温度和葡萄糖双重敏感性共聚物微凝胶的研究
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摘要
模拟生命活动过程中的分子识别现象,能识别特定生物分子而产生刺激响应性的生物分子识别响应性水凝胶非常接近于生物组织,用它构筑的智能系统类似于具有反馈和平衡功能的生物系统,因此在生物工程和生物医学领域有非常诱人的应用前景。本论文研究的葡萄糖分子识别响应性微凝胶是以N－异丙基丙烯酰胺(NIPAM)为主单体,含苯硼酸基团的乙烯基单体为共聚功能单体,通过无皂乳液聚合法合成。形成的葡萄糖敏感性微凝胶完全由人工合成材料组成,没有用到昂贵的生物活性物质,具有稳定性好、制备成本低等优势。由于合成过程中不使用乳化剂,微凝胶表面无乳化剂污染。葡萄糖敏感性微凝胶的潜在用途是作为胰岛素的给药载体,它可根据人体血糖水平控制释放胰岛素。另外,葡萄糖敏感性微凝胶还可作为葡萄糖氧化酶的载体,在产生葡萄糖酸的生化反应过程中,能起到根据葡萄糖浓度控制酶活性的作用。本文的具体研究工作主要分为以下几方面:
1.以碳二亚胺为催化剂,3－氨基苯硼酸(APBA)和丙烯酸(AA)为原料,在比较温和的条件下合成含苯硼酸基团的功能单体－3－丙烯酰胺基苯硼酸(AAPBA),重结晶后的产物用元素分析、红外吸收光谱、核磁共振氢谱、紫外吸收光谱、有机质谱对产物结构进行表征,确证合成所得产物为3－丙烯酰胺基苯硼酸。推测AAPBA的合成分为两步,第一步是1－(3－二甲氨基丙基)－3－乙基碳二亚胺盐酸盐(EDCI)中的碳二亚胺基团与AA中的羧基反应形成O－酰基脲中间体,第二步是O－酰基脲中间体与APBA中的氨基反应生成AAPBA。
2.采用无皂乳液聚合法合成poly(MPAM－co－AAPBA)共聚物微凝胶。扫描电镜和动态激光光散射分析结果证实合成的微凝胶具有良好的单分散性,表明无皂乳液聚合过程中微凝胶按均相成核机理进行成核,无二次成核过程。微凝胶的粒径和溶胀比随着AAPBA用量的增加逐渐减小。poly(NIPAM－co－AAPBA)微凝胶具有温敏性和葡萄糖敏感性,其相转变温度随着AAPBA用量增加而下降。
3.以4－乙烯基苯硼酸(VPBA)为共聚的功能单体,采用无皂乳液聚合法合成poly(NIPAM－co－VPBA)共聚物微凝胶。通过微凝胶中B元素含量分析,傅立叶变换红外光谱和BNMR谱的表征,确证了微凝胶的化学结构和组成。微凝胶的粒径和溶胀比均随着VPBA用量的增加逐渐减小,在中性水介质中,VPBA单元之间的疏水相互作用可能在微凝胶内的聚合物分子链间形成了物理交联点。poly(NIPAM－co－VPBA)微凝胶具有温敏性,其体积相转变温度(VPTT)随着微凝胶中VPBA单元含量的增加而减小。微凝胶在pH=10.5的水介质中具有葡萄糖敏感性,微凝胶水动力学直径随葡萄糖浓度增加的幅度是随着微凝胶中VPBA含量的增加而减少。
Biomolecule recognition responsive hydrogels,which can recognize specific biomolecules and respond to them mimicking the molecule-recognizing process of life activity,are very close to biological tissue.The intelligent systems fabricated from the hydrogels resemble the biological systems with feedback and equilibrium functions,and they have a great deal of potential applications in the fields of bioengineering and biomedicine.In this paper,the glucose molecule recognition responsive microgels were synthesized by surfactant-free emulsion polymerization based on N-isopropylacrylamide(NIPAM)as main monomer and the vinyl monomer with phenylboronic acid group as functional comonomers. The glucose-sensitive microgels were composed of artificial materials without using expensive bioactive substance,so they have the advantage of good stability and low preparation cost.Due to the fact that any surfactant was not used in the synthesis process,there was no surfactant pollution on the surface of the microgels.The glucose-sensitive microgels will potentially be utilized as self-regulated insulin delivery system,in which insulin can be released in respond to body blood glucose concentration,In addition,the glucose-sensitive microgels could be used as the carrier of glucose oxidase,in which the activity of the glucose oxidase can be controlled by glucose concentration in the biochemical reaction system for producing glucose acid.The detailed results are as follows:
1.3-acrylamidophenylboronic acid(AAPBA)was synthesized by the condensation reaction between carboxyl acid group(-COOH)and amino group,based on 3-aminophenylboronic acid(APBA)and acrylic acid (AA)as starting materials and N-Ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDCI)as condensating agent.The product purified by recrystallization was verified by elemental analysis,FTIR,~1H NMR,UVand MS.The synthesis mechanism of AAPBA was speculated to be divided into two steps:in the first step,the 0-acylcarbamide intermediate was formed by the reaction between ethylcarbodiimide groups of EDCI and carboxyl groups of acrylic acids;in the second step, AAPBA was formed by the reaction between 0-acylcarbamide intermediates and amino groups of APBA.
2.The poly(NIPAM-co-AAPBA)microgels were prepared by surfactant-free emulsion polymerization.The microgels displayed spherical shape and very narrow size distribution from the results obtained by scanning electron microscopy(SEM)and dynamic laser light scattering(DLLS),indicating that there was extremely short nucleation period without second nucleation process.The hydrodynamic diameters and swelling ratios of the microgels decreased with the increase of AAPBA component content.The poly(NIPAM-co-AAPBA)microgels were both temperature- and glucose- sensitive,their volume phase transition temperature(VPTT)decreased with the increase of AAPBA component content within the microgels. 3.The poly(NIPAM-co-VPBA)copolymer microgels were prepared by surfactant-free emulsion polymerization,in which 4-vinyl phenylboronic acid(VPBA)was used as functional comonomer.The chemical structure of the microgels was verified by the content analysis of B element,fourier transform infrared spectroscopy(FTIR)and ~(11)B NMR.The hydrodynamic diameters and swelling ratios of the microgels decreased with the increase of VPBA component content.In neutral water media, the physically crosslinked points within the microgels were formed between the polymer chains by the hydrophobic interaction between VPBA units.The poly(NIPAM-co-VPBA)microgels were temperature-sensitive,their VPTT decreased with the increase of VPBA component content.In the water media of pH=10.5,the microgels were glucose-sensitive,and the increase magnitude of their hydrodynamic diameters with the glucose concentration in the media was reduced with the enhancement of VPBA component content within the microgels.
1.以碳二亚胺为催化剂,3－氨基苯硼酸(APBA)和丙烯酸(AA)为原料,在比较温和的条件下合成含苯硼酸基团的功能单体－3－丙烯酰胺基苯硼酸(AAPBA),重结晶后的产物用元素分析、红外吸收光谱、核磁共振氢谱、紫外吸收光谱、有机质谱对产物结构进行表征,确证合成所得产物为3－丙烯酰胺基苯硼酸。推测AAPBA的合成分为两步,第一步是1－(3－二甲氨基丙基)－3－乙基碳二亚胺盐酸盐(EDCI)中的碳二亚胺基团与AA中的羧基反应形成O－酰基脲中间体,第二步是O－酰基脲中间体与APBA中的氨基反应生成AAPBA。
2.采用无皂乳液聚合法合成poly(MPAM－co－AAPBA)共聚物微凝胶。扫描电镜和动态激光光散射分析结果证实合成的微凝胶具有良好的单分散性,表明无皂乳液聚合过程中微凝胶按均相成核机理进行成核,无二次成核过程。微凝胶的粒径和溶胀比随着AAPBA用量的增加逐渐减小。poly(NIPAM－co－AAPBA)微凝胶具有温敏性和葡萄糖敏感性,其相转变温度随着AAPBA用量增加而下降。
3.以4－乙烯基苯硼酸(VPBA)为共聚的功能单体,采用无皂乳液聚合法合成poly(NIPAM－co－VPBA)共聚物微凝胶。通过微凝胶中B元素含量分析,傅立叶变换红外光谱和BNMR谱的表征,确证了微凝胶的化学结构和组成。微凝胶的粒径和溶胀比均随着VPBA用量的增加逐渐减小,在中性水介质中,VPBA单元之间的疏水相互作用可能在微凝胶内的聚合物分子链间形成了物理交联点。poly(NIPAM－co－VPBA)微凝胶具有温敏性,其体积相转变温度(VPTT)随着微凝胶中VPBA单元含量的增加而减小。微凝胶在pH=10.5的水介质中具有葡萄糖敏感性,微凝胶水动力学直径随葡萄糖浓度增加的幅度是随着微凝胶中VPBA含量的增加而减少。
Biomolecule recognition responsive hydrogels,which can recognize specific biomolecules and respond to them mimicking the molecule-recognizing process of life activity,are very close to biological tissue.The intelligent systems fabricated from the hydrogels resemble the biological systems with feedback and equilibrium functions,and they have a great deal of potential applications in the fields of bioengineering and biomedicine.In this paper,the glucose molecule recognition responsive microgels were synthesized by surfactant-free emulsion polymerization based on N-isopropylacrylamide(NIPAM)as main monomer and the vinyl monomer with phenylboronic acid group as functional comonomers. The glucose-sensitive microgels were composed of artificial materials without using expensive bioactive substance,so they have the advantage of good stability and low preparation cost.Due to the fact that any surfactant was not used in the synthesis process,there was no surfactant pollution on the surface of the microgels.The glucose-sensitive microgels will potentially be utilized as self-regulated insulin delivery system,in which insulin can be released in respond to body blood glucose concentration,In addition,the glucose-sensitive microgels could be used as the carrier of glucose oxidase,in which the activity of the glucose oxidase can be controlled by glucose concentration in the biochemical reaction system for producing glucose acid.The detailed results are as follows:
1.3-acrylamidophenylboronic acid(AAPBA)was synthesized by the condensation reaction between carboxyl acid group(-COOH)and amino group,based on 3-aminophenylboronic acid(APBA)and acrylic acid (AA)as starting materials and N-Ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDCI)as condensating agent.The product purified by recrystallization was verified by elemental analysis,FTIR,~1H NMR,UVand MS.The synthesis mechanism of AAPBA was speculated to be divided into two steps:in the first step,the 0-acylcarbamide intermediate was formed by the reaction between ethylcarbodiimide groups of EDCI and carboxyl groups of acrylic acids;in the second step, AAPBA was formed by the reaction between 0-acylcarbamide intermediates and amino groups of APBA.
2.The poly(NIPAM-co-AAPBA)microgels were prepared by surfactant-free emulsion polymerization.The microgels displayed spherical shape and very narrow size distribution from the results obtained by scanning electron microscopy(SEM)and dynamic laser light scattering(DLLS),indicating that there was extremely short nucleation period without second nucleation process.The hydrodynamic diameters and swelling ratios of the microgels decreased with the increase of AAPBA component content.The poly(NIPAM-co-AAPBA)microgels were both temperature- and glucose- sensitive,their volume phase transition temperature(VPTT)decreased with the increase of AAPBA component content within the microgels. 3.The poly(NIPAM-co-VPBA)copolymer microgels were prepared by surfactant-free emulsion polymerization,in which 4-vinyl phenylboronic acid(VPBA)was used as functional comonomer.The chemical structure of the microgels was verified by the content analysis of B element,fourier transform infrared spectroscopy(FTIR)and ~(11)B NMR.The hydrodynamic diameters and swelling ratios of the microgels decreased with the increase of VPBA component content.In neutral water media, the physically crosslinked points within the microgels were formed between the polymer chains by the hydrophobic interaction between VPBA units.The poly(NIPAM-co-VPBA)microgels were temperature-sensitive,their VPTT decreased with the increase of VPBA component content.In the water media of pH=10.5,the microgels were glucose-sensitive,and the increase magnitude of their hydrodynamic diameters with the glucose concentration in the media was reduced with the enhancement of VPBA component content within the microgels.
引文
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