title: Influence of Drugs Carried in Lipid Nanoparticles in Coronary Disease of Rabbit Transplanted Heart.
abstract: BACKGROUND
  Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and currently has no effective prevention and treatment. Lipid nanoparticles, termed LDE can carry chemotherapeutic agents in the circulation and concentrates them in the heart.
  
  
  METHODS
  Twenty-eight rabbits fed a cholesterol-rich diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg/kg daily) and allocated to four groups of 7 animals treated with intravenous LDE-methotrexate (MTX; 4 mg/kg weekly), with LDE-paclitaxel (PACLI; 4 mg/kg weekly), or with LDE-PACLI (4 mg/kg weekly) and LDE-MTX (4 mg/kg weekly). A control group was treated with only weekly intravenous saline solution. Animals were euthanized 6 weeks later for morphometric, histologic, immunohistochemical, and gene expression analysis of the graft and native hearts.
  
  
  RESULTS
  Compared with controls, grafts of rabbits treated with LDE-PACLI showed 50% reduction of coronary stenosis, and in the LDE-MTX and LDE-MTX/PACLI stenosis was approximately 18% less than in control, but this difference was not statistically significant. In the three treatment groups, macrophage infiltration was decreased. In the LDE-MTX group, gene expression of proinflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein 1, interleukin 18, vascular cellular adhesion molecule 1, and matrix metalloproteinase 12 was strongly diminished, whereas expression of antiinflammatory interleukin 10 increased. In the LDE-PACLI and LDE-PACLI/MTX groups, proinflammatory and antiinflammatory gene expressions were not consistently changed by the treatments.
  
  
  CONCLUSIONS
  LDE-PACLI promoted strong improvement of cardiac allograft vasculopathy, but the decrease in coronary stenosis by LDE-MTX and LDE-MTX/PACLI was not significant. All three treatments decreased macrophage infiltration in the graft. These results may encourage future clinical trials to test this new therapeutic approach to coronary allograft vasculopathy.
authors.affiliation: Department of Cardiovascular Surgery, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil; Lipid Metabolism Laboratory, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil. Electronic address: drlucasbarbieri@gmail.com.
authors.forename: Lucas R
authors.initials: LR
authors.lastname: Barbieri
authors.affiliation: Department of Cardiovascular Surgery, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil; Lipid Metabolism Laboratory, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil.
authors.forename: Domingos D
authors.initials: DD
authors.lastname: Lourenço-Filho
authors.affiliation: Lipid Metabolism Laboratory, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Tavares
authors.affiliation: Lipid Metabolism Laboratory, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil.
authors.forename: Priscila O
authors.initials: PO
authors.lastname: Carvalho
authors.affiliation: Laboratory of Pathology, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil.
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Gutierrez
authors.affiliation: Lipid Metabolism Laboratory, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil; Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Raul C
authors.initials: RC
authors.lastname: Maranhão
authors.affiliation: Department of Cardiovascular Surgery, The Heart Institute, University of São Paulo Medical Hospital, São Paulo, São Paulo, Brazil.
authors.forename: Noedir A G
authors.initials: NAG
authors.lastname: Stolf
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000209:etiology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004337:Drug Carriers; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009206:Myocardium / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012313:RNA / Q000235:genetics; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D004337:Drug Carriers; D007166:Immunosuppressive Agents; D012313:RNA; D017239:Paclitaxel; D008727:Methotrexate