【作者】 周文婷；

【导师】 安学勤；

【作者基本信息】 华东理工大学 ， 物理化学， 2011， 博士

【摘要】 脂质体作为药物载体以来,敏感性脂质体引起了越来越多的学者的关注。在这些敏感性脂质体中,pH敏感性脂质体倍受关注的原因是癌变细胞周围的组织液的pH值要比人体正常细胞的pH值要低,人们可利用这个特性设计pH促使膜破裂和融合作用导致活性组分进入细胞质的系统。目前研究工作表明,聚合物能够使脂质体具有pH敏感,可改变脂质体膜的组成或者修饰膜的表面,并且可以延长脂质体在体内的循环时间和增加在细胞内的积累。另外,研究表明温敏脂质体可在相变温度控制释放药物。脂质体的相变温度可以通过聚合物的亲水或疏水组分来调变。目前,pH—温度双敏脂质体鲜见报道。pH—温度双敏脂质体的合成及性质,在空间上和时间上控制释放药物都非常重要,是一个具有挑战性的研究课题。在本论文中,我们合成了具有pH—温度敏感共聚物和pH—温度敏感聚合物脂质体,研究了共聚物溶液和聚合物脂质体溶液的相行为,讨论了聚合物脂质体对药物的控制释放。得到主要结论如下：1、可以通过调节共聚物的组成控制合成不同pH相变的共聚物。共聚物溶液的相行为受到共聚物组成和溶液浓度的影响,随着共聚物中亲水组分甲基丙烯酸(MAA)含量的增加,共聚物溶液的温度和pH敏感性增强,共聚物溶液的相变温度(LCST)和相变pH (pH*)降低。共聚物溶液在pH*时,有着较高的相变温度。共聚物溶液浓度影响共聚物的LCST,但不影响相变pH2、共聚物的临界胶束浓度(CMC)与共聚物组成相关联,其疏水性越强,CMC越小。在固定共聚物丙烯酸十八酯(ODA)含量下,CMC随MAA含量的增加而增大。3、当共聚物溶液的温度低于LCST时,共聚物胶束不受温度和pH的影响。温度高于LCST,共聚物胶束的粒径随着温度的升高而增大。在相变pH,共聚物胶束的平均粒径达到最小值。4、聚合物脂质体的相变温度及粒径均受到共聚物以及盐酸小檗碱的影响,共聚物脂质体在相变pH时,脂质体的平均粒径和相变温度均为最大值。当共聚物与卵磷脂的质量比为1:2时,聚合物脂质体的相变温度和粒径都达到最大,聚合物脂质体最为稳定。盐酸小檗碱的加入,减小了聚合物脂质体的平均粒径,同时还降低了聚合物脂质体的相变温度,但是对相变pH没有影响。5、当释放条件同时满足聚合物脂质体的相变温度及相变pH时,从聚合物脂质体中释放盐酸小檗碱可以达到最大。更多还原

【Abstract】 Since liposome was proposed as a drug carrier, many attentions have been paid to design stimuli-sensitive liposome. Among these stimuli, pH-sensitive liposome has attracted many researchers’ attentions. As the pH of endosoma of the cancerous cell is lower than that of extracellular fluids, this feature has been exploited in the design of systems that facilitate the delivery of active compounds to the cytoplasm via a pH-dependent membrane-disruptive and/or fusogenic action. Recent studies have demonstrated that polymers have also investigated to confer pH-responsiveness to liposome. The addition of polymers can alter the composition of membrane or modify the surface of liposome, and it can exhibit prolonged circulation times in vivo and accumulate in tumors. Temperature sensitive liposome has been investigated to control release drug at phase transition temperature in many-studies. The phase transition temperature of the liposome can be changed by changing the hydrophilic or hydrophobic monomers of the polymer. However, to the best of our knowledge, the report regarding pH-temperature sensitive copolymer-liposome is scarce. The studies of synthesis and property of pH-temperature sensitive copolymer-liposome are hence of most importance and remains a challenging problem, and the research focuses on controlled drug release both spatially and temporally.In this thesis, we focused on synthesis of the pH-temperature sensitive copolymer and pH-temperature sensitive copolymer-liposome, the phase behaviors of the copolymer solution and copolymer-liposome solution, and the control drug release from the copolymer-liposome. The main results presented in this thesis are summarized below.1. Copolymer with various phase transition pH can be synthesized by controlling composition of the copolymer. The phase transition of the copolymer depends on the composition and concentration of the copolymer. The temperature-pH sensitivity of the copolymer solution increases with the MAA content in the copolymer. The lower critical solution temperature (LCST) and phase transition pH (pH*) of the copolymer solution decrease with the increasing MAA content. The LCST of the copolymer solution can reach a maximum at the pH*. The LCST decreases with the increasing copolymer concentration, but the pH* was not affected by the concentration.2. The critical micelle concentration (CMC) of the copolymer solution depends on the copolymer composition. The CMC decreases with increasing the hydrophobicity of the copolymer. The CMC increases with MAA content at the fixed ODA content.3. The micelle of the copolymer was not affected by the temperature and pH, when the temperature was below the LCST of the copolymer solution. The mean diameter of the micelle increases with temperature, and it can reach the minimum at pH*.4. The phase transition temperature and micelle size of the copolymer-liposome were affected by the copolymer and berberine hydrochloride (ber), and the mean diameter and phase transition temperature can reach the maximum at phase transition pH*. When the mass ration of the copolymer to SPC (w) was 1:2, the mean diameter and phase transition temperature was the maximum value. The copolymer-liposome was most stable at the pH* and w=1:2. The mean diameter and phase transition temperature were decreased by addition of berberine, but the pH* of the copolymer-liposome was not affected by addition of bererine.5. The berberine release from the copolymer-liposome was the maximum value at the phase transition temperature and pH* of the copolymer-liposome.更多还原