基于聚甲基丙烯酸为pH敏感单元的新型结构聚合物的合成、自组装及药物释放研究
发布时间：2018-08-24 19:39
【摘要】：两亲性嵌段共聚物或接枝共聚物由于其独特的结构和性能,在生命科学,材料科学,医学和药物载体等领域都有十分广泛的应用,尤其在作为靶向药物载体方面,已成为研究的新领域。具有pH响应性的两亲性聚合物作为药物载体,能够依托于环境的pH变化而产生相应的相转变,从而促使药物的释放行为也具有pH响应性,实现药物控制释放及靶向给药的目的。虽然pH响应型嵌段共聚物已经具备以上特性,但仍旧存在载药量低,稳定性不持久等问题。提高载药量,改善胶束在体内循环时的稳定性以及更好地实现靶向给药也是现在研究中亟待解决的问题。基于此,本文中的工作以聚甲基丙烯酸嵌段为pH响应的亲水段分别合成了以羟基碳纳米管(CNTs-OH)为疏水段的CNTs-g-PMAA接枝聚合物和以改性的端羟基丁二烯-丙烯腈共聚物(HTPBN)为疏水段的H型PMAA2-b-HTPBN-b-PMAA2嵌段共聚物,并对其结构进行了表征,研究了其在水溶液中的自组装行为,对其应用于疏水抗癌药物的负载和药物释放以及生物性能进行了研究,具体内容如下：第一,pH响应型碳纳米管接枝聚甲基丙烯酸接枝聚合物的合成自组装及药物释放行为研究。我们采用自由基链转移反应分别使用一锅法和分段法两种方法成功制备了一系列不同配比的CNTs-g-PMAA聚合物,并通过红外光谱技术(FT-IR)和核磁共振氢谱技术(1HNMR)进行表征验证。聚合物自组装成具有特殊核壳结构的纳米胶束,经表面张力仪,透射电子显微镜(TEM),动态光散射激光粒度仪(DLS)确定胶束的CMC,形状,大小等。实验确定在不同环境下胶束均为球形结构,经过测量其表面张力得到其CMC值在120.33-251.19 mg/L范围内。zeta电位值测量得到结果呈电负性,并且在不同pH环境中呈现规律性变化。紫外-可见分光光度计(UV-vis)和DLS测量结果均显示胶束粒径依赖于pH值变化,转变点约为pH=6.4,具有pH响应性。细胞毒性测量结果显示胶束无毒,可用于药物载体。包覆了10-羟基喜树碱(HCTP)的载药胶束在模拟人体环境中进行药物释放行为研究,表明其释放行为与环境pH有关。结果表明CNTs-g-PMAA可用于生物医用材料,尤其在增加载药量方面表现突出。第二,pH响应的H型两亲性嵌段共聚物PMAA2-b-HTPBN-b-PMAA2的合成,胶束化以及药物释放研究。我们通过原子转移自由基聚合的方法合成新型H型嵌段共聚物PMAA2-b-HTPBN-b-PMAA2,由疏水段HTPBN和聚甲基丙烯酸叔丁酯水解后的聚甲基丙烯酸亲水段组成。其结构通过FT-IR和1H NMR得以确定,并用GPC表征手段测量了其相对分子质量。共聚物自组装成的球形纳米胶束,CMC值在366-58.0 mg/L, zeta位值测量结果在-24到-34 mV, Dh采用动态光散射激光粒度仪(DLS)测量,得到结果与通过紫外-可见分光光度计(UV-vis)测得的透光率结果一致,都说明其具有pH响应性。相比起相同分子量的线型聚合物,H型聚合物胶束具有更小的粒径和CMC值,表明在体内循环时具有更好的稳定性。我们采用MTT法进行了细胞毒性研究,空白胶束和载药胶束毒性明显低于游离药物。通过模拟人体环境的体外药物释放行为的研究,我们得到可控的药物释放规律,在病灶部位具有更大的释放量,释放行为依赖于外界pH的变化。因此,该嵌段聚合物可以作为疏水药物载体并应用于控制释放的研究中。
[Abstract]:Amphiphilic block copolymers or graft copolymers have been widely used in life sciences, materials sciences, medicine and drug carriers due to their unique structures and properties, especially in targeting drug carriers. The pH-responsive block copolymers have the above characteristics, but there are still some problems such as low drug loading, unstable stability and so on. The stability of cycling in vivo and the better targeting of drug delivery are also urgent problems to be solved. Based on this, CNTs-g-PMAA graft polymers with hydroxy carbon nanotubes (CNTs-OH) as hydrophobic segments and modified hydroxy-terminated succinic acid as hydrophilic segments were synthesized using polymethacrylic acid as pH-responsive hydrophilic segments, respectively. H-type PMAA2-b-HTPBN-b-PMAA2 block copolymers with hydrophobic segments of ene-acrylonitrile copolymers (HTPBN) were characterized, and their self-assembly behavior in aqueous solution was studied. The loading, drug release and biological properties of the copolymers were studied. Firstly, pH-responsive carbon nanoparticles were prepared. A series of CNTs-g-PMAA polymers with different proportions were successfully prepared by one-pot method and one-step method respectively through free radical chain transfer reaction, and were characterized by infrared spectroscopy (FT-IR) and nuclear magnetic resonance hydrogen spectroscopy (1HNMR). The micelles were self-assembled into nano-micelles with special core-shell structure. The CMC, shape and size of the micelles were determined by surface tensiometer, transmission electron microscopy (TEM) and dynamic light scattering laser particle sizer (DLS). The micelles were spherical in different environments. The CMC value of the micelles was 1 by measuring the surface tension. In the range of 20.33-251.19 mg/L, zeta potential showed electronegativity and regular change under different pH conditions. The results of UV-vis and DLS measurements showed that the micelle size depended on pH value and the transition point was about pH=6.4. The results of cytotoxicity measurements showed that the micelles were non-toxic. The results showed that CNTs-g-PMAA could be used in biomedical materials, especially in increasing drug loading. Second, pH-responsive amphiphilic H-type amphiphilic block copolymers. Synthesis, Micellation and Drug Release of Polymer PMAA2-b-HTPBN-b-PMAA2. A novel H-type block copolymer PMAA2-b-HTPBN-b-PMAA2 was synthesized by atom transfer radical polymerization. The structure of the copolymer was obtained by FT-IR and 1H NMR. The copolymers were self-assembled into spherical nanomicelles with CMC values ranging from 366 to 58.0 mg/L, zeta values ranging from - 24 to - 34 mV, and Dh was measured by dynamic light scattering laser particle sizer (DLS). The results were obtained by UV-vis spectrophotometer. Compared with linear polymers with the same molecular weight, H-type micelles have smaller particle size and CMC value, indicating better stability in vivo circulation. We used MTT method to study the cytotoxicity of blank micelles and drug-loaded micelles. The toxicity of blank micelles and drug-loaded micelles was significantly lower than that of free drugs. In vitro drug release behavior in the body environment has been studied, and we have obtained a controllable drug release law, which has a greater release in the lesion site. The release behavior depends on the change of external pH. Therefore, the block polymer can be used as a hydrophobic drug carrier and used in controlled release research.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O631;TQ460.4
本文编号：2201826
[Abstract]:Amphiphilic block copolymers or graft copolymers have been widely used in life sciences, materials sciences, medicine and drug carriers due to their unique structures and properties, especially in targeting drug carriers. The pH-responsive block copolymers have the above characteristics, but there are still some problems such as low drug loading, unstable stability and so on. The stability of cycling in vivo and the better targeting of drug delivery are also urgent problems to be solved. Based on this, CNTs-g-PMAA graft polymers with hydroxy carbon nanotubes (CNTs-OH) as hydrophobic segments and modified hydroxy-terminated succinic acid as hydrophilic segments were synthesized using polymethacrylic acid as pH-responsive hydrophilic segments, respectively. H-type PMAA2-b-HTPBN-b-PMAA2 block copolymers with hydrophobic segments of ene-acrylonitrile copolymers (HTPBN) were characterized, and their self-assembly behavior in aqueous solution was studied. The loading, drug release and biological properties of the copolymers were studied. Firstly, pH-responsive carbon nanoparticles were prepared. A series of CNTs-g-PMAA polymers with different proportions were successfully prepared by one-pot method and one-step method respectively through free radical chain transfer reaction, and were characterized by infrared spectroscopy (FT-IR) and nuclear magnetic resonance hydrogen spectroscopy (1HNMR). The micelles were self-assembled into nano-micelles with special core-shell structure. The CMC, shape and size of the micelles were determined by surface tensiometer, transmission electron microscopy (TEM) and dynamic light scattering laser particle sizer (DLS). The micelles were spherical in different environments. The CMC value of the micelles was 1 by measuring the surface tension. In the range of 20.33-251.19 mg/L, zeta potential showed electronegativity and regular change under different pH conditions. The results of UV-vis and DLS measurements showed that the micelle size depended on pH value and the transition point was about pH=6.4. The results of cytotoxicity measurements showed that the micelles were non-toxic. The results showed that CNTs-g-PMAA could be used in biomedical materials, especially in increasing drug loading. Second, pH-responsive amphiphilic H-type amphiphilic block copolymers. Synthesis, Micellation and Drug Release of Polymer PMAA2-b-HTPBN-b-PMAA2. A novel H-type block copolymer PMAA2-b-HTPBN-b-PMAA2 was synthesized by atom transfer radical polymerization. The structure of the copolymer was obtained by FT-IR and 1H NMR. The copolymers were self-assembled into spherical nanomicelles with CMC values ranging from 366 to 58.0 mg/L, zeta values ranging from - 24 to - 34 mV, and Dh was measured by dynamic light scattering laser particle sizer (DLS). The results were obtained by UV-vis spectrophotometer. Compared with linear polymers with the same molecular weight, H-type micelles have smaller particle size and CMC value, indicating better stability in vivo circulation. We used MTT method to study the cytotoxicity of blank micelles and drug-loaded micelles. The toxicity of blank micelles and drug-loaded micelles was significantly lower than that of free drugs. In vitro drug release behavior in the body environment has been studied, and we have obtained a controllable drug release law, which has a greater release in the lesion site. The release behavior depends on the change of external pH. Therefore, the block polymer can be used as a hydrophobic drug carrier and used in controlled release research.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O631;TQ460.4
【参考文献】
相关期刊论文 前1条
1 赵群;倪沛红;;pH/温度响应的两亲性嵌段共聚物的研究[J];化学进展;2006年06期
，本文编号：2201826
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