Polymeric devices as a platform for the delivery of actives involved in heart repair

Résumé

Ischemic heart disease is the leading cause of death worldwide. In the last years, growth factor therapy appeared as a promising strategy to help the heart to regenerate, overcoming limitations of traditional therapy. However, clinical trials demonstrated lack of benefit when these molecules were freely administered due to their short half-life. Based on this, incorporation of these factors in drug delivery systems has been proposed to protect proteins from degradation and at the same time to allow a prolonged release. Our group has demonstrated the ability of VEGF polymeric microparticles to promote cardiac regeneration in an animal model of myocardial ischemia. In this work three strategies have been proposed and developed to improve the clinical benefit of the formulated delivery systems. In the first part of this work the surface of the microparticles was modified to decrease particle phagocytosis and consequently improve protein delivery. PLGA microparticles coated with PEG (stealth technology) resulted in significantly decreased uptake of the carriers by macrophages, compared with non PEGylated microparticles, as it was shown by flow cytometry and fluorescence microscopy. In the second part of the study, the efficacy of PEGylated microparticles containing VEGF has been tested in an animal model of myocardial ischemia. The treatment has been assayed alone and in combination with oral administration of the cardioprotective agent CoQ incorporated in polymeric nanoparticles. Results demonstrated significant improvement in the ejection fraction after three months with both treatment forms individually; however the combination therapy failed to offer any synergism, suggesting an antiangogenic effect of CoQ nanoparticles counteracting VEGF microparticles proangiogenic activity. In the third part of this work a new polymeric device was designed. Electrospinning was employed to encapsulate Neuregulin-1 in a polymeric fibrous scaffold, made of PEG-PLGA and a specific polymer designed to promote specific cell adhesion. The results of this preliminary study demonstrated the biocompatibility of this scaffold in the ischemic heart. In the future this system will allow combining growth factor and cell therapy, improving cell engraftment, the main limitation of cell therapy nowadays. This more integrative approach will presumably result in a more effective treatment for ischemic heart disease.