Gaber M H, Hong K, Huang S K, Papahadjopoulos D
Cancer Research Institute, University of California San Francisco 94143-0450, USA.
Pharm Res. 1995 Oct;12(10):1407-16. doi: 10.1023/a:1016206631006.
To formulate thermosensitive sterically stabilized liposomes and to study the effects of plasma and serum components in vitro.
The rate of release of encapsulated doxorubicin (Dox) from liposomes of various compositions was followed by fluorometric assay at 37 degrees, 42 degrees and 45 degrees C, in buffer and also in both calf serum and human plasma up to 50% by volume.
The optimal composition for the maximal differential release of doxorubicin between 37 degrees C and 42 degrees C in human plasma was a mixture of dipalmitoylphosphatidylcholine/hydrogenated soy phosphatidylcholine/cholesterol and distearoylphosphatidylethanolamine derivatized with polyethylene glycol at a molar ratio of 100:50:30:6. In experiments designed to study the mechanism causing increased permeability of liposomes in bovine serum, we found two different distinct release patterns: a slow linear rise of rate of Dox release for fluid liposomes and fast exponential rise reaching plateau within 5 minutes for solid phase (rigid) liposomes. This release of Dox from rigid but not fluid liposomes was inhibited by pre-heating serum at 55 degrees C for 30 minutes or by addition of EDTA (but not EGTA) or antiserum to the C3 component of complement.
A formulation of sterically stabilized liposomes with the proper thermal sensitivity in human plasma has been obtained. In addition, the results suggest that complement may play an important role in the interaction of rigid but not fluid liposomes with bovine serum. Human plasma did not show this effect.
制备热敏性空间稳定脂质体并研究血浆和血清成分的体外作用。
通过荧光测定法追踪不同组成的脂质体中包裹的阿霉素（Dox）在37℃、42℃和45℃下于缓冲液以及体积分数达50%的小牛血清和人血浆中的释放速率。
在人血浆中，37℃和42℃之间阿霉素最大差异释放的最佳组成是二棕榈酰磷脂酰胆碱/氢化大豆磷脂酰胆碱/胆固醇与聚乙二醇衍生化的二硬脂酰磷脂酰乙醇胺的混合物，摩尔比为100:50:30:6。在旨在研究牛血清中导致脂质体通透性增加机制的实验中，我们发现了两种不同的释放模式：对于流体脂质体，阿霉素释放速率呈缓慢线性上升；对于固相（刚性）脂质体，释放速率在5分钟内快速指数上升并达到平台期。刚性而非流体脂质体的阿霉素释放可通过将血清在55℃预热30分钟或添加EDTA（而非EGTA）或补体C3成分的抗血清来抑制。
已获得在人血浆中具有适当热敏性的空间稳定脂质体制剂。此外，结果表明补体可能在刚性而非流体脂质体与牛血清的相互作用中起重要作用。人血浆未显示此效应。
