Insights in the chemical components of liposomes responsible for P-glycoprotein inhibition

In this work we investigated how the surface charge and the presence of polyethylene glycol (PEG) on liposome carriers affect the delivery of the encapsulated doxorubicin in P-glycoprotein (Pgp)-overexpressing cells. We found that neutral net charge was critical to favour the liposome uptake and decrease the Vmax of doxorubicin efflux. PEG-coating was necessary to increase the Km of doxorubicin for Pgp. In particular the PEGylated phospholipid present in neutral liposomes, i.e. PEGylated distearoyl-phosphatidylethanolamine (DSPE-PEG), was a Pgp allosteric inhibitor, increased doxorubicin Km and inhibited Pgp ATPase activity. Site-directed mutagenesis experiments suggested that the domain centred around glycine 185 of Pgp was necessary for these inhibitory properties of DSPE-PEG and PEGylated neutral liposomes. We conclude that both surface charge and PEGylation must be considered to optimize the doxorubicin delivery within chemoresistant cells. DSPE-PEG-enriched particles may represent promising tools for therapeutic and diagnostic applications in tissues with high levels of Pgp.From the Clinical EditorThese authors investigated how surface charge and PEGylation of liposome carriers affect the delivery of encapsulated doxorubicin to Pgp-overexpressing cells, concluding that both factors need to be considered in order to optimize doxorubicin delivery to chemoresistant cells.

Graphical AbstractNeutral surface charge and PEGylation are critical features to optimize the uptake of liposomal doxorubicin and prevent its efflux by P-glycoprotein (Pgp). The presence of PEGylated phospholipids, i.e. PEGylated distearoyl-phosphatidylethanolammine (DSPE-PEG), in the liposomal formulation plays a crucial role, due to the interaction of DSPE-PEG with the Pgp drug-releasing site containing glycine 185. This interaction allosterically inhibits Pgp and increases the doxorubicin retention in drug-resistant cells.Figure optionsDownload high-quality image (169 K)Download as PowerPoint slide