title: LipoCardium: endothelium-directed cyclopentenone prostaglandin-based liposome formulation that completely reverses atherosclerotic lesions.
abstract: Atherosclerosis is a multifactorial inflammatory disease of blood vessels which decimates one in every three people in industrialized world. Despite the important newest clinical approaches, currently available strategies (e.g. nutritional, pharmacological and surgical) may only restrain the worsening of vascular disease. Since antiproliferative cyclopentenone prostaglandins (CP-PGs) are powerful anti-inflammatory agents, we developed a negatively charged liposome-based pharmaceutical formulation (LipoCardium) that specifically direct CP-PGs towards the injured arterial wall cells of atherosclerotic mice. In the blood stream, LipoCardium delivers its CP-PG contents only into activated arterial wall lining cells due to the presence of antibodies raised against vascular cell adhesion molecule-1 (VCAM-1), which is strongly expressed upon inflammation by endothelial cells and macrophage-foam cells as well. After 4 months in a high-lipid diet, all low-density lipoprotein receptor-deficient adult control mice died from myocardium infarction or stroke in less than 2 weeks, whereas LipoCardium-treated (2 weeks) animals (still under high-lipid diet) completely recovered from vascular injuries. In vitro studies using macrophage-foam cells suggested a tetravalent pattern for LipoCardium action: anti-inflammatory, antiproliferative (and pro-apoptotic only to foam cells), antilipogenic and cytoprotector (via heat-shock protein induction). These astonishing cellular effects were accompanied by a marked reduction in arterial wall thickness, neointimal hyperplasia and lipid accumulation, while guaranteed lifespan to be extended to the elderly age. Our findings suggest that LipoCardium may be safely tested in humans in a near future and may have conceptual implications in atherosclerosis therapy.
authors.affiliation: Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, Porto Alegre, RS, Brazil. pauloivo@ufrgs.br
authors.forename: Paulo I
authors.initials: PI
authors.lastname: Homem de Bittencourt
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Lagranha
authors.forename: Alexandre
authors.initials: A
authors.lastname: Maslinkiewicz
authors.forename: Sueli M
authors.initials: SM
authors.lastname: Senna
authors.forename: Angela M V
authors.initials: AM
authors.lastname: Tavares
authors.forename: Lisiane P
authors.initials: LP
authors.lastname: Baldissera
authors.forename: Daiane R
authors.initials: DR
authors.lastname: Janner
authors.forename: Joelso S
authors.initials: JS
authors.lastname: Peralta
authors.forename: Patrícia M
authors.initials: PM
authors.lastname: Bock
authors.forename: Lucila L P
authors.initials: LL
authors.lastname: Gutierrez
authors.forename: Gustavo
authors.initials: G
authors.lastname: Scola
authors.forename: Thiago G
authors.initials: TG
authors.lastname: Heck
authors.forename: Maurício S
authors.initials: MS
authors.lastname: Krause
authors.forename: Lavínia A
authors.initials: LA
authors.lastname: Cruz
authors.forename: Dulcinéia S P
authors.initials: DS
authors.lastname: Abdalla
authors.forename: Cláudia J
authors.initials: CJ
authors.lastname: Lagranha
authors.forename: Thais
authors.initials: T
authors.lastname: Lima
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000503:physiopathology; D003517:Cyclopentanes / Q000494:pharmacology; D004195:Disease Models, Animal; D005240:Feasibility Studies; D050356:Lipid Metabolism / Q000187:drug effects*; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D011453:Prostaglandins / Q000494:pharmacology* / Q000627:therapeutic use*; D011454:Prostaglandins A / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003517:Cyclopentanes; D008081:Liposomes; D011453:Prostaglandins; D011454:Prostaglandins A; C100008:prostaglandin A2