Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG-diortho ester-lipid conjugate
Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG-diortho ester-lipid conjugate
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DOI：
10.1021/bc000110v
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发表时间：
2001-03-01
影响因子：
4.7
通讯作者：
Szoka, FC
中科院分区：
文献类型：
--
作者：
Guo, X;Szoka, FC
我们描述了pH敏感的聚（乙二醇）-二原酸酯-二硬脂酰甘油共轭物（POD）的合成和表征。采用一步合成法制备了POD，并对其酸敏感性进行了薄层色谱表征。发现缀合物在中性pH下稳定超过3小时，但在pH 5下在1小时内完全降解。脂质体组成的10%的POD和90%的融合脂质，二油酰磷脂酰乙醇胺（DOPE）很容易制备，并保持稳定长达12小时，在中性缓冲液中所示的光子相关光谱和脂质体内容物泄漏试验。然而，当POD/DOPE脂质体孵育在酸性pH值为5.5温和，他们聚集，并在30分钟内释放大部分的内容。从POD/DOPE脂质体的内容释放动力学包括两个阶段，滞后期，和爆发相。滞后期与pH值呈负相关，滞后期长度的对数与缓冲液pH值呈线性关系。POD/DOPE脂质体在37 ℃下于75%胎牛血清中孵育12 h后，其稳定性与传统PEG接枝脂质体相当，但在随后的4 h内释放了84%的包封ANTS。静脉给药后，小鼠，脂质体组成的10%POD和90%DOPE从循环中清除的一室动力学的半衰期约为200分钟。POD是一个例子，设计一个新的类别的pH值敏感的脂质组成的头基，酸不稳定的二原酸酯接头和疏水性的尾巴。P0 D在pH 5-6下独特的快速降解动力学及其在血清中稳定脂质体的能力使得缀合物适用于靶向温和酸性生物环境如内体、实体瘤和炎性组织的触发药物释放系统的应用。
We describe the synthesis and characterization of a pH-sensitive poly(ethylene glycol)-diortho ester-distearoyl glycerol conjugate (POD). POD was prepared by a one-step synthesis, and its acid sensitivity characterized by TLC. The conjugate was found to be stable at neutral pH for greater than 3 h but degraded completely within 1 h at pH 5. Liposomes composed of 10% of POD and 90% of a fusogenic lipid, dioleoyl phosphatidylethanolamine (DOPE) were readily prepared and remained stable for up to 12 h in neutral buffer as shown by photon correlation spectrometry and a liposome contents leakage assay. However, when POD/DOPE liposomes were incubated in acidic pH as mild as 5.5, they aggregated and released most of their contents within 30 min. The kinetics of content release from POD/DOPE liposomes consisted of two phases, a lag phase, and a burst phase. The lag phase is inversely correlated with pH and the logarithm of the length of lag phase showed a linear relationship with the buffer pH. When the POD/DOPE liposomes were incubated in 75% of fetal bovine serum at 37 degreesC, they remained as stable as traditional PEG-grafted liposomes for 12 h but released 84% of the encapsulated ANTS in the following 4 h. Upon intravenous administration into mice, liposomes composed of 10% POD and 90% DOPE were cleared from circulation by a one-compartment kinetics with a half-life of about 200 min. POD is an example for the design of a novel category of pH sensitive lipids composed of a headgroup, an acid-labile diortho ester linker and a hydrophobic tail. The uniquely fast degradation kinetics of POD at pH 5-6 and its ability to stabilize liposomes in serum make the conjugate suitable for applications for triggered drug release systems targeted to mildly acidic bioenvironments such as endosomes, solid tumors, and inflammatory tissues.