Structure and interfacial aspects of self-assembled cationic lipid-DNA gene carrier complexes

Cationic lipid-DNA (CL-DNA) complexes were recently found to exhibit a novel multilamellar structure composed of alternating lipid bilayer and DNA monolayer with distinct interhelical DNA spacings (Radler et al. Science 1997, 275, 810). We report on the aggregation behavior, morphology, and interfacial properties related to the solution structure of DOPC/DOTAP-DNA complexes. Using optical microscopy and synchrotron X-ray diffraction, we found two discrete regimes for the complex size and surface charge as a function of the lipid-to-DNA mass ratio. The regimes correspond to the coexistence of complexes with either excess DNA or excess liposomes, characterized by a negative and positive surface potential of the complexes, respectively. The internal structure in these cases exhibited different but constant DNA packing distances of 35 and 46 Angstrom, respectively. The regimes are separated by a transition region around the isoelectric point, where the number of cationic lipids equals the number of DNA phosphate groups. At the isoelectric point the average complex size diverged and the DNA packing spacing is described by a simple volume fraction calculation. The complex formation occurred on three time scales: rapid condensation, a slower colloidal aggregation, and finally, a long term reorganization or compaction. Complexes with positive surface charge were shown to adhere to negatively charged giant liposomes.