PEG功能化磷脂与脂质体稳定性的应用（二）
2.4 PEG-磷脂脂质体的粒径
研究表明,用不同的PEG-磷脂可制备不同粒径的脂质微粒(多室、小单室、大单室脂质体),稳定性较好:半年后PEG-磷脂脂质体在缓冲溶液中释出的亲水性标记物小于5%,在血浆中tin长达几天16。Litzinger等171制备了>300nm、150~200nm
和<70nm的3种粒径分布的PEG-磷脂质脂体,并考察了在小鼠体内的分布,结果表明,大粒径和小粒径的PEG-磷脂脂质体分别在脾和肝中的浓度较高,中间粒径的具有长循环特性。小粒径脂质体长循环减弱的原因直接与PEG-PE的活性有关,而大粒径脂质体则可能是通过过滤机制被脾摄取。脂质体在血中的稳定性、清除率及生物分布情况都取决于其组成、粒径及荷电情况，其中100~200nm粒径范围内的脂质体由于空间位阻的原因在血液中较稳定[81。Unezaki等[91研究的温度敏感型PEG-磷脂脂质体,其最佳平均粒径也在180~200nm范围内.
3 PEG衍生化磷脂在新型脂质体中的应用
3.1pH敏感脂质体
结合PEG-磷脂的脂质体可制成低pH敏感的立体稳定脂质体。Guo等1201制备了对较低pH敏感的PEG结合物(POD)，在中性环境下能稳定3h以上,但在pH5下lh内就可能完全降解。含有10%POD和90%二油酰磷脂酰乙醇胺(DOPE)的脂质体在中性缓冲液中能稳定存在12h以上:然而当该脂质体处于温和酸性条件(pH5.5)下时,脂质体很快聚集并在30min内释出大部分内容物。因此可通过pH控制药物靶向至弱酸性的生理环境
(如核内体、固体瘤和炎性组织)释放。
3.2阳离子脂质体
当药物的电性与脂质体膜电性相反时.药物包封率高且稳定。结合不同类型的PEG聚合物可制得中性、负电性、正电性脂质体。如--种新型的结合阳离子PEG-磷脂(CPL)的脂质体2,能插入已形成的囊泡中并增强脂质体的稳定性。对以4种端基上含有不同正电荷的CPL(分别为CPL~CPL)制得的阳离子LUVs的胶束溶液的研究发现,CPL插入LUVs外部小叶上的方式在某种程度上取决于温度、时间、CPL/
磷脂的比例和LUVs的结构,同时也与LUVs中的CPL种类有关。CPLs可使脂质体与细胞的粘附增加3倍,而CPL可增加10倍。同时,磷脂摄取的增加与总的表面电荷无关,而与CPL末梢端基上增加的正电荷的密度有关.
3.3免疫脂质体
传统的免疫脂质体具有良好的靶向性,但在体内易被清除。采用PEG-磷脂连接特异性抗体则可以达到长循环的效果,但结合方式不同,脂质体的靶向性也不同。Maruyama等121研究了传统免疫脂质体(A)、含PEG的免疫脂质体(B)和含6%摩尔分数DSPE-PEG-COOH的PC-CH(2:
1)新型免疫脂质体(C)的靶向性。小鼠肺特异性免疫试验结果表明,由于PEG可减少RES的摄取而使B具有长循环特征,但B的抗原.抗体结合仅为A的一半,这可能与PEG链的空间位阻阻碍了抗原-抗体的特异性结合有关。而C不仅具有长循环特征,其抗原.抗体结合率约为A的1.3倍,表明免疫性抗体与PEG链的末端结合可以减少PEG链空间位阻对抗原.抗体结合的屏蔽作用。
4结语
PEG行生化磷脂对提高脂质体稳定性有众多优点，但新的PEG衍生化磷脂的结构鉴定、毒性研究等费时费力,限制了它的广泛应用。已有研究表明PPA、PVP、ATTAn低聚体、聚-2-甲基聪唑啉(PMOZ)、聚.2-乙基唔唑啉(PEOZ)等与磷脂结合后显示与PEG衍生化磷脂相似的体内行为,可为寻找替代品提供新的方向23~-25。PEG衍生化磷脂脂质体的良好稳定性使其可用于其它药物传递系统,如利用PEG-磷脂脂质体包裹造影剂,用于肾脏等器官的影像诊断:或制成喷雾剂,用于肺结核等肺部疾病的治疗,以减少口服抗结核药物的肝损害等。艾伟拓（上海）医药科技有限公司2007年至今，专注与脂质体，脂肪乳为代表的注射剂领域，为您分享脂质体与脂肪乳相关行业资讯。
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本文内容分享自《聚乙二醇衍生化磷脂与脂质体立体稳定性》作者：丁劲松,杨敏,陈―琼
