Abstract
Liposomes are useful drug delivery vehicles since they may protect encapsulated drugs from enzymatic degradation and rapid clearance in vivo, or alter biodistribution, potentially leading to reduced toxicities (1,2). A major limitation to the development of many specialized applications is the problem of directing liposomes to tissues where they would not normally accumulate. Consequently, a great deal of effort has been made over the years to develop liposomes that have targeting vectors attached to the bilayer surface. These vectors have included ligands such as oligosaccharides (3,4), peptides (5,6), proteins (7,8) and vitamins (9). Most studies have focused on antibody conjugates since procedures for producing highly specific monoclonal antibodies (MAbs) are well established. In principle it should be possible to deliver liposomes to any cell type as long as the cells are accessible to the carrier. In practice it is usually not this simple since access to tissue, competition, and rapid clearance are formidable obstacles. It has also been shown that antibodies become immunogenic when coupled to liposomes (10,11), although in similar experiments with ovalbumin we have demonstrated that immunogenicity can be suppressed by formulating the liposomes with the cytotoxic drug doxorubi-cin (12). Such issues as these suggest that the development of antibody-targeted liposomes for in vivo applications will present difficult challenges.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Boman, N. L., Bally, M. B., Cullis, P. R., Mayer, L. D., and Webb, M. S. (1995) Encapsulation of vincristine in liposome reduces toxicity and improves anti-tumour efficacy. J. Liposome Res. 5, 523–541.
Boman, N. L., Cullis, P. R., Bally, M. B., and Mayer, L. D. (1995) Preclinical and clinical activity of liposomal doxorubicin, in Liposomes in Biomedical Applications, HAP Academic Publishers, pp. 85–103.
Murohara, T., Margiotta, J., Phillips, L. M., Paulson, J. C., DeFrees, S., Zalipsky, S., Guo, L. S., and Lefer, A. M. (1995) Cardioprotection by liposome-conjugated sialyl Lewisx-oligosaccharide in myocardial ischaemia and reperfusion injury. Cardiovas. Res. 30, 965–974.
Shimada, K., Kamps, J. A. A. M., Regts, J., Ikeda, K, Shiozawa, T., Hirota, S., and Scherphof, G. L. (1997) Biodistribution of liposomes containing synthetic galactose-terminated diacylglyceryl poly(ethyleneglycol)s. Biochim. Biophys. Acta 1326, 329–341.
Hsu, M. J. and Juliano, R. L. (1982) Interactions of liposomes with the reticuloen-dothelial system. II: Nonspecific and receptor-mediated uptake of liposomes by mouse peritoneal macrophages. Biochim. Biophys. Acta 720, 411–419.
Vidal, M., Saite-Marie, J., Philippot, J. R., and Bienevue, A. (1987) The influence of coupling transferrin to liposomes or minibeads on its uptake and fate in leuke-mic L2C cells. FEBS Lett. 216, 159–163.
Nishiya, T. and Sloan, S. (1996) Interaction of RGD liposomes with platelets. Biochem. Biophys. Res. Commun. 224, 242–245.
Zalipsky, S., Mullah, N., Harding, J. A., Gittleman, J., Guo, L., and DeFrees, S. A. (1997) Poly(ethylene glycol)-grafted liposomes with oligopeptide or oligosaccharide ligands appended to the termini of the polymer chains. Bioconj. Chem. 8, 111–118.
Lee, R. J. and Low, P. S. (1994) Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. J. Biol. Chem. 2651, 3198–3204.
Harding, J. A., Engbers, G. M., Newman, M. S., Goldstein, N. I., and Zalipsky, S. (1997) Immunogenicity and pharmacokinetic attributes of poly(ethylene glycol)-grafted immunoliposomes. Biochim. Biophys. Acta 1327, 181–192.
Phillips, N. C. and Dahman, J. (1995) Immunogenicity of immunoliposomes: reactivity against species-specific IgG and liposomal phospholipids. Immunology Letters 45, 149–152.
Tardi, P. G., Swartz, E. N., Harasym, T. O., Cullis, P. R., and Bally, M. B. (1999) An immune response to ovalbumin covalently coupled to liposomes is prevented when liposomes used contain doxorubicin. J. Immun. Meth., submitted.
Heath, T. D. and Martin, F. J. (1986) The development and application of protein-liposome conjugation techniques. Chem. Phys. Lipids 40, 347–358.
Hashimoto, Y., Endoh, H., and Sugawara, M. (1993) Chemical methods for the modification of liposomes with proteins or antibodies, in Liposome Technology, vol. 3, CRC, Boca Raton, FL, pp. 41–49.
Leserman, L. D., Machy, P., and Barbet, J. (1993) Co valent coupling of monoclonal antibodies and protein A to liposomes: specific interaction with cells in vitro and in vivo, in Liposome Technology, vol. 3, CRC, Boca Raton, FL, pp. 29–40.
Torchilin, V. P. (1993) Immobilization of specific proteins on liposome surface: systems for drug targeting, in Liposome Technology vol. 3, CRC, Boca Raton, FL, pp. 75–90.
Hermanson, G. T., Mallia, A. K., and Smith, P. K. (1992) Immobilized Affinity Ligand Techniques. Academic, San Diego, CA.
Coulter, A. and Harris, R. (1983) Simplified preparation of rabbit Fab fragments J. Immunol. Meth. 59, 199–203.
Rousseaux, J., Rousseaux-Prevost, R., and Bazin, H. (1983) Optimal conditions for the preparation of Fab and F(ab’)2 fragments from monoclonal IgG of different rat IgG subclasses. J. Immunol. Meth. 64, 141–146.
Aragonal, D. and Leserman, L. D. (1986) Immune clearance of liposomes inhibited by an anti-Fc receptor antibody in vivo. Proc. Natl. Acad. Sci. USA 83, 2699–2703.
Winter, G. and Milstein, C. (1990) Man-made antibodies. Nature 349, 293–299.
Huang, C. H. (1969) Studies on phosphatidylcholine vesicles: formation and physical characteristics. Biochemistry 8, 344–352.
Hope, M. J., Nayar, R., Mayer, L. D., and Cullis, P. R. C. (1993) Reduction of liposome size and preparation of unilamellar vesicles by extrusion techniques, in Liposome Technology vol. 1, CRC, Boca Raton, FL, pp. 123–139.
Szoka, F. and Papahadjopoulos, D. (1978) 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.
Szoka, F. and Papahadjopoulos, D. (1980) Comparative properties and methods of preparation of lipid vesicles (liposomes). Ann. Rev. Biophys. Bioeng. 9, 467–508.
Mayer, L. D., Madden, T. M., Bally, M. B., and Cullis, P. R. (1993) pH gradient-mediated drug entrapment of liposomes, in Liposome Technology vol. 2, CRC, Boca Raton, FL, pp. 27–44.
Endoh, H., Suzuki, Y., and Hashimoto, Y. (1981) Antibody coating of liposomes with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the effect on target specificity. J. Immun. Meth. 44, 79–85.
Dunnick, J. K., McDougall, I. R., Aragon, S., Goris, M. L., and Kriss, J. P. (1975) Vesicle interactions with polyamino acids and antibody: in vitro and in vivo studies. J. Nuclear Med. 16, 483–487.
Huang, A., Huang, L., and Kennel, S. J. (1980) Monoclonal antibody covalently coupled with fatty acid. A reagent for in vitro liposome targeting. J. Biol. Chem. 255, 8015–8018.
Maruyama, K., Takizawa, T., Yuda, T., Kennel, S. J., Huang, L., and Iwatsuru, M. (1995) Targetability of novel immunoliposomes modified with amphipathic poly(ethylene glycol)s conjugated at their distal terminals to monoclonal antibodies. Biochim. Biophys. Acta 1234, 74–80.
Barbet, J., Machy, P., and Leserman, L. O. (1981) Monoclonal antibody covalently coupled to liposomes: specific targeting to cells. J. Supramolec. Struct. Cell. Biochem. 16, 243–258.
Jones, M. N. and Hudson, M. J. (1993) The targeting of immunoliposomes to tumour cells (A431) and the effects of encapsulated methotrexate. Biochim. Biophys. Acta 1152, 231–242.
Schwendener, R. A., Trub, T., Schott, H., Langhals, H., Barth, R. F., Groscurth, P., and Hengartner, H. (1990) Comparative studies of the preparation of immunoliposomes with the use of two bifunctional coupling agents and investigation of in vitro immunoliposome-target cell binding by cytofluorometry and electron microscopy. Biochim. Biophys. Acta 1026, 69–79.
Hansen, C. B., Kao, G. Y., Moase, E. H., Zalipsky, S., and Allen, T. M. (1995) Attachment of antibodies to sterically stabilized liposomes: evaluation, comparison and optimization of coupling procedures. Biochim. Biophys. Acta 1239, 133–144.
Carlsson, J., Drevin, H., and Axen, R. (1978) Protein thiolation and reversible protein-protein conjugation. Biochem. J. 173, 723–737.
Ansell, S. M., Tardi, P. G., and Buchkowsky, S. S. (1996) 3-(2-pyridyldithio)-propionic acid hydrazide as a cross-linker in the formation of liposome-antibody conjugates. Bioconj. Chem. 7, 490–496.
Domen, P. L., Nevens, J. R., Mallia, K., Hermanson, G. T., and Klenk, D. C. (1980) Site directed immobilization of proteins. J. Chromatogr. 510, 293–302.
Chua, M. M, Fan, S. T., and Karush, F. (1984) Attachment of immunoglobulin to liposomal membrane via protein carbohydrate. Biochim. Biophys. Acta 800, 291–300.
Shahinian, S. and Silvius J. R. (1995) A novel strategy affords high yield coupling of antibody Fab’ fragments to liposomes. Biochim. Biophys. Acta 1239, 157–167.
Kirpotin, D., Park, J. W., Hong, K., Zalipsky, S., Li, W. L., Carter, P., Benz, C. C., and Papahadjopoulos, D. Sterically stabilized anti-HER2 immunoliposomes: design and targeting to human breast cancer cells in vitro. Biochemistry 36, 66–75.
Martin, F. J. and Papahadjopoulos, D. (1982) Irreversible coupling of immunoglobulin fragments to preformed vesicles. An improved method for liposome targeting. J. Biol. Chem. 257, 286–288.
Longman S. A., Cullis, P. R., and Bally, M. B. (1995) A model approach for assessing liposome targeting in vivo. Drug Delivery 2, 156–165.
Longman, S. A., Cullis, P. R., Choi, L., de Jong, G., and Bally, M. (1995) A two step targeting approach for delivery of doxorubicin loaded liposomes to tumour cells in vivo. Cancer Chem. Pharmacol. 36, 91–101.
Matthay, K. K., Heath, T. D., Badger, C. C., Bernstein, I. D., and Papahadjopoulos, D. (1986) Antibody-directed liposomes: comparison of various ligands for association, endocytosis, and drug delivery. Cancer Res. 46, 4904–4910.
Machy, P. and Leserman, L. D. (1983) Small liposomes are better than large liposomes for specific drug delivery in vitro. Biochim. Biophys. Acta 730, 313–320.
Lougrey, H. L., Bally, M. B., and Cullis, P. R. (1987) A novel-covalent method of attaching antibodies to liposomes. Biochim. Biophys. Acta 901, 157–160.
Singh, R., Blattler, W. A., and Collinson, A. R. (1993) An amplified assay for thiols based on reactivation of papain. Anal. Biochem. 213, 49–56.
Harasym, T. O., Tardi, P., Longman, S. A., Ansell, S. M., Bally, M. B., Cullis, P. R. C., and Choi, L. S. L. (1995) Poly(ethylene glycol)-modified phospholipids prevent aggregation during covalent conjugation of proteins to liposomes. Bioconj. Chem. 6, 187–194.
Allen, T. M., Hansen, C., Martin, F., Redemann, C., and Yau-Young, A. (1991) Liposomes containing synthetic lipid derivatives of polyethylene glycol show prolonged circulation half-lives in vivo. Biochim. Biophys. Acta 1066, 29–36.
Allen, T. M., Agrawal, A. K., Ahmad, I., I., Hansen, C. B., and Zalipsky, S. (1994) The use of glycolipids and hydrophilic polymers in avoiding rapid uptake of lipo-somes by the mononuclear phagocyte system. J. Liposome Res. 4, 1–26.
Chonn, A. and Cullis, P. R. (1992) Ganglioside GMI and hydrophilic polymers increase liposome circulation times by inhibiting the association of blood proteins. J. Liposome Res. 2, 397–410.
Devine, D. V. and Marjan, J. M. (1997) The role of immunoproteins in the survival of liposomes in the circulation. Crit. Rev. Ther. Drug Carrier Systems 14, 105–131.
Klibanov, A. L., Maruyama, K., Beckerleg, A. M., Torchilin, V. P., and Huang, L. (1991) Activity of amphipathic poly(ethylene glycol)5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavourable for immunoliposome linking to target. Biochim. Biophys. Acta 1062, 142–148.
Matthay, K. K., Abai, A. M., Cobb, S., Hong, K., Papahadjopoulos, D., and Straubinger, R. M. (1989) Role of ligand in antibody-directed endocytosis of liposomes by human T-leukemia cells. Cancer Res. 49, 4879–4886.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Humana Press Inc.
About this protocol
Cite this protocol
Ansell, S.M., Harasym, T.O., Tardi, P.G., Buchkowsky, S.S., Bally, M.B., Cullis, P.R. (2000). Antibody Conjugation Methods for Active Targeting of Liposomes. In: Francis, G.E., Delgado, C. (eds) Drug Targeting. Methods in Molecular Medicine™, vol 25. Humana Press. https://doi.org/10.1385/1-59259-075-6:51
Download citation
DOI: https://doi.org/10.1385/1-59259-075-6:51
Publisher Name: Humana Press
Print ISBN: 978-0-89603-531-7
Online ISBN: 978-1-59259-075-9
eBook Packages: Springer Protocols