Targeting antibodies dissociate from drug delivery liposomes during blood circulation.

Despite three decades of intense research, active targeting of liposomes have not been successfully achieved in a clinical setting. A potential explanation is that the clinically used liposomes lose their targeting abilities upon circulation. Here, we investigated if DSPE-PEG anchored antibody-based targeting ligands dissociate from clinically relevant drug delivery liposomes during circulation in mice. We found that during 4 h of circulation, a significant fraction of the liposomes lose all targeting ligands, while the liposomes with some targeting ligands remaining on their surface, show a > 50 % reduction in surface density of ligands. This was detected irrespective of antibody format (IgG, Fab, F(ab')2), ability to interact with Fc receptors or linking chemistry. Dissociation of targeting antibodies did however not take place when incubating liposomes in serum, but required an in vivo setup, demonstrating that in vitro setups are unsuitable for quantifying such liposome disassembly processes. The observation unravels a problem that researchers developing targeted drug delivery vehicles should take into account when designing novel formulations.