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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Prevention of Antibody-Mediated Elimination of Ligand-Targeted Liposomes by Using Poly(Ethylene glycol)-Modified Lipids

Wai Ming Li, Lawrence D. Mayer and Marcel B. Bally
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 976-983; DOI: https://doi.org/10.1124/jpet.300.3.976
Wai Ming Li
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Lawrence D. Mayer
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Marcel B. Bally
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Abstract

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.

Footnotes

  • This study was supported by a grant from the Canadian Institute of Health Research.

  • Abbreviations:
    PEG
    poly(ethylene glycol)
    BSA
    bovine serum albumin
    biotin-X-DSPE (Bx-DSPE)
    N-(((6-biotinoyl)amino)hexanoyl)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine
    DSPC
    1,2-distearoyl-sn-glycero-3-phosphocholine
    DSPE-PEG2000
    1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000]
    DMPE-PEG2000
    1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000]
    DPPE-PEG2000
    1,2-dipalmatoyl-sn-glycero-3-phosphoethanolamine-n-methoxy(polyethylene glycol)-2000]
    DSPE-PEG5000
    1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol) 5000]
    Chol
    cholesterol
    ELISA
    enzyme-linked immunosorbent assay
    ANOVA
    analysis of variance
    1% Bx-lipo
    DSPC/Chol liposomes containing 1% biotin
    • Received October 4, 2001.
    • Accepted November 29, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Prevention of Antibody-Mediated Elimination of Ligand-Targeted Liposomes by Using Poly(Ethylene glycol)-Modified Lipids

Wai Ming Li, Lawrence D. Mayer and Marcel B. Bally
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 976-983; DOI: https://doi.org/10.1124/jpet.300.3.976

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Prevention of Antibody-Mediated Elimination of Ligand-Targeted Liposomes by Using Poly(Ethylene glycol)-Modified Lipids

Wai Ming Li, Lawrence D. Mayer and Marcel B. Bally
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 976-983; DOI: https://doi.org/10.1124/jpet.300.3.976
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