Environment-responsive multifunctional liposomes.
Environment-responsive multifunctional liposomes.
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DOI：
10.1007/978-1-60327-360-2_15
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
Torchilin, Vladimir P
中科院分区：
文献类型：
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作者：
Kale, Amit A;Torchilin, Vladimir P
用细胞穿透肽和pH敏感性PEG屏蔽物修饰的脂质体纳米载体同时表现出更好的体循环和细胞穿透肽的位点特异性暴露。PEG链通过PEG连接的磷脂酰乙醇胺（PE）残基掺入脂质体膜中，其中PEG和PE与降低的pH可降解的腙键（PEG-HZ-PE）缀合，而细胞穿透肽（TATp）作为TATp-PEG-PE缀合物加入。在正常条件下，脂质体接枝的PEG“屏蔽”脂质体连接的TATp部分，因为用于TATp连接的PEG间隔基（PEG（1000））比保护性PEG（2000）短。PEG化脂质体通过EPR效应在靶标中积累，但在“酸化”的肿瘤或缺血组织内部由于降低的pH诱导的HZ水解而失去其PEG涂层，并通过现在暴露的TATp部分渗透到细胞内部。这些构建体的pH响应行为在体外细胞培养物中以及在体内实验小鼠的肿瘤中被成功地测试。与对照pH不敏感的对应物相比，这些纳米载体在小鼠中肿瘤内施用时也显示出增强的pGFP转染效率。这些结果可以被认为是开发肿瘤特异性刺激敏感药物和基因递送系统的重要一步。
Liposomal nanocarriers modified with cell-penetrating peptide and a pH-sensitive PEG shield demonstrate simultaneously a better systemic circulation and site-specific exposure of the cell-penetrating peptide. PEG chains were incorporated into the liposome membrane via the PEG-attached phosphatidylethanolamine (PE) residue with PEG and PE being conjugated with the lowered pH-degradable hydrazone bond (PEG-HZ-PE), while cell-penetrating peptide (TATp) was added as TATp-PEG-PE conjugate. Under normal conditions, liposome-grafted PEG “shielded” liposome-attached TATp moieties, since the PEG spacer for TATp attachment (PEG(1000)) was shorter than protective PEG(2000). PEGylated liposomes accumulate in targets via the EPR effect, but inside the “acidified” tumor or ischemic tissues lose their PEG coating because of the lowered pH-induced hydrolysis of HZ and penetrate inside cells via the now-exposed TATp moieties. pH-responsive behavior of these constructs is successfully tested in cell cultures in vitro as well as in tumors in experimental mice in vivo. These nanocarriers also showed enhanced pGFP transfection efficiency upon intratumoral administration in mice, compared to control pH nonsensitive counterpart. These results can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems.