Bio-inspired negatively-charged calcium phosphate nanocarriers for cardiac delivery of therapeutic molecules

Abstract

Event Abstract Back to Event Bio-inspired negatively-charged calcium phosphate nanocarriers for cardiac delivery of therapeutic molecules Michele Iafisco1, Vittoria Di Mauro2, 3, Nicolò Salvarani2, 3, Gloria Belén Ramírez-Rodríguez1, Tatiana Patrício1, Michele Miragoli2, 3, Daniele Catalucci2, 3 and Anna Tampieri1 1 National Research Council (CNR), Institute of Science and Technology for Ceramics (ISTEC), Italy 2 Humanitas Clinical and Research Center, Italy 3 National Research Council (CNR), Institute of Genetics and Biomedical Research (IRGB), Italy Cardiovascular disease (CVD) is a worldwide growing problem that afflicts close to 1% of the population and causes 17.3 million annual premature deaths. Causes include ischemic, toxic, genetic, post-inflammatory, and structural defects, overall resulting in a mortality of ~50% within 5 years from diagnosis[1]. Clinical management of CVDs has improved during the last decades, but despite significant advancements, these pathologies still lead to a poor quality of life and reduced longevity. Therefore, a great challenge is the identification of innovative therapeutic compounds and the development of more efficient, safe, and “patient-friendly” drug-delivery systems. Nanoparticles (NPs) hold great promise for nanomedical systems and provide an alternative strategy for more efficient, controlled, and safe approaches of drug delivery[2]. While largely investigated in the cancer field, the development and use of efficient NPs for the treatment of CVDs is still in its infancy. In fact, to the best of our knowledge, only liposomes or NPs based on synthetic polymers have been investigated so far for the delivery of various therapeutic molecules to myocardial cells[3],[4]. Their use is drastically limited due to the lack of biodegradability and biocompatibility of these kinds of nano-carriers, the uncontrolled drug release in the bloodstream, the poor encapsulation efficacy, and the poor stability. In summary, there is a strong need for the identification of new formulations based on biocompatible and biodegradable NPs to overcome the limitations of NPs currently used for CVD treatment. In this study, novel biocompatible and bioresorbable negatively charged biodegradable calcium phosphate nanoparticles (CaP-NPs) were developed as an innovative therapeutic system for the delivery of bioactive molecules to the heart. Synthesis of CaP-NPs was performed according to a new, straightforward one-pot inspired biomineralization protocol employing citrate as a stabilizing agent and regulator of crystal growth. Via the classical clathrin-mediated path, CaP-NPs were shown to efficiently internalize into HL-1 cardiac cells without promoting toxicity. Additionally, acute and chronic administration of CaP-NPs did not interfere with Ca2+ handling properties and electrophysiological features of HL-1 cells and adult cardiomyocytes. Finally, preliminary experiments validated that CaP-NPs were successfully able to encapsulate bioactive synthetic microRNAs and mimetic peptides, which were efficiently delivered into cardiac cell line in vitro and surprisingly even into cardiac tissue when admistered in vivo. To sum up, our results showed that the CaP-NPs generated in this work are safe and effective drug-delivery systems for a new potential therapeutic treatment of polarized cells such as cardiomyocytes. The Italian Flagship Project NANOMAX – miRnano (Progetto Bandiera MIUR PNR 2011–2013)