Mechanistic studies of the triggered release of liposomal contents by matrix metalloproteinase-9.
Mechanistic studies of the triggered release of liposomal contents by matrix metalloproteinase-9.
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DOI：
10.1021/ja801548g
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发表时间：
2008-08-13
影响因子：
15
通讯作者：
Mallik S
中科院分区：
文献类型：
--
作者：
Elegbede AI;Banerjee J;Hanson AJ;Tobwala S;Ganguli B;Wang R;Lu X;Srivastava DK;Mallik S
基质金属蛋白酶（MMPs）是一类在许多癌症中过度表达的细胞外基质降解酶，有助于癌细胞的转移能力。我们最近已经证明，脂质体内容物可以被释放时，触发的酶MMP-9。在此，我们报告我们的结果的机制研究的MMP-9触发释放的脂质体内容物。我们合成了含有MMP-9切割位点的肽，并将其与脂肪酸缀合以制备相应的脂肽。通过采用圆二色谱法，我们证明了脂肽，当纳入脂质体，在脂质双层中被分层，并产生三重螺旋结构。MMP-9切割三螺旋肽，导致脂质体内容物的释放。其它不能水解三螺旋肽的MMP不能从脂质体释放内容物。我们还观察到，脂质体内容物的释放速率和程度取决于合成的脂肽和脂质体的磷脂组分的酰基链之间的错配。圆二色谱研究表明，所观察到的释放差异反映了脂质体膜在脂质体掺入脂肽的酶促裂解后退火缺陷的能力。
Matrix metalloproteinases (MMPs) are a class of extracellular matrix degrading enzymes over-expressed in many cancers and contribute to the metastatic ability of the cancer cells. We have recently demonstrated that liposomal contents can be released when triggered by the enzyme MMP-9. Herein, we report our results on the mechanistic studies of the MMP-9 triggered release of the liposomal contents. We synthesized peptides containing the cleavage site for MMP-9 and conjugated them with fatty acids to prepare the corresponding lipopeptides. By employing Circular Dichroism spectroscopy, we demonstrate that the lipopeptides, when incorporated in liposomes, are de-mixed in the lipid bilayers and generate triple helical structures. MMP-9 cleaves the triple helical peptides, leading to the release of the liposomal contents. Other MMPs, which cannot hydrolyze triple helical peptides, failed to release the contents from the liposomes. We also observed that the rate and the extent of release of the liposomal contents depend on the mismatch between acyl chains of the synthesized lipopeptide and phospholipid components of the liposomes. Circular Dichroism spectroscopic studies imply that the observed differences in the release reflect the ability of the liposomal membrane to anneal the defects following the enzymatic cleavage of the liposome-incorporated lipopeptides.
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