Exploiting Membrane Lipidation for Advanced Drug Delivery

A fundamental concept in medicinal chemistry is the ability of a drug to cross the blood brain barrier. The blood brain barrier is a layer of cells that restricts the ability of molecules to pass from the blood stream into the nervous system. Some molecules, such as nutrients, are able to cross the blood brain barrier selectively through the use of specific transporters. Other molecules, such as drugs, must cross the blood brain barrier non-selectively by virtue of their molecular properties. Conventionally, molecules that are more hydrophobic (fat soluble) cross the barrier more easily. However, if molecules are too hydrophobic they are insoluble in water. This tension between ability to cross the blood brain barrier and solubility leads to a parabolic relationship between drug hydrophobicity and activity. In simple terms, as hydrophobicity increases, up to an optimal value, the activity increases due to more facile partitioning across the blood brain barrier. As hydrophobicity increases above the optimal value, aqueous solubility becomes a limiting factor and the activity decreases.

The primary goal of this project is to furnish a new method for drug delivery that exploits the inherent reactivity of molecules with lipids in cell membranes. Highly soluble (low hydrophobicity) compounds will be transformed into hydrophobic derivatives only upon reaching their target cell membranes, such as the membranes of cells in the blood brain barrier. Once across the barrier, the hydrophobic derivatives will be converted back to soluble compounds inside the cell. This approach will specifically enable highly polar compounds to traverse the blood brain barrier and disrupt the parabolic relationship between hydrophobicity and drug activity. Our approach has the potential to enable the development of drugs with high target selectivity at sites that would previously have been considered difficult or impossible to reach.