Influence of Drugs Carried in Lipid Nanoparticles in Coronary Disease of Rabbit Transplanted Heart

• Published in: The Annals of thoracic surgery Vol. 104; no. 2; pp. 577 - 583
• Main Authors: Barbieri, Lucas R., MD, Lourenço-Filho, Domingos D., MD, PhD, Tavares, Elaine R., PhD, Carvalho, Priscila O., PhD, Gutierrez, Paulo S., MD, PhD, Maranhão, Raul C., MD, PhD, Stolf, Noedir A.G., MD, PhD
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-08-2017
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Cardiothoracic Surgery; Coronary Artery Disease - drug therapy; Coronary Artery Disease - etiology; Cytokines - biosynthesis; Cytokines - genetics; Disease Models, Animal; Drug Carriers; Gene Expression Regulation; Graft Rejection - genetics; Graft Rejection - metabolism; Graft Rejection - prevention & control; Graft Survival - drug effects; Heart Transplantation - adverse effects; Immunohistochemistry; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Injections, Intravenous; Methotrexate - administration & dosage; Methotrexate - pharmacokinetics; Myocardium - metabolism; Nanoparticles - administration & dosage; Paclitaxel - administration & dosage; Paclitaxel - pharmacokinetics; Rabbits; Real-Time Polymerase Chain Reaction; RNA - genetics; Surgery
• ISSN: 0003-4975; 1552-6259
• DOI: 10.1016/j.athoracsur.2016.12.044

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.