In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP)

作者：Atobe Kazutaka; Ishida Tatsuhiro; Ishida Emi; Hashimoto Kouichi; Kobayashi Hideo; Yasuda Jyunko; Aoki Takanori; Obata Ken ichi; Kikuchi Hiroshi; Akita Hidetaka; Asai Tomohiro; Harashima Hideyoshi; Oku Naoto; Kiwada Hiroshi^*

来源：Biological & Pharmaceutical Bulletin, 2007, 30(5): 972-978.

DOI：10.1248/bpb.30.972

• immunoliposome
• targeting
• PEGylation
• membrane type 1 matrix metalloprotemase (MT1-MMP)
• human umbilical vein endothelial cell (HUVEC)
• cellular uptake

The poor selective cytotoxicity of anticancer drugs lead to dose-limiting adverse effects which compromise the clinical outcome. Solid tumors recruit new blood vessels to support their growth, and epitopes that are uniquely expressed on tumor cells and tumor endothelial cells (ECs) can function as targets for immunoliposomal anticancer drugs. Membrane type 1 matrix metalloproteinase (MT1-MMP), an important protein related to tumor growth and angiogenesis, is expressed on malignant tumor cells and is activated ECs. Selective delivery could be achieved by targeting MT1-MMP, as well as other angiogenic ECs. In this regard, an anti-MT1-MMP Fab' antibody was used to prepare a MT1-MMP targeted sterically stabilized immunoliposomes (SIL[anti-MT1-MMP(Fab')]). The binding and intracellular distribution of S1L[anti-MT1-MMP(Fab')] and a non-targeted sterically stabilized liposomes (SL) were examined using human fibrosarcoma HT-1080 cells. SIL[anti-MT1-MMP(Fab')] was taken up by the cells in a lipid concentration, temperature, and time dependent manner, ultimately accumulating in the lysosomes. The cytotoxicity of doxorubicin (DXR)-containing SIL[anti-MT1-MMP(Fab')] (DXR-SIL[anti-MT1-MMP(Fab')1) was significantly higher than that of DXR-containing SL. The cellular internalization of S1L[anti-MT1-MMP(Fab')I was inhibited by endocytosis inhibitors, suggesting that their internalization was mediated via clathrin- or caveolae-depen dent endocytosis. Furthermore, the efficient binding of S1L[anti-MT1-MMP(Fab')1 was observed on human umbilical vein endothelial cells (HUVEC). Based on these results, it would be expected that DXR-SIL[anti-MT1-MMP(Fab')] may achieve direct tumor cell kill and indirect tumor cell kill via the destruction of the tumor endothelium in vivo. This strategy may have the potential for overcoming some major limitations in conventional chemotherapy in vivo.

• 出版日期2007-5