Guanidine-based molecular transporters for drug delivery

One way to solve problems with drugs that have formulation issues along with poor penetration of biological barriers is to couple them to molecules that do not rely on passive diffusion to move into cells and tissues. It has recently been discovered that certain classes of polar peptides efficiently penetrate through the cell membranes. Furthermore, it has been shown that these peptides, when conjugated to therapeutics, enable the penetration of the therapeutics through membranes that would otherwise limit uptake. In particular, the highly basic domain of the HIV-1 TAT protein has been shown to rapidly enter cells in an energy dependent fashion through a mechanism that is to date poorly understood. Researchers at the Stanford Medical Center discovered that the highly basic arginine residues appear to be responsible for the ability of the short oligopeptide to cross the cell membrane. Furthermore, it has been demonstrated that short homooligomers of arginine cross the cell membrane much more rapidly than the parent TAT sequence. This thesis outlines some of our work to apply this discovery to the delivery of potent therapeutics into a biological setting.