title: Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice.
abstract: This study sought to determine whether angiogenic blood vessels in disease models preferentially bind and internalize cationic liposomes injected intravenously. Angiogenesis was examined in pancreatic islet cell tumors of RIP-Tag2 transgenic mice and chronic airway inflammation in Mycoplasma pulmonis-infected C3H/HeNCr mice. For comparison, physiological angiogenesis was examined in normal mouse ovaries. We found that endothelial cells in all models avidly bound and internalized fluorescently labeled cationic liposomes (1,2-dioleoyl-3-trimethylammonium-propane [DOTAP]/cholesterol or dimethyldioctadecyl ammonium bromide [DDAB]/cholesterol) or liposome-DNA complexes. Confocal microscopic measurements showed that angiogenic endothelial cells averaged 15-33-fold more uptake than corresponding normal endothelial cells. Cationic liposome-DNA complexes were also avidly taken up, but anionic, neutral, or sterically stabilized neutral liposomes were not. Electron microscopic analysis showed that 32% of gold-labeled liposomes associated with tumor endothelial cells were adherent to the luminal surface, 53% were internalized into endosomes and multivesicular bodies, and 15% were extravascular 20 min after injection. Our findings indicate that angiogenic endothelial cells in these models avidly bind and internalize cationic liposomes and liposome-DNA complexes but not other types of liposomes. This preferential uptake raises the possibility of using cationic liposomes to target diagnostic or therapeutic agents selectively to angiogenic blood vessels in tumors and sites of chronic inflammation.
authors.affiliation: Department of Anatomy and Cardiovascular Research Institute, University of California, San Francisco, California 94143, USA. gavint@itsa.ucsf.edu
authors.forename: G
authors.initials: G
authors.lastname: Thurston
authors.forename: J W
authors.initials: JW
authors.lastname: McLean
authors.forename: M
authors.initials: M
authors.lastname: Rizen
authors.forename: P
authors.initials: P
authors.lastname: Baluk
authors.forename: A
authors.initials: A
authors.lastname: Haskell
authors.forename: T J
authors.initials: TJ
authors.lastname: Murphy
authors.forename: D
authors.initials: D
authors.lastname: Hanahan
authors.forename: D M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D001692:Biological Transport; D002412:Cations; D002451:Cell Compartmentation; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000503:physiopathology*; D007515:Islets of Langerhans / Q000098:blood supply; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic; D010053:Ovary / Q000098:blood supply; D010179:Pancreas / Q000098:blood supply; D011019:Pneumonia, Mycoplasma / Q000473:pathology; D014132:Trachea / Q000098:blood supply
chemical_list: D002412:Cations; D008081:Liposomes