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Structural basis of DOTMA for its high intravenous transfection activity in mouse

Gene Therapy volume 7, pages 764–768 (2000)Cite this article

Abstract

Eleven structural analogues of two known cationic lipids, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) and N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP) were synthesized and utilized to evaluate the structural characteristics of DOTMA for its high intravenous transfection activity. Using a CMV-driven expression system and luciferase gene as a reporter, the transfection activity of these analogues was evaluated in mice using tail vein injection. Results concerning the structure–activity relationship with regard to the influence of the backbone, relative position between head group and the hydrophobic chains on the backbone, linkage bonds, as well as the composition of the aliphatic chains revealed that cationic lipids which give a higher in vivo transfection activity share the following structural characteristics: (1) cationic head group and its neighboring aliphatic chain being in a 1,2-relationship on the backbone; (2) ether bond for bridging the aliphatic chains to the backbone; and (3) paired oleyl chains as the hydrophobic anchor. Cationic lipids without these structural features had lower in vivo transfection activity. These structural characteristics, however, did not significantly influence their in vitro transfection activity. The contribution that cationic lipids make to the overall in vivo transfection activity is likely to be determined by the structure of DNA/lipid complexes and by the outcome of the interaction between the DNA/lipid complexes and blood components upon intravenous administration.

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Acknowledgements

Assistance from Professor Balwant Dixit for critical reading of this manuscript is acknowledged. DOTMA was kindly provided by Roche Bioscience. This work was supported in part by a grant from NIH (CA 72925) and research contract with Targeted Genetics Corporation.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 527 Salk Hall, Pittsburgh, PA 15261, USA

    T Ren, Y K Song, G Zhang & D Liu

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Ren, T., Song, Y., Zhang, G. et al. Structural basis of DOTMA for its high intravenous transfection activity in mouse. Gene Ther 7, 764–768 (2000). https://doi.org/10.1038/sj.gt.3301153

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