Tumor targeting of doxorubicin by anti-MT1-MMP antibody-modified PEG liposomes

• Published in: International journal of pharmaceutics 2007-09, Vol.342 (1), p.194-200
• Main Authors: Hatakeyama, Hiroto, Akita, Hidetaka, Ishida, Emi, Hashimoto, Koichi, Kobayashi, Hideo, Aoki, Takanori, Yasuda, Junko, Obata, Kenichi, Kikuchi, Hiroshi, Ishida, Tatsuhiro, Kiwada, Hiroshi, Harashima, Hideyoshi
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - therapeutic use; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - pharmacology; Cancer therapy; Doxorubicin - administration & dosage; Doxorubicin - therapeutic use; Drug Compounding; Drug delivery; Drug Delivery Systems; Excipients; Immunochemistry; Immunoglobulin Fab Fragments - chemistry; Immunoliposomes; Liposomes; Male; Matrix metalloproteinase; Matrix Metalloproteinase 14 - immunology; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Polyethylene Glycols - chemistry
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2007.04.037

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.