title: Tumor targeting of doxorubicin by anti-MT1-MMP antibody-modified PEG liposomes.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.forename: Emi
authors.initials: E
authors.lastname: Ishida
authors.forename: Koichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Takanori
authors.initials: T
authors.lastname: Aoki
authors.forename: Junko
authors.initials: J
authors.lastname: Yasuda
authors.forename: Kenichi
authors.initials: K
authors.lastname: Obata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005079:Excipients; D007120:Immunochemistry; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D008081:Liposomes; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D005079:Excipients; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin; D053511:Matrix Metalloproteinase 14