPC),Raman spectrum,rotational rheometer,and ultraviolet-visible(UV-Vis) spectrophotometry.Results demonstrated that the hydrogel with a lower crosslinking degree showed a higher swelling ratio.In addition,the dissolution of hydrogel was observed visually after adding H_2O_2 solution due to the decomposition of diselenide bonds in the polymer network,indicating that the resultant hydrogel could be in response to the oxidation stimulus.Furthermore,in vitro drug release experiments were carried out by using rhodamin B(RhB)as a model agent.The results revealed that the hydrogel could only release 45%of the loaded drug in 24 hwithout H_2O_2,while 90%of the loaded drug could be released in 14 hunder an oxidizing environment(i.e.,w(H_2O_2)=0.2%),indicating that the diselenide dextran hydrogel was a promising candidate for drug release.
The reactive oxygen species(ROS),like hydrogen peroxide(H_2O_2),generated commonly during metabolism,and the increased level of H_2O_2 in tumor cells could be up to 0.5nmol/(104 cells·h)in comparison with that in normal cells,which provided a possibility for the usage of oxidation-responsive hydrogels in biomedical field.Herein,di-(1-hydroxylundecyl)diselenide was prepared by the nucleophilic substitution reaction between sodium diselenide(Na2Se2) and 11-bromoundecanol,and then reacted with isophorone diisocyanate(IPDI)into an isocyanate-terminated diselenide crosslinker.Finally,a diselenide dextran hydrogel was synthesized by crosslinking dextran with the diselenide agent.The structure,swelling profile,oxidation-responsive capability,rheology property,and in vitro drug release behavior of the diselenide dextran hydrogel were characterized by proton nuclear magnetic resonance(1 H-NMR)spectrum,Fourier-transform infrared(FT-IR)spectra,gel permeation chromatography(GPC),Raman spectrum,rotational rheometer,and ultraviolet-visible(UV-Vis) spectrophotometry.Results demonstrated that the hydrogel with a lower crosslinking degree showed a higher swelling ratio.In addition,the dissolution of hydrogel was observed visually after adding H_2O_2 solution due to the decomposition of diselenide bonds in the polymer network,indicating that the resultant hydrogel could be in response to the oxidation stimulus.Furthermore,in vitro drug release experiments were carried out by using rhodamin B(RhB)as a model agent.The results revealed that the hydrogel could only release 45%of the loaded drug in 24 hwithout H_2O_2,while 90%of the loaded drug could be released in 14 hunder an oxidizing environment(i.e.,w(H_2O_2)=0.2%),indicating that the diselenide dextran hydrogel was a promising candidate for drug release.
引文
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[2]YU S H,ZHANG X Y,TAN G X,et al.A novel pH-induced thermosensitive hydrogel composed of carboxymethyl chitosan and poloxamer cross-linked by glutaraldehyde for ophthalmic drug delivery[J].Carbohydrate Polymers,2017,155:208-217.
[3]KROGSGAARD M,BEHRENS M A,PEDERSEN J S,et al.Self-healing mussel-inspired multi-pH-responsive hydrogels[J].Biomacromolecules,2013,14(2):297-301.
[4]WANG L,LI B Q,XU F,et al.UV-crosslinkable and thermo-responsive chitosan hybrid hydrogel for NIR-triggered localized on-demand drug delivery[J].Carbohydrate Polymers,2017,174:904-914.
[5]WANG C,ZHANG G Y,LIU G H,et al.Photo-and thermo-responsive multicompartment hydrogels for synergistic delivery of gemcitabine and doxorubicin[J].Journal of Controlled Release,2017,259:149-159.
[6]王煜,王杰,张凯强,等.能源化工新材料热致变色水凝胶在智能窗上的应用[J].华东理工大学学报(自然科学版),2018,44(1):1-8.
[7]XUE Y A,XIA X Y,YU B,et al.Selenylsulfide bond-launched reduction-responsive superparamagnetic nanogel combined of acid-responsiveness for achievement of efficient therapy with low side effect[J].Acs Applied Materials&Interfaces,2017,9(36):30253-30257.
[8]ZHANG M,SONG C C,DU F S,et al.Supersensitive oxidation-responsive biodegradable peg hydrogels for glucosetriggered insulin delivery[J].Acs Applied Materials&Interfaces,2017,9(31):25905-25914.
[9]韩学武,戴文卿,高玫香,等.磺化明胶水凝胶的制备及其电场响应性能[J].功能高分子学报,2016,29(3):335-340.
[10]CHENG X F,JIN Y,SUN T B,et al.Oxidation-and thermo-responsive poly(N-isopropylacrylamide-co-2-hydroxyethyl acrylate)hydrogels cross-linked via diselenides for controlled drug delivery[J].Rsc Advances,2014,5(6):4162-4170.
[11]LIAO J F,TIAN T R,SHI S R,et al.The fabrication of biomimetic biphasic CAN-PAC hydrogel with a seamless interfacial layer applied in osteochondral defect repair[J].Bone Research,2017,5(2):137-151.
[12]CAO L Y,WERKMEISTER J A,WANG J,et al.Bone regeneration using photocrosslinked hydrogel incorporating rhBMP-2loaded 2-N,6-O-sulfated chitosan nanoparticles[J].Biomaterials,2014,35(9):2730-2742.
[13]YANG X F,LIU G Q,PENG L,et al.Highly efficient self-healable and dual responsive cellulose-based hydrogels for controlled release and 3Dcell culture[J].Advanced Functional Materials,2017,27(40):1703174.
[14]SIES H.Role of metabolic H2O2generation:Redox signaling and oxidative stress[J].Journal of Biological Chemistry,2014,289(13):8735-8741.
[15]KIM E J,BHUNIYA S,LEE H,et al.An activatable prodrug for the treatment of metastatic tumors[J].Journal of the American Chemical Society,2014,136(39):13888-13894.
[16]LIU J Y,PANG Y,ZHU Z Y,et al.Therapeutic nanocarriers with hydrogen peroxide-triggered drug release for cancer treatment[J].Biomacromolecules,2013,14(5):1627-1636.
[17]KIM Jinhwan,KIM Hyunwoo,KIM W J.Single-layered MoS2-PEI-PEG nanocomposite-mediated gene delivery controlled by photo and redox stimuli[J].Small,2016,12(9):1184-1192.
[18]OOMS N,JANSENS K,PAREYT B,et al.The impact of disulfide bond dynamics in wheat gluten protein on the development of fermented pastry crumb[J].Food Chemistry,2017,242:68-74.
[19]YU H S,WANG Y A,YANG H Y,et al.Injectable self-healing hydrogels formed via thiol/disulfide exchange of thiol functionalized F127and dithiolane modified PEG[J].Journal of Materials Chemistry B,2017,5(22):4121-4127.
[20]MA N,LI Y,XU H P,et al.Dual redox responsive assemblies formed from diselenide block copolymers[J].Journal of the American Chemical Society,2010,132(2):442-443.
[21]WEI C,ZHANG Y,XU H,et al.Well-defined labile diselenide-centered poly(ε-caprolactone)-based micelles for activated intracellular drug release[J].Journal of Materials Chemistry B,2016,4:5059-5067.
[22]BAE K H,LEE F,XU K M,et al.Microstructured dextran hydrogels for burst-free sustained release of PEGylated protein drugs[J].Biomaterials,2015,63:146-157.
[23]JI S B,FAN F Q,SUN C X,et al.Visible light-induced plasticity of shape memory polymers[J].ACS Applied Materials&Interfaces,2017,9(38):33169-33175.
[24]YANG X L.A novel method to prepare sodium dise lenide and organic diselenides[J].Chinese Journal of Inorganic Chemistry,2001,17(6):905-907.
[25]SOCRATES G.Infrared and Raman Characteristic Group Frequencies Table and Charts[M].New York:John Wiley&Sons,2004.
[26]WANG H Q,LI S,CHEN Z X,et al.A novel type of one-dimensional organic selenium-containing fiber with superior performance for lithium-selenium and sodium-selenium batteries[J].Rsc Advances,2014,4(106):61673-61678.
[27]HELIOS K,PIETRASZKO A,ZIERKIEWICZ W,et al.The crystal structure,infrared,Raman and density functional studies of bis(2-aminophenyl)diselenide[J].Polyhedron,2011,30(15):2466-2472.
[28]CHENG X F,JIN Y,QI R,et al.Dual pH and oxidation-responsive nanogels crosslinked by diselenide bonds for controlled drug delivery[J].Polymer,2016,101:370-378.