Novel PEG-matrix metalloproteinase-2 cleavable peptide-lipid containing galactosylated liposomes for hepatocellular carcinoma-selective targeting
Novel PEG-matrix metalloproteinase-2 cleavable peptide-lipid containing galactosylated liposomes for hepatocellular carcinoma-selective targeting
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DOI：
10.1016/j.jconrel.2005.12.023
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发表时间：
2006-04-10
影响因子：
10.8
通讯作者：
Hashida, M
中科院分区：
文献类型：
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作者：
Terada, T;Iwai, M;Hashida, M
为了获得肝细胞癌选择性给药系统，开发了一种新型的功能性脂质，该脂质被基质金属蛋白酶-2(MMP2)的活性所切割。将二油酰磷脂酰乙醇胺(DOPE)的氨基与聚乙二醇化的基质金属蛋白酶-2底物多肽(Gly-Pro-Leu-Gly-Lie-Ala-Gly-Gly-Gln)偶联，合成了可切割的聚乙二醇二脂酰磷脂酰乙醇胺(PEGPD)。当聚乙二醇钯被掺入半乳糖化脂质体(Gal-PEGPD-脂质体)时，我们预计Gal-PEGPD-脂质体不会由于空间位阻效应而被正常肝细胞摄取，但会被分泌的MMPs激活在肝癌细胞周围。在hMMP2(1、5和10mU g/ml)的预处理中，hMMP2浓度依赖的hMMP2对Gal-PEG-Pd-脂质体的摄取增加，提示PEGPD被切割。在过量的半乳糖存在下，hMMP2对Gal-PEG-Pd-脂质体的摄取受到显著抑制，提示去唾液酸糖蛋白受体介导的Gal-PEG-Pd-脂质体在聚乙二醇-PD裂解后摄取。用含有分泌MMPs的B16BL6条件培养基预处理Gal-PEGPD-脂质体，可增强与HepG2细胞的结合，与hMMP2处理的情况相同。此外，hMMPs(5mU g/ml)可增强N-4-octadecyl-1-beta-D-arabinofuranosylcytosine(NOAc)-Gal-PEGPd-脂质体的细胞毒作用，过量的半乳糖可显著降低其细胞毒作用。综上所述，半乳糖-聚乙二醇钯-脂质体是一种新型的肝细胞癌靶向药物。(C)2006爱思唯尔B.V.保留所有权利。
In order to obtain an HCC-selective drug delivery system, a novel functional lipid, which is cleaved by the protease activity of matrix metalioproteinase-2 (MMP-2), was developed. The amino group of dioleoylphosphatidylethanolamine (DOPE) was conjugated with PEGylated MMP-2 substrate peptide (Gly-Pro-Leu-Gly-lie-Ala-Gly-Gln), and MMP-2-cleavable PEG-Peptide-DOPE (PEG-PD) was synthesized. When PEG-PD was incorporated in galactosylated liposomes (Gal-PEG-PD-liposomes), we expected that Gal-PEG-PD-liposomes would not be taken up by normal hepatocytes due to the steric hindrance effect, but would be activated around HCC cells by secreted MMPs. In the pretreatment by hMMP2 (1, 5, and 10 mu g/ml), an hMMP2 concentration-dependent higher uptake of Gal-PEG-PD-liposomes was observed in HepG2 cells, suggesting PEG-PD cleavage. In the presence of an excess of galactose, the uptake of Gal-PEG-PD-liposomes with hMMP2 was significantly inhibited, suggesting asialoglycoprotein receptor-mediated uptake of Gal-PEG-PD-liposomes following the PEG-PD cleavage. Pretreatment of Gal-PEG-PD-liposomes with the conditioned medium of B16BL6, which contained secreted MMPs, enhanced the binding to HepG2 cells, as in the case of hMMP-2 treatment. Moreover, the cytotoxicity of N-4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) incorporated Gal-PEG-PD-liposomes was enhanced by hMMPs (5 mu g/ml) and its cytotoxicity was significantly reduced by the presence of an excess of galactose in HepG2 cells. In conclusion, Gal-PEG-PD-liposomes were successfully developed for novel HCC-selective targeting. (c) 2006 Elsevier B.V. All rights reserved.