title: Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death.
abstract: Partial inactivation and transient depletion of monocytes/macrophages by liposomal bisphosphonates (LIP-BPs) is widely experimented in various inflammatory disorders including restenosis. Previous studies on activation of cytokines by LIP-BPs are limited to certain cell lines. Moreover, the correlation between in vitro and in vivo studies and complement (C) activation has not been reported. We report here a comprehensive study on the bioactivity of LIP-BPs on various cells' internalization and proliferation, mechanism of cell death, cytokines (in vitro and in vivo) and C activation (in the rat, rabbit and pig). The role of the following parameters has been determined i) drug type (clodronate/alendronate); ii) vesicles size (60-800nm); iii) charge (neutral/negative/ positive); and iv) cell culture type (various cell lines and primary cultures). It was found that monocyte/macrophage inhibition and cytokine activation depend on the cell type, with a limited correlation to the bioactivity obtained in the rat and rabbit models of restenosis. Negatively charged liposomes (85+/-20nm) effectively depleted rabbit's monocytes (67% depletion), with a minor activation of cytokines and no C activation. It is concluded that cell culture studies are insufficient for assessing cytokine activation, and that by controlling LIP-BP properties (size, charge and drug type) optimal bioactivity could be achieved.
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Epstein-Barash
authors.forename: Dikla
authors.initials: D
authors.lastname: Gutman
authors.forename: Ela
authors.initials: E
authors.lastname: Markovsky
authors.forename: Galit
authors.initials: G
authors.lastname: Mishan-Eisenberg
authors.forename: Nickolay
authors.initials: N
authors.lastname: Koroukhov
authors.forename: Janos
authors.initials: J
authors.lastname: Szebeni
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects*; D023903:Coronary Restenosis / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004164:Diphosphonates / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000276:immunology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D011817:Rabbits; D051381:Rats
chemical_list: D016207:Cytokines; D004164:Diphosphonates; D008081:Liposomes