Lipitoids--novel cationic lipids for cellular delivery of plasmid DNA in vitro.
BACKGROUND
Although synthetic nonviral vectors hold promise for the delivery of plasmid DNA, their gene-transfer efficiencies are far from matching those of viruses. To systematically investigate the structure-activity relationship of cationic lipids, a small library of cationic lipid-peptoid conjugates (lipitoids) was synthesized. The compounds were evaluated for their ability to form complexes with plasmid DNA and to mediate DNA transfer in vitro.


RESULTS
Lipid-peptoid conjugates were conveniently prepared in high yield using solid-phase synthesis. Several lipitoids condensed plasmid DNA into 100 nm spherical particles and protected the DNA and DNase digestion. A subset of lipitoids with a repeated (aminoethyl, neutral, neutral) sidechain trimer motif conjugated with dimyristoyl phosphatidyl-ethanolamine (DMPE) mediated DNA transfer with high efficiency.


CONCLUSIONS
Automated solid-phase synthesis of cationic lipids allowed the rapid synthesis of a diverse set of transfection reagents. The most active compound DMPE-(Nae-Nmpe-Nmpe)3 (Nae, N-aminoethyl glycine; Nmpe, N-p-methoxyphenethyl-glycine) is more efficient than lipofectin or DMRIE-C (two commercial cationic lipid transfection reagents) and is active in the presence and absence of serum. The activity in the presence of serum suggests potential for applications in vivo.
Huang
C Y
CY
Chiron Technologies, Chiron Corporation, Emeryville, CA 94608, USA.
Uno
T
T
Murphy
J E
JE
Lee
S
S
Hamer
J D
JD
Escobedo
J A
JA
Cohen
F E
FE
Radhakrishnan
R
R
Dwarki
V
V
Zuckermann
R N
RN
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002412:Cations / Q000138:chemical synthesis / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D003850:Deoxyribonuclease I / Q000378:metabolism; D004337:Drug Carriers / Q000138:chemical synthesis / Q000633:toxicity; D004587:Electrophoresis, Agar Gel; D005354:Fibrosarcoma; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008854:Microscopy, Electron; D010316:Particle Size; D034444:Peptoids; D010743:Phospholipids / Q000138:chemical synthesis* / Q000633:toxicity; D010957:Plasmids / Q000187:drug effects / Q000378:metabolism*; D013499:Surface Properties; D014162:Transfection / Q000379:methods
D002412:Cations; D004337:Drug Carriers; D046911:Macromolecular Substances; D034444:Peptoids; D010743:Phospholipids; D004247:DNA; D003850:Deoxyribonuclease I