A lung-to-heart nanomedicine for chronic heart failure
Eride Quarta1,2, Paolo Colombo1,2, Ruggero Bettini1, Daniele Catalucci3,4, Claudio De Luca5, Paul Steendijk6, Barry Borlaug7, Fabio Sonvico1, Alessio Alogna8,9 & Francesca Buttini1
1Food and Drug Department, University of Parma, 43124 Parma, Italy;2PlumeStars s.r.l., Parma, 43125, Italy
3Institute of Genetic and Biomedical Research (IRGB), National Research Council of Italy,Milan Unit, Milan, 20138, Italy; 4IRCCS Humanitas Research Hospital, Milano, 20089, Italy;
5NanoPhoria S.r.l, Milano, 20123, Italy;
6Department of Cardiology, Leiden University Medical Center, Leiden, 2311G The Netherlands;
7The Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55906, USA;
8Herzzentrum der Charité, Department of Cardiology, Angiology and Intensive Care Medicine, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353 Berlin, Germany; 93DZHK (German Centre for Cardiovascular Research), partner site; Berlin, 10785, Germany;
Summary
Peptides are highly selective molecules with the potential for a direct impact at the cardiomyocyte level. Yet, a strategy for effective delivery of therapeutic peptides to the heart is lacking. The aim of the present study was to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), first in class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of heart failure (HF). HF with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction (LV EF) 30 ± 8%), animals were randomized, and treatment started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) with high fraction of extra-fine particles (<2µm) of 47.2±0.7% or dpCaP without MP. Efficacy was evaluated by serial echocardiography and invasive hemodynamics. DpCaP-MP inhalation restored systolic function, as shown by an absolute LV EF increase over the treatment time of 17 ± 6%, while reversing cardiac remodelling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC-modulator point towards a game-changing treatment for HFrEF patients, while demonstrating the effective delivery of a therapeutic peptide to the diseased heart.