Stretching the limits of membrane charge density using Dendrimer Lipids - New Highly Transfecting Hexagonal Phases for Gene Delivery

Newly designed multivalent lipids ranging in head group charge from 4+ to 16+ have been synthesized and investigated as DNA delivery vectors. These dendritic lipids (DLs) allow a controlled study of the relationship between membrane charge density ($\sigma )$ and transfection efficiency (TE). An earlier report from our group described that TE of different cationic lipids of charge 1+ to 5+ follows a common, bell shaped curve as a function of membrane charge density [1]. To further probe this universal behavior, the dendritic lipids with higher valence were designed in order to reach higher values of $\sigma $. Structural studies using x-ray diffraction reveal new phases, where cylindrical micelles of DLs form a hexagonal lattice which holds together a continuous DNA network, described as H$_{I}^{C}$ [2]. The new hexagonal phase is highly transfecting in the regime where the TE of lamellar complexes follows a decrease in the bell curve. Small angle x-ray scattering studies have revealed a rich phase diagram of micelles made from DL/DOPC mixtures. Funding provided by NIH GM-59288 and NSF DMR-0503347. [1] A. Ahmad et al., \textit{J. Gene Med., }2005, V7:739-748. [2] K. Ewert et al., \textit{J. Am. Chem. Soc., (submitted).}