Synthesis, Activity, and Structure−Activity Relationship Studies of Novel Cationic Lipids for DNA Transfer

• Published in: Journal of medicinal chemistry Vol. 41; no. 2; pp. 224 - 235
• Main Authors: Byk, Gerardo, Dubertret, Catherine, Escriou, Virginie, Frederic, Marc, Jaslin, Gabrielle, Rangara, Ravi, Pitard, Bruno, Crouzet, Joel, Wils, Pierre, Schwartz, Bertrand, Scherman, Daniel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.01.1998; Amer Chemical Soc
• Subjects: 3T3 Cells; Animals; Biological and medical sciences; Biotechnology; Carcinoma, Lewis Lung - genetics; Cations - administration & dosage; Cations - chemical synthesis; Chemistry, Medicinal; DNA - administration & dosage; DNA - metabolism; Electrophoresis, Agar Gel; Fundamental and applied biological sciences. Psychology; Gene therapy; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Life Sciences & Biomedicine; Lipid Metabolism; Lipids - chemical synthesis; Mice; Mice, Inbred C57BL; Models, Chemical; Neoplasm Transplantation; Pharmacology & Pharmacy; Polyamines - chemistry; Quaternary Ammonium Compounds - chemical synthesis; Quaternary Ammonium Compounds - metabolism; Science & Technology; Structure-Activity Relationship; Transfection - methods; Tumor Cells, Cultured; THERAPY; GENE-TRANSFER; MAMMALIAN-CELLS; EFFICIENT; PLASMID DNA; DELIVERY; Carcinoma; Organic cation; Lipids; Drug carrier; Transfection; Structure activity relation; Established cell line; Chemical synthesis; Tumor cell; Human; Lung disease; Polyamine; Rodentia; Malignant tumor; In vitro; Hela cell line; Genetic transfer; Quaternary ammonium compound; In vivo; α-Aminoacid; Vertebrata; Experimental disease; Mammalia; Mouse; Animal; DNA; Carboxamide; Solid phase; Gene therapy
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9704964

We have designed and synthesized original cationic lipids for gene delivery. A synthetic method on solid support allowed easy access to unsymmetrically monofunctionalized polyamine building blocks of variable geometries. These polyamine building blocks were introduced into cationic lipids. To optimize the transfection efficiency in the novel series, we have carried out structure−activity relationship studies by introduction of variable-length lipids, of variable-length linkers between lipid and cationic moiety, and of substituted linkers. We introduce the concept of using the linkers within cationic lipids molecules as carriers of side groups harboring various functionalities (side chain entity), as assessed by the introduction of a library composed of cationic entities, additional lipid chains, targeting groups, and finally the molecular probes rhodamine and biotin for cellular traffic studies. The transfection activity of the products was assayed in vitro on Hela carcinoma, on NIH3T3, and on CV1 fibroblasts and in vivo on the Lewis Lung carcinoma model. Products from the series displayed high transfection activities. Results indicated that the introduction of a targeting side chain moiety into the cationic lipid is permitted. A primary physicochemical characterization of the DNA/lipid complexes was demonstrated with this leading compound. Selected products from the series are currently being developed for preclinical studies, and the labeled lipopolyamines can be used to study the intracellular traffic of DNA/cationic lipid complexes.