PEG vs. zwitterions: How these surface decorations determine cellular uptake of lipid-based nanocarriers

Aim: To evaluate the impact of polyethylene glycol (PEG) and zwitterionic surface decoration of lipid-based nanocarriers (NC) on cellular uptake.Methods: Anionic, neutral and cationic zwitterionic lipid-based NCs based on lecithin were compared with conventional PEGylated lipid-based NCs regarding stability in biorelevant fluids, interaction with endosome mimicking membranes, cytocompatibility, cellular uptake and permeation across intestinal mucosa.Results: PEGylated and zwitterionic lipid-based NCs exhibited a droplet size between 100 and 125 nm with a narrow size distribution. For the PEGylated and zwitterionic lipid-based NCs only minor alterations in size and PDI in fasted state intestinal fluid and mucus containing buffer were observed, demonstrating similar bioinert properties. Erythrocytes interaction studies revealed enhanced endosomal escape properties for zwitterionic lipid-based NCs compared to PEGylated lipid-based NCs. For the zwitterionic lipid-based NCs negligible cytotoxicity on Caco-2 and HEK cells, even in the highest tested concentration of 1 % (v/v) was recorded. The PEGylated lipid-based NCs showed a cell survival of >= 75 % for concentrations <= 0.05 % on Caco-2 and HEK cells, which was considered as non-toxic. For the zwitterionic lipid-based NCs up to 60-fold higher cellular uptake on Caco-2 cells was determined compared to PEGylated lipid-based NCs. For the cationic zwitterionic lipid-based NCs the highest cellular uptake with 58.5 % and 40.0 % in Caco-2 and HEK cells, respectively, was deter-mined. The results were confirmed visually by life cell imaging. Ex-vivo permeation experiments using rat in-testinal mucosa demonstrated up to 8.6-fold enhanced permeation of the lipophilic marker coumarin-6 in zwitterionic lipid-based NCs compared to the control. Up to 6.9-fold enhanced permeation of coumarin-6 in neutral zwitterionic lipid-based NCs compared to the PEGylated counterpart was recorded.Conclusion: The replacement of PEG surfactants with zwitterionic surfactants is a promising approach to over-come the drawbacks of conventional PEGylated lipid-based NCs regarding intracellular drug delivery.