Application of Oligo-(14-amino-3,6,9,12-tetraoxatetradecanoic acid) Lipid Conjugates as Steric Barrier Molecules in Liposomal Formulations

Lipid conjugates of oligo-(14-amino-3,6,9,12-tetraoxatetradecanoic acid) (ATTAn) were synthesized as monodisperse analogues of poly(ethylene glycol) (PEG) derivatives used in liposomal drug delivery systems. The new lipids were shown to be at least equivalent to MePEGA-2000-DSPE in assays designed t...

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Bibliographic Details
Published in:	Bioconjugate chemistry Vol. 10; no. 4; pp. 653 - 666
Main Authors:	Ansell, Steven M, Kojic, Ljiljana D, Hankins, Janet S, Sekirov, Laura, Boey, Anthony, Lee, Dora K, Bennett, Athena R, Klimuk, Sandra K, Harasym, Troy O, Santos, Nancy Dos, Semple, Sean C
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 01-07-1999
Subjects:	Animals Antibiotics, Antineoplastic - administration & dosage Complement Activation - drug effects Cytokines - chemistry Doxorubicin - administration & dosage Drug Carriers - chemistry Enzyme-Linked Immunosorbent Assay Female Fluorescent Dyes - chemistry Indicators and Reagents Lipids - chemistry Liposomes - chemistry Mice Mice, Inbred BALB C Mitogens - toxicity Myristic Acids - chemistry Myristic Acids - toxicity Oligonucleotides, Antisense - chemistry Organic Chemicals Pharmaceutic Aids - chemistry Phenotype Polyethylene Glycols - chemistry
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Summary:	Lipid conjugates of oligo-(14-amino-3,6,9,12-tetraoxatetradecanoic acid) (ATTAn) were synthesized as monodisperse analogues of poly(ethylene glycol) (PEG) derivatives used in liposomal drug delivery systems. The new lipids were shown to be at least equivalent to MePEGA-2000-DSPE in assays designed to evaluate the effectiveness of polymers as steric barrier molecules in liposomes. Liposomes containing 1−5% of ATTA8−DSPE (octamer) showed comparable long circulation behavior relative to PEG-2000-DSPE analogues. Surprisingly, the shorter ATTA4−DSPE (tetramer) appeared to be quite effective in reducing clearance. Liver enzyme levels and systemic single dose tolerability of ATTA8−DSPE liposomes were comparable to controls, suggesting that the new materials are nontoxic. Prolonged exposure of ATTA8−DSPE liposomes to splenocytes in vitro showed no evidence of mitogenicity relative to controls or MePEGA-2000-DSPE liposomes. ATTA8−DSPE was as effective as MePEGC-2000-DSPE in preventing complement activation by cationic liposome systems. Repeat dosage in vivo regimes in ICR mice using DSPC/cholesterol liposomes, with and without 5% ATTA8−DSPE and MePEGC-2000-DSPE, showed no evidence of enhanced clearance on successive doses. Splenocytes recovered after repeat doses showed no significant evidence of mitogenicity on restimulation with liposomes. Cellular differentiation and activation marker levels in splenocytes recovered after the fourth in vivo administration were at normal levels. These results suggest that ATTAn oligomers do not induce an immune response in isolation. It was demonstrated that ATTA8−DSPE could be used to replace PEG−lipids in the formulation of doxorubicin, plasmid DNA and oligonucleotides using a variety of formulation techniques. The study demonstrates that ATTAn oligomers can be safely and effectively used in place of poly(ethylene glycol) as well-defined biomaterials in liposomal applications where reproducible behavior is critical.
Bibliography:	ark:/67375/TPS-FR5WBW9M-S istex:592D59927AEFEA558162008CBB0008D75F73E51A
ISSN:	1043-1802 1520-4812
DOI:	10.1021/bc990005p