Methotrexate associated to lipid core nanoparticles improves cardiac allograft vasculopathy and the inflammatory profile in a rabbit heart graft model

Abstract

Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and has no effective treatment. A lipid nanoemulsion (LDE) can carry chemotherapeutic agents in the circulation and concentrates them in the heart graft. The aim of the study was to investigate the effects of methotrexate (MTX) associated to LDE. Rabbits fed a 0.5% cholesterol diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg·kg–1·day–1 orally) and allocated to treatment with intravenous LDE-MTX (4 mg/kg, weekly, n=10) or with weekly intravenous saline solution (control group, n=10), beginning on the day of surgery. Animals were euthanized 6 weeks later. Compared to controls, grafts of LDE-MTX treated rabbits showed 20% reduction of coronary stenosis, with a four-fold increase in vessel lumen and 80% reduction of macrophage staining in grafts. Necrosis was attenuated by LDE-MTX. Native hearts of both LDE-MTX and Control groups were apparently normal. Gene expression of lipoprotein receptors was significantly greater in grafts compared to native hearts. In LDE-MTX group, gene expression of the pro-inflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-18, vascular cell adhesion molecule-1, and matrix metalloproteinase-12 was strongly diminished whereas expression of anti-inflammatory interleukin-10 increased. LDE-MTX promoted improvement of the cardiac allograft vasculopathy and diminished inflammation in heart grafts.

Organ preservation with targeted rapamycin nanoparticles: a pre-treatment strategy preventing chronic rejection in vivo

“…Along with pre-treatment strategies, delivery mechanisms intended to allow for organ level immunosuppression while leaving the patient's global immune system intact may represent the future of organ specific immunosuppression. These disruptive technologies include micro and nanoparticles carrying immunosuppressants and chemotherapeutics, for example, delivered both systemically and directly to an organ allograft 25,26,28…”

“…Various studies suggest that systemic delivery of nanoparticles and emulsions containing chemotherapeutics concentrated in a transplanted heart can prevent vasculopathy. 25 , 26 Yet others advocate for the use of nanoparticles decorated with immunotherapeutics as a delivery device for tissues such as allo-islets to allow for implantation under the shield of immunomodulating therapeutics. 27 Pharmacotheapeutic delivery of immunosuppressants via micro and nanoparticles have been touted to represent the “next era” of transplantation, as increased doses of drug may be delivered directly to the area of need.…”

“…These disruptive technologies include micro and nanoparticles carrying immunosuppressants and chemotherapeutics, for example, delivered both systemically and directly to an organ allograft. 25 , 26 , 28 …”

Noninvasive methods to reduce cardiac complications postheart transplant

“…Although immunosuppressive regimens have not undergone substantive changes in the past year, there have been multiple animal studies assessing new delivery systems for immunosuppressive medications using lipid nanoparticles [63][64][65]. Most recently, mycophenolate mofetil (MMF)-laden nanoparticles directly perfused into the donor allograft of a murine model prior to transplantation were shown to reduce posttransplant cellular injury and CAV development, compared to systemic MMF provided after transplantation as part of a standard immunosuppressive regimen [66].…”

Nanoparticle-Based Approaches towards the Treatment of Atherosclerosis

“…It was proposed that such drugs as paclitaxel [112], methotrexate [113], or docetaxel (DTX) [114] can prevent numerous atherosclerotic manifestations. The research group of professor Raul Maranhão achieved significant progress in the development of lipid-based nanoparticles (LDE) aimed at the regression of atherosclerotic plaques [55,[114][115][116]. Nanoformulation of DTX as solid lipid particles with an average diameter of 45-60 nm considerably lowers its cytotoxicity and side effects.…”