title: In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP).
abstract: 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 SIL[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')]) was significantly higher than that of DXR-containing SL. The cellular internalization of SIL[anti-MT1-MMP(Fab')] was inhibited by endocytosis inhibitors, suggesting that their internalization was mediated via clathrin- or caveolae-dependent endocytosis. Furthermore, the efficient binding of SIL[anti-MT1-MMP(Fab')] 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.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Atobe
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Emi
authors.initials: E
authors.lastname: Ishida
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Jyunko
authors.initials: J
authors.lastname: Yasuda
authors.forename: Takanori
authors.initials: T
authors.lastname: Aoki
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Obata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004355:Drug Stability; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D008081:Liposomes; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis* / Q000276:immunology; D018613:Microscopy, Confocal
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D004317:Doxorubicin; D053511:Matrix Metalloproteinase 14