Hyaluronan-modified and regular multilamellar liposomes provide sub-cellular targeting to macrophages, without eliciting a pro-inflammatory response.
Macrophages, pivotal cells in onset and progression of inflammation, can benefit from sub-cellular drug targeting to the molecular loci of drug action, whether cell membrane or cell interior. Postulating manipulation of liposome size and surface properties can provide sub-cellular targeting, we studied: thermodynamics of liposome-macrophage binding; liposome cellular localizations; liposome safety including pro-inflammatory cytokine production. We aimed at extending the body of knowledge on interactions of regular unilamellar (RL-ULV) and multilamellar (RL-MLV) liposomes with macrophages. We investigated, for the first time, the interactions of hyaluronan (HA) surface-modified liposomes (HA-ULV and HA-MLV) with macrophages, with respect to multiple equilibria binding combined with cellular localization. Macrophages bound all four liposome types, substantially-favoring the two MLV species over the two ULV species, and internalizing only RL-MLV. Three macrophage-internalization inhibitors (2-deoxyglucose, LY294002 and Wortmannin) reduced RL-MLV internalization but not binding affinity nor binding capacity. Both MLV types were not detrimental to cell proliferation, nor did they elicit TNF-α production in resting and in LPS-activated macrophages. Moreover, a 24-hour exposure of LPS-activated macrophages to HA-MLV reduced TNF-α production by 40%, indicating potential for anti-inflammatory activity. In conclusion RL-MLV and HA-MLV are the liposomes of choice for delivering anti-inflammatory drugs to the macrophage surface or its interior, according to the loci of drug action.
Department of Biochemistry and Molecular Biology, the George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Yifat
Y
Glucksam-Galnoy
Tsaffrir
T
Zor
Rimona
R
Margalit
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D016207:Cytokines / Q000276:immunology*; D004337:Drug Carriers / Q000737:chemistry*; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D006820:Hyaluronic Acid / Q000737:chemistry*; D042541:Intracellular Space / Q000187:drug effects* / Q000276:immunology; D008081:Liposomes; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D018613:Microscopy, Confocal; D010316:Particle Size; D013499:Surface Properties
C476399:Cd44 protein, mouse; D016207:Cytokines; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D008081:Liposomes; D006820:Hyaluronic Acid