氧化响应性含硒聚己内酯-b-聚磷酸酯三嵌段聚合物胶束的合成及性能
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摘要
以聚己内酯为大分子引发剂、异辛酸亚锡为催化剂引发磷酸酯单体2-乙氧基-2-氧-1,3,2-二氧磷酸酯环戊烷(EOP)开环聚合得到二嵌段的聚己内酯-b-聚磷酸酯聚合物PCL-PEEP。以1-(3-二甲氨基丙基)-3-乙基碳二亚胺,4-二甲氨基吡啶为偶合催化体系,以新合成的二羧酸含硒小分子3,3′-硒代二丙酸(Se-DCP)为偶联剂,得到含硒三嵌段聚合物PCL-PEEP-Se-PEEP-PCL,并采用溶剂挥发法制备该聚合物的胶束。通过核磁共振、红外光谱和凝胶渗透色谱对聚合物的结构进行了表征,通过荧光光谱、核磁共振氢谱、动态光散射和透射电镜对聚合物胶束的临界胶束浓度和氧化响应性进行了分析表征,利用噻唑蓝(MTT)比色法评价了聚合物胶束的生物相容性。结果表明:硒元素成功引入到聚合物中;聚合物胶束的临界胶束质量浓度为0.022mg/mL,胶束为平均粒径约91nm的球形;在过氧化氢的氧化条件下,胶束粒径出现不规则变化且球形胶束发生解组装;聚合物胶束具有良好的生物相容性。
The diblock poly(ε-caprolactone)-b-polyphosphoester(PCL-PEEP)was synthesized by ringopening polymerization(ROP)of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane(EOP)with PCL as macroinitiator and Sn(Oct)2as the ROP catalyst.Subsequently,the selenium-containing triblock polymer PCLPEEP-Se-PEEP-PCL was synthesized by using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 4-dimethylaminopyridine as coupling catalyst and newly prepared dicarboxylic acid di-(3,3′-carboxyl propylene)selenide(Se-DCP)as the coupling agent.As-synthezied PCL-PEEP-Se-PEEP-PCL micelles were produced after removing solvent by evaporation.The structure characteristics were confirmed by nuclear magnetic resonance(NMR),Fourier transform infrared spectroscopy(FT-IR)and gel permeation chromatography(GPC).The critical micelle concentration(CMC)and oxidative stimuli-response of micelles were determined by fluorescence spectroscopy,1H-NMR,dynamic light scattering(DLS)and transmission electron microscope(TEM).MTT assay was also applied to evaluate the biocompatibility of micelles.The results showed that the element of selenium was introduced into the polymer successfully.The CMC was determined around 0.022 mg/mL and the micelles were spherical structure with the diameter about 91 nm.The micelles disassembled and the size became irregular in the presence of H_2O_2.MTT assay revealed that the PCL-PEEP-Se-PEEP-PCL micelles had considerable biocompatibility and low cytotoxicity even the mass concentration was up to 500μg/mL.The newly designed selenium-containing PCL-PEEP-Se-PEEP-PCL micelles with oxidation-responsive properties could provide a platform for controlled drug release toward targeted cancer therapy.
The diblock poly(ε-caprolactone)-b-polyphosphoester(PCL-PEEP)was synthesized by ringopening polymerization(ROP)of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane(EOP)with PCL as macroinitiator and Sn(Oct)2as the ROP catalyst.Subsequently,the selenium-containing triblock polymer PCLPEEP-Se-PEEP-PCL was synthesized by using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 4-dimethylaminopyridine as coupling catalyst and newly prepared dicarboxylic acid di-(3,3′-carboxyl propylene)selenide(Se-DCP)as the coupling agent.As-synthezied PCL-PEEP-Se-PEEP-PCL micelles were produced after removing solvent by evaporation.The structure characteristics were confirmed by nuclear magnetic resonance(NMR),Fourier transform infrared spectroscopy(FT-IR)and gel permeation chromatography(GPC).The critical micelle concentration(CMC)and oxidative stimuli-response of micelles were determined by fluorescence spectroscopy,1H-NMR,dynamic light scattering(DLS)and transmission electron microscope(TEM).MTT assay was also applied to evaluate the biocompatibility of micelles.The results showed that the element of selenium was introduced into the polymer successfully.The CMC was determined around 0.022 mg/mL and the micelles were spherical structure with the diameter about 91 nm.The micelles disassembled and the size became irregular in the presence of H_2O_2.MTT assay revealed that the PCL-PEEP-Se-PEEP-PCL micelles had considerable biocompatibility and low cytotoxicity even the mass concentration was up to 500μg/mL.The newly designed selenium-containing PCL-PEEP-Se-PEEP-PCL micelles with oxidation-responsive properties could provide a platform for controlled drug release toward targeted cancer therapy.
引文
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[2]曹玮,许华平.含硒高分子:一类新型生物材料[J].化学通报,2013,76(4):291-298.
[3]XU H,CAO W,ZHANG X.Selenium-containing polymers:Promising biomaterials for controlled release and enzyme mimics[J].Accounts of Chemical Research,2013,46(7):1647-1658.
[4]STUART M A,HUCK W T,GENZER J,et al.Emerging applications of stimuli-responsive polymer materials[J].Nature Materials,2010,9(2):101-113.
[5]THEATO P,SUMERLIN B S,OREILLY R K,et al.Stimuli responsive materials[J].Chemical Society Reviews,2013,42(17):7055-7056.
[6]KWEONA H Y,MI K Y,PARKB I K,et al.A novel degradable polycaprolactone networks for tissue engineering[J].Biomaterials,2003,24(5):801-808.
[7]戴一星,郎美东.羧甲基壳聚糖基胶束的制备及其缓释性[J].功能高分子学报,2018,31(1):75-81.
[8]STEINBACH T,WURM F R.Poly(phosphoester)s:A new platform for degradable polymers[J].Angewandte Chemie,2015,54(21):6098-6108.
[9]张震,谭连江,龚兵,等.基于“分子胶”的新型两亲性嵌段聚合物β-CD-PLA的合成及其胶束化[J].功能高分子学报,2017,30(3):321-326.
[10]MA N,LI Y,REN H,et al.Selenium-containing block copolymers and their oxidation-responsive aggregates[J].Polymer Chemistry,2010,1(10):1609-1614.
[11]LIU J,PANG Y,ZHU Z,et al.Therapeutic nanocarriers with hydrogen peroxide-triggered drug release for cancer treatment[J].Biomacromolecules,2013,14(5):1627-1636.
[12]WANG Y,LI Y,YANG X,et al.Tunable thermosensitivity of biodegradable polymer micelles of poly(ε-caprolactone)and polyphosphoester block copolymers[J].Macromolecules,2009,42(8):3026-3032.
[13]SUN Y,DU X,HE J,et al.Dual-responsive core-crosslinked polyphosphoester-based nanoparticles for pH/redoxtriggered anticancer drug delivery[J].Journal of Materials Chemistry B,2017,5(20):3771-3782.
[14]XIONG M,WU J,WANG Y,et al.Synthesis of PEG-armed and polyphosphoester core-cross-linked nanogel by one-step ring-opening polymerization[J].Macromolecules,2009,42(4):893-896.
[15]顾晓瑜,王朝阳,童真.两亲性双硒聚合物的制备及其聚集体形成[J].化学学报,2013,71(8):1136-1140.
[16]REN H,WU Y,MA N,et al.Side-chain selenium-containing amphiphilic block copolymers:Redox-controlled selfassembly and disassembly[J].Soft Matter,2012,8(5):1460-1466.
[17]LI C,HUANG W,ZHOU L,et al.PEGylated poly(diselenide-phosphate)nanogel as efficient self-delivery nanomedicine for cancer therapy[J].Polymer Chemistry,2015,6(36):6498-6508.
[18]ZENG H.Selenium as an essential micronutrient:Roles in cell cycle and apoptosis[J].Molecules,2009,14(3):1263-1278.