Liposomes Bearing Polyethyleneglycol-Coupled Transferrin with Intracellular Targeting Property to the Solid Tumors In Vivo
- 772 Downloads
Purpose. The purpose of this study was to determine the usefulness of transferrin (TF)-pendant-type polyethyleneglycol (PEG)-liposomes (TF-PEG-liposomes), in which TF was covalently linked to the distal terminal of PEG chains on the external surface of PEG-liposomes as a carrier for in vivo cytoplasmic targeting to tumor cells.
Methods. Small unilamellar TF-PEG-liposomes (100-140 nm in diameter) were prepared from DSPC, CH, DSPE-PEG, and DSPE-PEG-COOH (2:1:0.11:0.021, molar ratio), and were conjugated to TF via the carboxyl residue of DSPE-PEG-COOH. The intracellular targeting ability of TF-PEG-liposomes to tumor cells was examined in vitro and in Colon 26 tumor-bearing mice.
Results. TF-PEG-liposomes, bearing approximately 25 TF molecules per liposome, readily bound to mouse Colon 26 cells in vitro and were internalized by receptor-mediated endocytosis. TF-PEG-liposomes showed a prolonged residence time in the circulation and low RES uptake in Colon 26 tumor-bearing mice, resulting in enhanced extravasation of the liposomes into the solid tumor tissue. Electron microscopic studies in Colon 26 tumor-bearing mice revealed that the extravasated TF-PEG-liposomes were internalized into tumor cells by receptor-mediated endocytosis.
Conclusion. TF-PEG-liposomes had the capabilities of specific receptor binding and receptor-mediated endocytosis to target cells after extravasation into solid tumors in vivo. Such liposomes should be useful for in vivo cytoplasmic targeting of chemotherapeutic agents or plasmid DNAs to target cells.
Unable to display preview. Download preview PDF.
- 1.T. M. Allen. Liposomal drug formulations. Drugs 56: 747-756 (1998).Google Scholar
- 2.K. Maruyama, O. Ishida, T. Takizawa, and K. Moribe. Possibility of active targeting to tumor tissues with liposomes. Adv. Drug Deliv. Rev. 40:89-102 (1999).Google Scholar
- 3.D. Aragnol and L. D. Leserman. Immune clearance of liposomes inhibited by an anti-Fc receptor antibody in vivo. Proc. Natl. Acad. Sci. USA 83:2699-2703 (1986).Google Scholar
- 4.J. T. P. Derksen, H. W. M. Marselt, and G. L. Scherphof. Uptake and processing of immunoglobulin-coated liposomes by subpopulation of rat liver macrophages. Biochim. Biophys. Acta 971:127-136 (1988).Google Scholar
- 5.K. Maruyama, E. Holmberg, S. J. Kennel, A. Klibanov, V. P. Torchilin, and L. Huang. Characterization of in vivo immunoliposome targeting to pulmonary endothelium. J. Pharm. Sci. 79:978-984 (1990).Google Scholar
- 6.K. Maruyama, T. Takizawa, T. Yuda, S. J. Kennel, L. Huang, and M. Iwatsuru. Targetability of novel immunoliposomes modified with amphipathic polyethyleneglycols conjugated at their distal terminals to monoclonal antibodies. Biochim. Biophys. Acta 1234:74-80 (1995).Google Scholar
- 7.K. Maruyama, N. Takahashi, T. Tagawa, K. Nagaike, and M. Iwatsuru. Immunoliposomes bearing polyethyleneglycol-coupled Fab' fragment show prolonged circulation time and high extravasation into target solid tumors in vivo. FEBS Lett. 413:177-180 (1997).Google Scholar
- 8.E. Wagner, D. Curiel, and M. Cotton. Delivery of drugs, proteins and genes into cells using transferrin as a ligand for receptor-mediated endocytosis. Adv. Drug Deliv. Rev. 14:113-135 (1994).Google Scholar
- 9.H. A. Huebers and C. A. Finch. The physiology of transferrin and transferrin receptors. Physiol. Rev. 67:520-582 (1987).Google Scholar
- 10.P. Aisen. The transferrin receptor and the release of iron from transferrin. Adv. Exp. Med. Biol. 365:31-40 (1994).Google Scholar
- 11.F. Szoka and D. Papahadjopoulos. Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc. Natl. Acad. Sci. USA 75:4194-4198 (1978).Google Scholar
- 12.A. Dautry-Varsat, A. Ciechanover, and H. F. Lodish. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc. Natl. Acad. Sci. USA 80:2258-2262 (1983).Google Scholar
- 13.S. K. Huang, K. Hong, K. D. Lee, D. Papahadjopoulos, and D. S. Friend. Light microscopic localization of silver-enhanced liposome-entrapped colloidal gold in mouse tissue. Biochim. Biophys. Acta 1069:117-121 (1991).Google Scholar
- 14.C. H. Fiske and Y. Subbarow. The colorimetric determination of phosphorus. J. Biol. Chem. 66:375-400 (1925).Google Scholar
- 15.H. G. Enoch and P. Strittmatter. Formation and properties of 1000-Å-diameter, single-bilayer phospholipid vesicles. Proc. Natl. Acad. Sci. USA 76:145-149 (1979).Google Scholar
- 16.R. D. Klausner, G. Ashwell, J. Renswoude, J. B. Harford, and K. R. Bridges. Binding of apotransferrin to K562 cells: Explanation of the transferrin cycle. Proc. Natl. Acad. Sci. USA 80:2263-2266 (1983).Google Scholar
- 17.O. Ishida, K. Maruyama, K. Sasaki, and M. Iwatsuru. Size-dependent extravasation ant interstitial localization of polyethyleneglycol liposomes in solid tumor-bearing mice. Int. J. Pharm. 190:49-56 (1999).Google Scholar
- 18.K. Sasaki. Dynamic change of the vascular wall from transmural to intracellular passage of red blood cells observed in splenic regeneration. Acta Anat. 139:315-319 (1990).Google Scholar
- 19.A. Klibanov, K. Maruyama, A. M. Beckerleg, V. P. Torchilin, and L. Huang. Activity of amphipatihic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim. Biophys. Acta 1062:142-148 (1991).Google Scholar
- 20.A. Klibanov and L. Huang. Long-circulating liposomes: Development and perspectives. Liposome Res. 2:321-334 (1992).Google Scholar
- 21.T. Yuda, Y. Pongpaibul, K. Maruyama, and M. Iwatsuru. Activity of amphipathic polyethyleneglycols to prolong the circulation time of liposomes. J. Pharm. Sci. Technol. Jpn. 59:32-42 (1999).Google Scholar
- 22.R. K. Jain and L. E. Gerlowski. Extravascular transport in normal and tumor tissue. Crit. Rev. Oncol. Hematol. 5:115-170 (1986).Google Scholar
- 23.Y. Matsumura and H. Maeda. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46:6387-6392 (1986).Google Scholar
- 24.S. Unezaki, K. Maruyama, J. Hosoda, I. Nagae, Y. Koyanagi, M. Nakata, O. Ishida, M. Iwatsuru, and S. Tsuchiya. Direct measurement of extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy. Int. J. Pharm. 144:11-17 (1996).Google Scholar
- 25.D. Liu, A. Mori, and L. Huang. Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. Biochim. Biophys. Acta 1104:95-101 (1992).Google Scholar
- 26.P. K. Bali, O. Zak, and P. Aisen. A new role for the transferrin receptor in the release of iron from transferrin. Biochemistry 30:324-328 (1991).Google Scholar
- 27.D. C. Litzinger and L. Huang. Phosphatidylethanolamine liposomes: Drug delivery, gene transfer and immunodiagnostic applications. Biochim. Biophys. Acta 1113:201-227 (1992).Google Scholar