Structure-transfection activity relationships in a series of novel cationic lipids with heterocyclic head-groups.
Cationic liposomes are promising candidates for the delivery of various therapeutic nucleic acids. Here, we report a convenient synthesis of carbamate-type cationic lipids with various hydrophobic domains (tetradecanol, dialkylglycerol, cholesterol) and positively charged head-groups (pyridinium, N-methylimidazolium, N-methylmorpholinium) and data on the structure-transfection activity relationships. It was found that single-chain lipids possess high surface activity, which correlates with high cytotoxicity due to their ability to disrupt the cellular membrane by combined hydrophobic and electrostatic interactions. Liposomes containing these lipids also display high cytotoxicity with respect to all cell lines. Irrespective of chemical structures, all cationic lipids form liposomes with similar sizes and surface potentials. The characteristics of complexes composed of cationic liposomes and nucleic acids depend mostly on the type of nucleic acid and P/N ratios. In the case of oligodeoxyribonucleotide delivery, the transfection activity depends on the type of cationic head-group regardless of the type of hydrophobic domain: all types of cationic liposomes mediate efficient oligonucleotide transfer into 80-90% of the eukaryotic cells, and liposomes based on lipids with N-methylmorpholinium cationic head-group display the highest transfection activity. In the case of plasmid DNA and siRNA, the type of hydrophobic domain determines the transfection activity: liposomes composed of cholesterol-based lipids were the most efficient in DNA transfer, while liposomes containing glycerol-based lipids exhibited reasonable activity in siRNA delivery under serum-free conditions.
M. V. Lomonosov Moscow State University of Fine Chemical Technology, 86 Vernadskiy ave., Moscow, Russian Federation. mamaslov@mail.ru.
Ekaterina A
EA
Ivanova
Mikhail A
MA
Maslov
Tatyana O
TO
Kabilova
Pavel A
PA
Puchkov
Anna S
AS
Alekseeva
Ivan A
IA
Boldyrev
Valentin V
VV
Vlassov
Galina A
GA
Serebrennikova
Nina G
NG
Morozova
Marina A
MA
Zenkova
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry; D002412:Cations / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D010957:Plasmids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D000970:Antineoplastic Agents; D002219:Carbamates; D002412:Cations; D004337:Drug Carriers; D006571:Heterocyclic Compounds; D008055:Lipids; D008081:Liposomes; D020319:Oligodeoxyribonucleotides, Antisense; D034741:RNA, Small Interfering; D004247:DNA