Abstract
Background:
Synthetic cationic lipids hold much potential as gene packaging and delivery agents for the treatment of inherited and acquired life threatening diseases, such as cancer, AIDS, cardiovascular diseases, and certain autoimmune disorders.
Methods:
We report the synthesis, self-assembly as characterized by critical micelle concentrations and plasmid DNA gel retardation using two novel cyclic, phosphonate cationic lipids
2a
and
2b
, which were synthesized by derivatizing two diastereomeric macrocyclic phosphonates
1a
and
1b
with a 2-carbon hydroxylamine linker,
N
,
N
-dimethylethanolamine (
3
).
Results:
The production of cyclic phosphonate lipids
2a
and
2b
in 73% and 60% yields, respectively, was achieved using classical synthetic methods involving nucleophilic substitution at the phosphorus centre. The characterization of these lipids with Mass Spectrometry,
1
H,
13
C and
31
P Nuclear Magnetic Resonance supported the proposed stereochemistry and molecular structure of C
17
H
36
NO
3
P for these lipids. Critical micelle concentrations (CMC) for
2a
and
2b
were found to be 1.2 mM and 1.4 mM, respectively, at 25°C, providing evidence for the self-assembling ability of these novel cyclic lipids. Finally, lipid-DNA complexes (lipoplexes) formulated at various N/P (+/ − ) molar charge ratios and containing the co-lipid, 1,2-dioleoyl-
sn
-glycero-3-phosphoethanolamine (DOPE) were shown to retard DNA in an agarose gel retardation assay.
Conclusions:
The synthesis, aggregation and DNA binding properties of these novel cyclic phosphonate lipids suggest that they may have utility serving as gene packaging and delivery agents.