Prevention of antibody-mediated elimination of ligand-targeted liposomes by using poly(ethylene glycol)-modified lipids.
One of the major obstacles in the development of ligand-targeted liposomes is poor liposome circulation longevity as a result of antibody-mediated elimination of these highly immunogenic carriers. Because studies from our laboratory suggest that it is not possible to reduce the immunogenicity of ligand-conjugated liposomes by using surface-grafted poly(ethylene glycol) (PEG), we investigated the usefulness of PEG in protecting hapten-conjugated liposomes from elimination by an existing immune response that was previously established against the hapten. Using biotin as a model hapten, a strong biotin-specific antibody response was generated in mice by using bovine serum albumin-biotin. When these animals were challenged with liposomes containing biotin-conjugated lipid (1 or 0.1%), these liposomes were rapidly eliminated. Incorporation of PEG-lipids into these liposomes substantially reduced biotin-specific antibody binding as measured using an in vitro antibody consumption assay. However, depending on the hapten concentration, significant reductions in antibody binding through the use of PEG-lipids may not be sufficient to protect these liposomes from rapid elimination in vivo. Complete protection of liposomes was only achieved when the biotin concentration on liposome surface was low (0.1%) and with 5 mol% of either 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000] or 1,2-dipalmatoyl-sn-glycero-3-phosphoethanolamine-n-methoxy(polyethylene glycol)-2000]. The use of 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000] (up to 15 mol%) was not effective in protecting liposomes from rapid elimination in vivo, indicating the limited usefulness of this highly exchangeable PEG-lipid. In conclusion, our in vivo and in vitro data indicate that liposomes can be protected from antibody-mediated elimination by using the right type and concentration of PEG-lipids. This result has important implication in the development of ligand-targeted liposomes.
Li
Wai Ming
WM
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. mli@bccancer.bc.ca
Mayer
Lawrence D
LD
Bally
Marcel B
MB
D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000502:physiology*; D000937:Antigen-Antibody Reactions; D001710:Biotin / Q000276:immunology; D004337:Drug Carriers; D004797:Enzyme-Linked Immunosorbent Assay; D006241:Haptens; D008024:Ligands; D008055:Lipids / Q000138:chemical synthesis / Q000737:chemistry*; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000737:chemistry*
D000906:Antibodies; D004337:Drug Carriers; D006241:Haptens; D008024:Ligands; D008055:Lipids; D008081:Liposomes; D011092:Polyethylene Glycols; D001710:Biotin