Highly packed polycationic ammonium, sulfonium and phosphonium lipids

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel, highly packed polycationic ammonium, sulfonium and phosphonium lipid compounds having unique properties and advantages not heretofore available to the liposome art.
The compounds can be used alone or in combination with other compounds (e.
g.
, DOPE, DOTMA and DOSPA) to prepare liposomes and other lipid aggregates suitable for transfection or delivery of compounds other than DNA to target cells, either in vitro or in vivo.
The novel compounds of general formula (I) are polycationic and thus form highly stable complexes with various anionic macromolecules, particularly polyanions such as nucleic acids.
These compounds have the property, when dispersed in water, of forming lipid aggregates which associate strongly, via their cationic portions, with polyanions, compacting and encapsulating the latter within a lipid layer.
By using an excess of cationic charges relative to the anionic compound, the polyanion-lipid complexes may be adsorbed on cell membranes, thereby facilitating uptake of the desired compound by the cells.
The cationic lipids disclosed herein offer three unique advantages over prior art compounds.
First, the compounds of general formula (I) represent novel liposomal precursors wherein the polycationic binding regions are optimally spaced, preferably equidistance between charges, to provide proper alignment with the anionic phosphates of nucleic acids.
Proper alignment of charges increases the binding constant of the lipid to nucleic acid via cooperative interaction.
This increased affinity produces a more stable liposome, which in turn increases the efficiency of delivery.
Thus, lower concentrations of these agents are required to encapsulate the molecules and bind to the target cells, thereby maximizing efficiency of delivery while minimizing cell toxicity.
The second unique advantage of the compounds disclosed herein is their unusually high affinity for the lipid bilayer of cell membranes.
Unlike the mono-substituted lipopolyamine compounds currently in use, the compounds of the invention comprise lipidic substituents at each cationic binding region