An artificial nanoemulsion carrying paclitaxel decreases the transplant heart vascular disease: a study in a rabbit graft model.

Abstract

OBJECTIVE:

In previous studies cholesterol-rich nanoemulsions (LDE) resembling low-density lipoprotein were shown to concentrate in atherosclerotic lesions of rabbits. Lesions were pronouncedly reduced by treatment with paclitaxel associated with LDE. This study aimed to test the hypothesis of whether LDE-paclitaxel is able to concentrate in grafted hearts of rabbits and to ameliorate coronary allograft vasculopathy after the transplantation procedure.

METHODS:

Twenty-one New Zealand rabbits fed 0.5% cholesterol were submitted to heterotopic heart transplantation at the cervical position. All rabbits undergoing transplantation were treated with cyclosporin A (10 mg · kg(-1) · d(-1) by mouth). Eleven rabbits were treated with LDE-paclitaxel (4 mg/kg body weight paclitaxel per week administered intravenously for 6 weeks), and 10 control rabbits were treated with 3 mL/wk intravenous saline. Four control animals were injected with LDE labeled with [(14)C]-cholesteryl oleate ether to determine tissue uptake.

RESULTS:

Radioactive LDE uptake by grafts was 4-fold that of native hearts. In both groups the coronary arteries of native hearts showed no stenosis, but treatment with LDE-paclitaxel reduced the degree of stenosis in grafted hearts by 50%. The arterial luminal area in grafts of the treated group was 3-fold larger than in control animals. LDE-paclitaxel treatment resulted in a 7-fold reduction of macrophage infiltration. In grafted hearts LDE-paclitaxel treatment reduced the width of the intimal layer and inhibited the destruction of the medial layer. No toxicity was observed in rabbits receiving LDE-paclitaxel treatment.

CONCLUSIONS:

LDE-paclitaxel improved posttransplantation injury to the grafted heart. The novel therapeutic approach for heart transplantation management validated here is thus a promising strategy to be explored in future clinical studies.

• Authors: Domingos D Lourenço-Filho, Raul C Maranhão, Carlos A Méndez-Contreras, Elaine R Tavares, Fatima R Freitas, Noedir A Stolf
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 141 Issue 6 Pg. 1522-8 (Jun 2011) ISSN: 1097-685X [Electronic] United States
• PMID: 21458008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011. Published by Mosby, Inc.

Chemical References

• Cardiovascular Agents
• Drug Carriers
• Emulsions
• Lipids
• Paclitaxel

Topics

• Analysis of Variance
• Animals
• Cardiovascular Agents (administration & dosage, chemistry)
• Coronary Stenosis (blood, etiology, pathology, prevention & control)
• Drug Carriers
• Emulsions
• Graft Rejection (etiology, pathology, prevention & control)
• Graft Survival (drug effects)
• Heart Transplantation (adverse effects)
• Lipids (blood)
• Macrophages (drug effects, pathology)
• Male
• Myocardium (pathology)
• Nanoparticles
• Paclitaxel (administration & dosage, chemistry)
• Rabbits
• Severity of Illness Index
• Time Factors