Tumor targeting of doxorubicin by anti-MT1-MMP antibody-modified PEG liposomes
Tumor targeting of doxorubicin by anti-MT1-MMP antibody-modified PEG liposomes
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DOI：
10.1016/j.ijpharm.2007.04.037
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发表时间：
2007-09-05
影响因子：
5.8
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Hatakeyama, Hiroto;Akita, Hidetaka;Harashima, Hideyoshi
免疫脂质体是将治疗药物靶向至特定细胞的有效载体。膜型基质金属蛋白酶（MT 1-MMP）在血管生成中起重要作用，它不仅表达于肿瘤细胞，也表达于血管生成内皮细胞。因此，MT 1-MMP可能作为肿瘤和新生血管的靶分子。在本研究中，我们解决了一个效用的MT 1-MMP抗体作为靶向配体的脂质体抗癌药物。将抗MT 1-MMP抗体的Fab'片段修饰在多柔比星（DXR）-包封脂质体的聚乙二醇（PEG）的远端，DXR-空间稳定的免疫脂质体（DXR-SIL[anti-MT 1-MMP（Fab '）]）。与非靶向脂质体（DXR-stealthliposomes（DXR-SL））相比，用抗体修饰显著增强DXR-SIL[抗MT 1-MMP（Fab '）]向高度表达MT 1-MMP的HT 1080细胞中的细胞摄取，表明MT 1-MMP抗体（Fab'）是MT 1-MMP表达细胞的有效靶向配体。与DXR-SL相比，DXR-SIL[抗MT 1-MMP（Fab '）]在荷瘤小鼠体内全身给药显示出对肿瘤生长的显著抑制。这可能是由于免疫脂质体主动靶向肿瘤和新生血管。然而，DXR-SIL[抗MT 1-MMP（Fab '）]和DXR-SL的肿瘤积累是相当的，表明两种脂质体制剂通过增强的渗透和保留（EPR）效应而不是通过靶向内皮细胞和肿瘤细胞上表达的MT 1-MMP而在肿瘤中积累。DXR-SIL[anti-MT 1-MMP（Fab '）]的抗肿瘤活性增强可能是由于脂质体从肿瘤毛细血管外渗后掺入抗体，加速了细胞对脂质体的摄取。(c)2007 Elsevier B. V.保留所有权利。
Immunoliposomes are potent carriers for targeting of therapeutic drugs to specific cells. Membrane type-1 matrix metalloproteinase(MT1-MMP), which plays an important role in angiogenesis, is expressed on angiogenic endothelium cells as well as tumor cells. Then, the MT1-MMP might be useful as a target molecule for tumor and neovascularity. In the present study, we addressed a utility of antibodies against the MT1-MMP as a targeting ligand of liposomal anticancer drug. Fab' fragments of antibody against the MT1-MMP were modified at distal end of polyethylene glycol (PEG) of doxorubicin (DXR)-encapsulating liposomes, DXR-sterically stabilized immunoliposomes (DXR-SIL[anti-MT1-MMP(Fab ')]). Modification with the antibody significantly enhanced cellular uptake of DXR-SIL[anti-MT1-MMP(Fab ')] into the HT1080 cells, which highly express MT1-MMP, compared with the non-targeted liposomes (DXR-stealthliposomes (DXR-SL)), suggesting that MT1-MMP antibody (Fab') is a potent targeting ligand for the MT1-MMP expressed cells. In vivo systemic administration of DXR-SIL[anti-MT1-MMP(Fab ')] into the tumor-bearing mice showed significant suppression of tumor growth compared to DXR-SL. This is presumably due to the active targeting of immunoliposomes for tumor and neovascularity. However, tumor accumulation of DXR-SIL[anti-MT1-MMP(Fab ')] and DXR-SL were comparable, suggesting that both liposomal formulations accumulated in tumor via enhanced permeation and retention (EPR) effect, but not via targeting to the MT1-MMP expressed on both the endothelial and tumor cells. It appears that the enhanced antitumor activity of DXR-SIL[anti-MT1-MMP(Fab ')] resulted from acceleration of cellular uptake of lioposomes owing to the incorporated antibody after extravasation from capillaries in tumor. (c) 2007 Elsevier B.V. All rights reserved.