2.4 PEG-磷脂脂質體的粒徑
研究表明,用不同的PEG-磷脂可制備不同粒徑的脂質微粒(多室、小單室、大單室脂質體),穩定性較好:半年后PEG-磷脂脂質體在緩沖溶液中釋出的親水性標記物小于5%,在血漿中tin長達幾天16。Litzinger等171制備了>300nm、150~200nm
和<70nm的3種粒徑分布的PEG-磷脂質脂體,并考察了在小鼠體內的分布,結果表明,大粒徑和小粒徑的PEG-磷脂脂質體分別在脾和肝中的濃度較高,中間粒徑的具有長循環特性。小粒徑脂質體長循環減弱的原因直接與PEG-PE的活性有關,而大粒徑脂質體則可能是通過過濾機制被脾攝取。脂質體在血中的穩定性、清除率及生物分布情況都取決于其組成、粒徑及荷電情況，其中100~200nm粒徑范圍內的脂質體由于空間位阻的原因在血液中較穩定[81。Unezaki等[91研究的溫度敏感型PEG-磷脂脂質體,其最佳平均粒徑也在180~200nm范圍內.
3 PEG衍生化磷脂在新型脂質體中的應用
3.1pH敏感脂質體
結合PEG-磷脂的脂質體可制成低pH敏感的立體穩定脂質體。Guo等1201制備了對較低pH敏感的PEG結合物(POD)，在中性環境下能穩定3h以上,但在pH5下lh內就可能完全降解。含有10%POD和90%二油酰磷脂酰乙醇胺(DOPE)的脂質體在中性緩沖液中能穩定存在12h以上:然而當該脂質體處于溫和酸性條件(pH5.5)下時,脂質體很快聚集并在30min內釋出大部分內容物。因此可通過pH控制藥物靶向至弱酸性的生理環境
(如核內體、固體瘤和炎性組織)釋放。
3.2陽離子脂質體
當藥物的電性與脂質體膜電性相反時.藥物包封率高且穩定。結合不同類型的PEG聚合物可制得中性、負電性、正電性脂質體。如--種新型的結合陽離子PEG-磷脂(CPL)的脂質體2,能插入已形成的囊泡中并增強脂質體的穩定性。對以4種端基上含有不同正電荷的CPL(分別為CPL~CPL)制得的陽離子LUVs的膠束溶液的研究發現,CPL插入LUVs外部小葉上的方式在某種程度上取決于溫度、時間、CPL/
磷脂的比例和LUVs的結構,同時也與LUVs中的CPL種類有關。CPLs可使脂質體與細胞的粘附增加3倍,而CPL可增加10倍。同時,磷脂攝取的增加與總的表面電荷無關,而與CPL末梢端基上增加的正電荷的密度有關.
3.3免疫脂質體
傳統的免疫脂質體具有良好的靶向性,但在體內易被清除。采用PEG-磷脂連接特異性抗體則可以達到長循環的效果,但結合方式不同,脂質體的靶向性也不同。Maruyama等121研究了傳統免疫脂質體(A)、含PEG的免疫脂質體(B)和含6%摩爾分數DSPE-PEG-COOH的PC-CH(2:
1)新型免疫脂質體(C)的靶向性。小鼠肺特異性免疫試驗結果表明,由于PEG可減少RES的攝取而使B具有長循環特征,但B的抗原.抗體結合僅為A的一半,這可能與PEG鏈的空間位阻阻礙了抗原-抗體的特異性結合有關。而C不僅具有長循環特征,其抗原.抗體結合率約為A的1.3倍,表明免疫性抗體與PEG鏈的末端結合可以減少PEG鏈空間位阻對抗原.抗體結合的屏蔽作用。
4結語
PEG行生化磷脂對提高脂質體穩定性有眾多優點，但新的PEG衍生化磷脂的結構鑒定、毒性研究等費時費力,限制了它的廣泛應用。已有研究表明PPA、PVP、ATTAn低聚體、聚-2-甲基聰唑啉(PMOZ)、聚.2-乙基唔唑啉(PEOZ)等與磷脂結合后顯示與PEG衍生化磷脂相似的體內行為,可為尋找替代品提供新的方向23~-25。PEG衍生化磷脂脂質體的良好穩定性使其可用于其它藥物傳遞系統,如利用PEG-磷脂脂質體包裹造影劑,用于腎臟等器官的影像診斷:或制成噴霧劑,用于肺結核等肺部疾病的治療,以減少口服抗結核藥物的肝損害等。艾偉拓（上海）醫藥科技有限公司2007年至今，專注與脂質體，脂肪乳為代表的注射劑領域，為您分享脂質體與脂肪乳相關行業資訊。
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本文內容分享自《聚乙二醇衍生化磷脂與脂質體立體穩定性》作者：丁勁松,楊敏,陳―瓊