温度敏感性PNIPAAm-b-PA1a材料的制备、性能及药物控释应用研究
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摘要
聚N-异丙基丙烯酰胺(PNIPAAm)水凝胶是一种温度敏感性凝胶,能对环境的温度变化产生响应。当其水溶液温度低于33℃时,PNIPAAm可以充分溶解于水中,温度超过33℃时,其分子链由亲水向疏水转变,分子间相互聚集发生沉淀。基于这种温度敏感特性,PNIPAAm凝胶已经被应用到了许多领域,特别是在药物释放系统方面有着重要的应用价值。本文将链状的PNIPAAm末端用疏水性聚(L-丙氨酸)均聚物进行改性,合成出具有温敏特性的两亲嵌段共聚物聚N-异丙基丙烯酰胺-b-聚(L-丙氨酸)(PNIPAAm-b-PAla),对其组成和结构,水凝胶的形态、性能等进行了研究,主要工作如下：
1、采用巯基化合物链转移技术,通过自由基聚合的方式制备了均聚物PNIPAAm-NH2。讨论了不同浓度的链转移剂、引发剂对均聚物分子量的影响。采用“三光气”法制备出L-丙氨酸环内酸酐(L-Ala-NCA),并通过L-Ala-NCA开环聚合法、调节L-Ala-NCA的摩尔量制备出具有不同PAla链长的共聚物聚N-异丙基丙烯酰胺-b-聚(L-丙氨酸)。2、利用傅里叶红外光谱红外、核磁共振和透射电镜等表征手段,证明共聚物PNIPAAm-b-PAla的形成。共聚物水凝胶中可以形成较为均匀的“核-壳”结构。采用紫外-可见光谱和差示扫描量热(DSC)测定了PNIPAAm-b-PAla水凝胶的LCST,研究聚(L-丙氨酸)链段长短对共聚物LCST的影响。共聚物的LCST随聚(L-丙氨酸)链的增长而有轻微的降低,但是与均聚物PNIPAAm-NH2相比LCST几乎不变。激光粒度分析仪检测发现共聚物粒径大小比由透射电镜方法测得的粒径稍大,且温度升高共聚物胶束的粒径增大。这是因为温度超过其LCST时,共聚物凝胶发生体积相转变,疏水性的链段在水溶液中聚集,粒径增大。用紫外可见分光光度计检测水凝胶在温度为20℃和37℃交替刺激下的吸光度变化,发现其吸光度呈现可逆性变化,表明PNIPAAm-b-PAla水凝胶体积相转变具有可逆性。
3、采用制备的共聚物作为药物载体研究了阿霉素在该载药体系中的控释行为。结果表明PNIPAAm-b-PAla作为药物载体能延长药物释放的时间,而且可通过温度来控制药物的释放量,释放行为随温度震荡呈现“快／慢”的响应特性。总之,PNIPAAm-b-PAla共聚物可以作为有效的药物载体对药物进行控制和释放。
Poly(N-isopropylacrylamide) is a typical thermosensitive polymeric material, which exhibits a reversible thermoresponsive phase transition to respond to these changes in their external environment. PNIPAAm is water-soluble and hydrophilic at the environmental temperature below its 33℃, but after undergoing a phase transition it becomes an insoluble and hydrophobic aggregate as the temperature exceeds 33℃. Owing to the thermal-sensitive property, the PNIPAAm polymers have been used in many fields, especially for the control and release of drugs. The main content of this research consists of:
1、The amino-terminated PNIPAAm is prepared by radical polymerization using thiol compounds as a chain transfer agent. The effects of initiating agent and chain transfer agent on the molecular weight of PNIPAAm-NH2 are investigated respectively. L-Ala-NCA is synthesized by triphosgene method and PNIPAAm-b-PAla is prepared by thermal ring-opening polymerization of L-Ala-NCA. Copolymers of different poly(L-alanine) molecular weights are obtained by changing the concentration ratio of L-Ala-NCA.
2、The products are characterized by FT-IR and 1H NMR spectra and TEM. The PNIPAAm-b-PAla copolymer micelles in aqueous solution form a spherical core-shell structure. Temperature-responsive property of block copolymer micelles is measured by a turbidity method and differential scanning calorimeter (DSC). With the increase of the composition of the PAla block, the LCST decreases. However, the LCST changes of the copolymer is slight, almost the same as the unmodified PNIPAAm. The hydrodynamic diameters of the particles in water measured by the quasi-elastic light scattering are larger than measured by TEM. The size distribution of micelle increases with the temperature. It is because the micelles show intermicellar aggregations in response to temperature cycles through the LCST. the micelles show reversible temperature-responsive of PNIPAAm-b-PAla hydrogels in response to impulse temperature changes between 22℃and 37℃.
3、An adriamycin delivery system is synthesized by using PNIPAAm-b-PAla block copolymers to investigate the loading and release properties of drugs. It is found that PNIPAAm-b-PAla drug carrier could prolong the release time and control the release amount by changing the temperature. Therefore, the PNIPAAm-b-PAla copolymer is very promising drug carrier for the delivery and controlled release application.
1、采用巯基化合物链转移技术,通过自由基聚合的方式制备了均聚物PNIPAAm-NH2。讨论了不同浓度的链转移剂、引发剂对均聚物分子量的影响。采用“三光气”法制备出L-丙氨酸环内酸酐(L-Ala-NCA),并通过L-Ala-NCA开环聚合法、调节L-Ala-NCA的摩尔量制备出具有不同PAla链长的共聚物聚N-异丙基丙烯酰胺-b-聚(L-丙氨酸)。2、利用傅里叶红外光谱红外、核磁共振和透射电镜等表征手段,证明共聚物PNIPAAm-b-PAla的形成。共聚物水凝胶中可以形成较为均匀的“核-壳”结构。采用紫外-可见光谱和差示扫描量热(DSC)测定了PNIPAAm-b-PAla水凝胶的LCST,研究聚(L-丙氨酸)链段长短对共聚物LCST的影响。共聚物的LCST随聚(L-丙氨酸)链的增长而有轻微的降低,但是与均聚物PNIPAAm-NH2相比LCST几乎不变。激光粒度分析仪检测发现共聚物粒径大小比由透射电镜方法测得的粒径稍大,且温度升高共聚物胶束的粒径增大。这是因为温度超过其LCST时,共聚物凝胶发生体积相转变,疏水性的链段在水溶液中聚集,粒径增大。用紫外可见分光光度计检测水凝胶在温度为20℃和37℃交替刺激下的吸光度变化,发现其吸光度呈现可逆性变化,表明PNIPAAm-b-PAla水凝胶体积相转变具有可逆性。
3、采用制备的共聚物作为药物载体研究了阿霉素在该载药体系中的控释行为。结果表明PNIPAAm-b-PAla作为药物载体能延长药物释放的时间,而且可通过温度来控制药物的释放量,释放行为随温度震荡呈现“快／慢”的响应特性。总之,PNIPAAm-b-PAla共聚物可以作为有效的药物载体对药物进行控制和释放。
Poly(N-isopropylacrylamide) is a typical thermosensitive polymeric material, which exhibits a reversible thermoresponsive phase transition to respond to these changes in their external environment. PNIPAAm is water-soluble and hydrophilic at the environmental temperature below its 33℃, but after undergoing a phase transition it becomes an insoluble and hydrophobic aggregate as the temperature exceeds 33℃. Owing to the thermal-sensitive property, the PNIPAAm polymers have been used in many fields, especially for the control and release of drugs. The main content of this research consists of:
1、The amino-terminated PNIPAAm is prepared by radical polymerization using thiol compounds as a chain transfer agent. The effects of initiating agent and chain transfer agent on the molecular weight of PNIPAAm-NH2 are investigated respectively. L-Ala-NCA is synthesized by triphosgene method and PNIPAAm-b-PAla is prepared by thermal ring-opening polymerization of L-Ala-NCA. Copolymers of different poly(L-alanine) molecular weights are obtained by changing the concentration ratio of L-Ala-NCA.
2、The products are characterized by FT-IR and 1H NMR spectra and TEM. The PNIPAAm-b-PAla copolymer micelles in aqueous solution form a spherical core-shell structure. Temperature-responsive property of block copolymer micelles is measured by a turbidity method and differential scanning calorimeter (DSC). With the increase of the composition of the PAla block, the LCST decreases. However, the LCST changes of the copolymer is slight, almost the same as the unmodified PNIPAAm. The hydrodynamic diameters of the particles in water measured by the quasi-elastic light scattering are larger than measured by TEM. The size distribution of micelle increases with the temperature. It is because the micelles show intermicellar aggregations in response to temperature cycles through the LCST. the micelles show reversible temperature-responsive of PNIPAAm-b-PAla hydrogels in response to impulse temperature changes between 22℃and 37℃.
3、An adriamycin delivery system is synthesized by using PNIPAAm-b-PAla block copolymers to investigate the loading and release properties of drugs. It is found that PNIPAAm-b-PAla drug carrier could prolong the release time and control the release amount by changing the temperature. Therefore, the PNIPAAm-b-PAla copolymer is very promising drug carrier for the delivery and controlled release application.
引文
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