title: Novel cationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery.
abstract: In order to find new efficient and safe agents for gene delivery, we have designed and synthesized nine novel single- and double-charged amphiphiles on the base of 1,4-dihydropyridine (1,4-DHP) ring. Some biophysical properties of the amphiphilic dihydropyridines and their complexes with DNA were examined. We investigated the transfer of beta-galactosidase gene into fibroblasts (CV1-P) and retinal pigment epithelial (D 4O7) cell lines in vitro. The structure-property relationships of the compounds were investigated in various ways. The net surface charges of 1,4-DHP liposomes were highly positive (25-49 mV). The double-charged compounds condensed DNA more efficiently than single-charged and the condensation increases with the increasing +/- charge ratio between the carrier and DNA. Double-charged compounds showed also buffering properties at endosomal pH and these compounds were more efficient in transfecting the cells, but transfection efficiency of amphiphiles was cell type-dependent. The length of alkyl chains in double-charged compounds affected the transfection efficacy. The most active amphiphile (compound VI) was double-charged and had two C(12) alkyl chains. At optimal charge ratio (+/- 4), it was 2.5 times more effective than PEI 25 and 10 times better than DOTAP, known efficient polymeric and liposomal transfection agents. Formulation of amphiphiles with DOPE did not change their activities. Our data demonstrate some important effects of amphiphile structure on biophysics and activity. The data also suggest that cationic amphiphilic 1,4-DHP derivatives may find use as DNA delivery system.
authors: Department of Pharmaceutics, University of Kuopio, Finland.
authors: Z
authors: Z
authors: Hyvönen
authors: A
authors: A
authors: Plotniece
authors: I
authors: I
authors: Reine
authors: B
authors: B
authors: Chekavichus
authors: G
authors: G
authors: Duburs
authors: A
authors: A
authors: Urtti
mesh_terms: D000818:Animals; D002021:Buffers; D002412:Cations; D002460:Cell Line; D004247:DNA / Q000737:chemistry*; D004095:Dihydropyridines / Q000737:chemistry*; D015195:Drug Design; D004587:Electrophoresis, Agar Gel; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D005696:Galactosidases / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D020404:Glycerophospholipids / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D015394:Molecular Structure; D010316:Particle Size; D010714:Phosphatidylethanolamines; D010957:Plasmids; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000138:chemical synthesis* / Q000145:classification / Q000633:toxicity; D014162:Transfection
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D002021:Buffers; D002412:Cations; D004095:Dihydropyridines; D005229:Fatty Acids, Monounsaturated; D020404:Glycerophospholipids; D008081:Liposomes; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents; C038806:1,4-dihydropyridine; D004247:DNA; D005696:Galactosidases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane