Figure 1.

Schematic representation of the concept of the lipase-cleavable Sn 2 phosphatidylcholine docetaxel prodrug: The lipophilic docetaxel prodrug is incorporated into the phospholipid surfactant, where the drug enters the protective hydrophobic acyl layer. The active pharmaceutical ingredient (API) is protected from premature dissolution into serum or serum lipase liberation during circulation to the target. The API is delivered to the target cell through a “contact facilitated drug delivery” (CFDD) mechanism wherein the prodrug exchanges passively into the outer target cell leaflet. The prodrug transfers through an ATP dependent mechanism into the inner cell membrane leaflet, which is contiguous with the internal cell membranes (except the mitochondria). The prodrug undergoes a region-selective enzymatic cleavage at the Sn 2 site by phospholipases, such as phospholipase A-2 (PLA-2), but up to 60 endothelial lipases could functionally participate in drug liberation into the cytosol.