Development of nanoparticles incorporating a novel liposomal membrane destabilization peptide for efficient release of cargos into cancer cells.
Development of nanoparticles incorporating a novel liposomal membrane destabilization peptide for efficient release of cargos into cancer cells.
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DOI：
10.1371/journal.pone.0111181
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kogure K
中科院分区：
文献类型：
--
作者：
Itakura S;Hama S;Ohgita T;Kogure K
在以纳米颗粒为基础的药物递送系统（DDS）介导的抗癌治疗中，总体疗效取决于纳米颗粒在癌细胞中的释放效率以及向肿瘤组织递送的特异性。然而，传统的基于脂质体的DDS没有在癌细胞内特异性释放包裹货物的机制。为了克服这一障碍，我们开发了含有新型脂质体膜不稳定肽（LMDP）的纳米颗粒，它可以通过与癌细胞上/内的膜内蛋白酶的切割来破坏膜的稳定。用LMDP修饰的脂质体（LMDP-lipo）封装的钙黄蛋白在含有LMDP可切割蛋白酶的膜组分存在下有效释放。这种释放被一种蛋白酶抑制剂抑制，这表明LMDP-lipo可以有效地将其货物释放到细胞中，以响应癌症特异性蛋白酶。此外，当LMDP-lipo含有融合性脂质时，货物的释放加速，这表明LMDP-lipo与细胞膜的融合是细胞内递送的第一步。延时显微镜观察显示，在ldl -lipo与靶细胞结合后，货物立即被释放。因此，lp -脂质可能是一种有用的纳米颗粒，能够有效地将货物释放到靶向癌细胞中。
In anti-cancer therapy mediated by a nanoparticle-based drug delivery system (DDS), overall efficacy depends on the release efficiency of cargos from the nanoparticles in the cancer cells as well as the specificity of delivery to tumor tissue. However, conventional liposome-based DDS have no mechanism for specifically releasing the encapsulated cargos inside the cancer cells. To overcome this barrier, we developed nanoparticles containing a novel liposomal membrane destabilization peptide (LMDP) that can destabilize membranes by cleavage with intramembranous proteases on/in cancer cells. Calcein encapsulated in liposomes modified with LMDP (LMDP-lipo) was effectively released in the presence of a membrane fraction containing an LMDP-cleavable protease. The release was inhibited by a protease inhibitor, suggesting that LMDP-lipo could effectively release its cargo into cells in response to a cancer-specific protease. Moreover, when LMDP-lipo contained fusogenic lipids, the release of cargo was accelerated, suggesting that the fusion of LMDP-lipo with cellular membranes was the initial step in the intracellular delivery. Time-lapse microscopic observations showed that the release of cargo from LMDP-lipo occurred immediately after association of LMDP-lipo with target cells. Consequently, LMDP-lipo could be a useful nanoparticle capable of effective release of cargos specifically into targeted cancer cells.
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