Selective protein interactions with phosphatidylserine containing liposomes alter the steric stabilization properties of poly(ethylene glycol).
Incorporation of 5 mol% poly(ethylene glycol)-conjugated lipids (PEG-lipids) has been shown to extend the circulation longevity of neutral liposomes due to steric repulsion of PEG at the membrane surface. The effects of PEG-lipids on protein interactions with biologically reactive membranes were examined using phosphatidylserine (PS) containing liposomes as the model. Incorporating 15 mol% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEG 2000 into PS liposomes resulted in circulation lifetimes comparable to that obtained with neutral liposomes containing 5 mol% DSPE-PEG 2000. These results suggested that 15 mol% DSPE-PEG 2000 may be effective in protecting PS liposomes from the high affinity, PS-mediated binding of plasma proteins. This was determined by monitoring the effects of PEG-lipids on calcium-mediated blood coagulation protein interactions with PS liposomes. Prothrombin binding and procoagulant activity of PS liposomes could be inhibited >80% when 15 mol% DSPE-PEG 2000 was used. These results are consistent with PS on membrane surfaces forming transient nucleation sites for protein binding that may result in lateral exclusion of PEG-lipids incorporated at <10 mol%. These nucleation sites may be inaccessible when PEG-lipids are present at elevated levels where they adopt a highly compressed brush conformation. This suggests that liposomes with reactive groups and PEG-lipids may be appropriately designed to impart selectivity to protein interactions with membrane surfaces.
Chiu
G N
GN
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Bally
M B
MB
Mayer
L D
LD
D000818:Animals; D001779:Blood Coagulation Factors / Q000737:chemistry; D002850:Chromatography, Gel; D004337:Drug Carriers; D015195:Drug Design; D004355:Drug Stability; D005260:Female; D007275:Injections, Intravenous; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008956:Models, Chemical; D010718:Phosphatidylserines / Q000737:chemistry* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D011516:Prothrombin / Q000737:chemistry; D011517:Prothrombin Time; D013499:Surface Properties
D001779:Blood Coagulation Factors; D004337:Drug Carriers; D008081:Liposomes; D010718:Phosphatidylserines; D011506:Proteins; D011092:Polyethylene Glycols; D011516:Prothrombin