A NEW STRATEGY FOR ATTACHMENT OF ANTIBODIES TO STERICALLY STABILIZED LIPOSOMES RESULTING IN EFFICIENT TARGETING TO CANCER-CELLS
A NEW STRATEGY FOR ATTACHMENT OF ANTIBODIES TO STERICALLY STABILIZED LIPOSOMES RESULTING IN EFFICIENT TARGETING TO CANCER-CELLS
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DOI：
10.1016/0005-2736(95)00085-h
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发表时间：
1995-07-26
影响因子：
3.4
通讯作者：
ZALIPSKY, S
中科院分区：
文献类型：
--
作者：
ALLEN, TM;BRANDEIS, E;ZALIPSKY, S
用聚乙二醇（PEG）的脂质衍生物进行空间稳定的脂质体长循环制剂（S - 脂质体）的开发，增加了这些与靶向配体（如抗体）偶联的脂质体可作为药物载体在体内将治疗药物递送至特定靶细胞群的可能性。我们开发了一种将单克隆抗体连接到S - 脂质体上PEG末端的新方法。为此目的合成了一种新的端基官能化PEG - 脂质衍生物吡啶硫代丙酰氨基 - PEG - 二硬脂酰磷脂酰乙醇胺（PDP - PEG - DSPE）。将PDP - PEG - DSPE掺入S - 脂质体中，然后对PDP基团进行温和的硫解，导致在脂质囊泡的周边形成反应性巯基。马来酰亚胺衍生化的抗体能够高效连接：即使在S - 脂质体中官能化PEG - 脂质的含量低于总脂质的1%时，在温和条件下也能实现。与不含PEG的脂质体相比，所得的S - 免疫脂质体显示出高效的药物远程装载、缓慢的药物释放速率以及在循环中存活时间的增加。当识别几种不同肿瘤相关抗原的抗体与S - 脂质体的PEG末端偶联时，观察到脂质体在体外与靶细胞的结合显著增加。与不含靶向抗体的脂质体相比，含有包封的多柔比星的S - 免疫脂质体与它们的靶细胞群结合导致细胞毒性增加。
The development of long-circulating formulations of liposomes (S-liposomes), sterically stabilized with lipid derivatives of poly(ethylene glycol) (PEG), has increased the likelihood that these liposomes, coupled to targeting ligands such as antibodies, could be used as drug carriers to deliver therapeutic drugs to specific target cell populations in vivo. We have developed a new methodology for attaching monoclonal antibodies to the terminus of PEG on S-liposomes. A new end-group functionalized PEG-lipid derivative pyridylthiopropionoylamino-PEG-distearoylphosphatidylethanolamine (PDP-PEG-DSPE) was synthesized for this purpose. Incorporation of PDP-PEG-DSPE into S-liposomes followed by mild thiolysis of the PDP groups resulted in formation of reactive thiol groups at the periphery of the lipid vesicles, Efficient attachment of maleimide-derivatized antibodies took place: under mild conditions even when the content of the functionalized PEG-lipid in S-liposomes was below 1% of total lipid. The resulting S-immunoliposomes showed efficient drug remote loading, slow drug release rates and increased survival times in circulation compared to liposomes lacking PEG. When antibodies recognizing several different turner-associated antigens were coupled to the PEG terminus of S-liposomes, a significant increase in the in vitro binding of liposomes to the target cells was observed. The binding of S-immunoliposomes containing entrapped doxorubicin to their target cell population resulted in increased cytotoxicity compared to liposomes lacking the targeting antibody.