Immunogenicity and Rapid Blood Clearance of Liposomes Containing Polyethylene Glycol-Lipid Conjugates and Nucleic Acid
- 3 November 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 312 (3), 1020-1026
- https://doi.org/10.1124/jpet.104.078113
Abstract
Polyethylene glycol (PEG) is used widely in the pharmaceutical industry to improve the pharmacokinetics and reduce the immunogenicity of therapeutic and diagnostic agents. The incorporation of lipid-conjugated PEG into liposomal drug delivery systems greatly enhances the circulation times of liposomes by providing a protective, steric barrier against interactions with plasma proteins and cells. Here we report that liposome compositions containing PEG-lipid derivatives and encapsulated antisense oligodeoxynucleotide (ODN) or plasmid DNA elicit a strong immune response that results in the rapid blood clearance of subsequent doses in mice. The magnitude of this response is sufficient to induce significant morbidity and, in some instances, mortality. This effect has been observed in several strains of mice and was independent of sequence motifs, such as immunostimulatory CpG motifs. The ODN-to-lipid ratio and ODN dose was also determined to be important, with abrogation of the response occurring at a ratio between 0.04 and 0.08 (w/w). Rapid elimination of liposome-encapsulated ODN from blood depends on the presence of PEG-lipid in the membrane because the use of nonpegylated liposomes or liposomes containing rapidly exchangeable PEG-lipid also abrogated the response. These studies have important implications for the evaluation and therapeutic use of liposomal formulations of nucleic acid, as well as the potential development of liposomal vaccines.Keywords
This publication has 35 references indexed in Scilit:
- Intracellular targeting and functional analysis of single-chain Fv fragments in mammalian cellsMethods, 2004
- Progress in the Delivery of Therapeutic Oligonucleotides: Organ/Cellular Distribution and Targeted Delivery of OligonucleotidesIn VivoAntisense and Nucleic Acid Drug Development, 2003
- CpG Motifs in Bacterial DNA and Their Immune EffectsAnnual Review of Immunology, 2002
- PegylationClinical Pharmacokinetics, 2001
- Accelerated Clearance of Polyethylene Glycol-Modified Proteins by Anti-Polyethylene Glycol IgMBioconjugate Chemistry, 1999
- Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor‐α‐mediated shockEuropean Journal of Immunology, 1997
- Immunogenicity of immunoliposomes: reactivity against species-specific IgG and liposomal phospholipidsImmunology Letters, 1995
- Immunologic aspects of liposomes: presentation and processing of liposomal protein and phospholipid antigensBiochimica et Biophysica Acta (BBA) - Reviews on Biomembranes, 1992
- Biological stability of [3H]cholesteryl oleyl ether in cultured fibroblasts and intact ratFEBS Letters, 1980
- Liposomes in Immunology: Multilamellar Phosphatidylcholine Liposomes as a Simple, Biodegradable and Harmless Adjuvant Without any Immunogenic Activity of its ownImmunological Communications, 1980