Pyridinium cationic lipids in gene delivery: a structure-activity correlation study.
Three series of pyridinium cationic lipids useful as nonviral gene delivery agents were prepared by reaction of pyrylium salts with aminodiols, followed by acylation with fatty acyl chlorides. On the basis of this set of compounds, we undertook a comprehensive structure-activity relationship study at the level of the linker, hydrophobic anchor, and counterion in order to identify the structural elements that generate the highest transfection efficiency for this new type of cationic lipid. The results revealed that when formulated with cholesterol at a 1:1 molar ratio, the 1-(1,3-dimyristoyloxyprop-2-yl)-2,4,6-trimethylpyridinium, under the form of hexafluorophosphate (5AMyr) or chloride (5DMyr), was able to transfect NCI-H23 lung carcinoma with efficiencies surpassing classic DOTAP-based formulations and with lower cytotoxicity. Subsequent tests on other malignancies yielded similarly promising results.
Ilies
Marc Antoniu
MA
Department of Marine Sciences, Texas A & M University at Galveston, 5007 Avenue U, Galveston, TX 77551, USA.
Seitz
William A
WA
Ghiviriga
Ion
I
Johnson
Betty H
BH
Miller
Aaron
A
Thompson
E Brad
EB
Balaban
Alexandru T
AT
D002412:Cations; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry; D004075:Diglycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D018014:Gene Transfer Techniques; D006801:Humans; D008055:Lipids / Q000138:chemical synthesis* / Q000737:chemistry; D008081:Liposomes; D015394:Molecular Structure; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship; D014162:Transfection; D014465:Ultrasonics
C488440:1-(1,3-dimyristoyloxypropane-2-yl)-2,4,6-trimethylpyridinium; D002412:Cations; D004075:Diglycerides; D004337:Drug Carriers; D008055:Lipids; D008081:Liposomes; D011726:Pyridinium Compounds; D004247:DNA; D002784:Cholesterol