2024, Articolo in rivista, ENG
Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure
Alessio Alogna 1 , Leonhard Berboth 2 , Alessandro Faragli 2 , Jens Ötvös 2 , Francesco Paolo Lo Muzio 2 , Vittoria di Mauro 3 , Jessica Modica 3 , Eride Quarta 4 , Lukas Semmler 2 , Peter Maximilian Deißler 2 , Yannic Wanja Berger 2 , Khai Liem Tran 2 , Beatrice de Marchi 5 , Gianluigi Longinotti-Buitoni 5 , Lorenzo Degli Esposti 6 , Etienne Guillot 7 , Didier Bazile 7 , Michele Iafisco 6 , Alessandro Dotti 8 , Marie-Louise Bang 3 , Claudio de Luca 9 , Christina Brandenberger 10 , Louise Benazzi 11 , Dario di Silvestre 11 , Antonella de Palma 11 , Uwe Primeßnig 12 , Felix Hohendanner 12 , Simone Perna 13 , Francesca Buttini 14 , Paolo Colombo 4 , Christian Mühlfeld 15 , Paul Steendijk 16 , Pierluigi Mauri 11 , Carsten Tschöpe 2 , Barry Borlaug 17 , Burkert M Pieske 12 , Philipp Attanasio 18 , Heiner Post 2 , Frank R Heinzel 19 , Daniele Catalucci 20
Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. Objectives: In this study, the authors sought 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), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. Methods: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was 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) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. Results: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling 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. Conclusions: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.
2024, Articolo in rivista, ENG
Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure
Alessio Alogna, MD, PHD,a,b,c Leonhard Berboth, MD,a Alessandro Faragli, MD,a Jens Ötvös, DVM,a Francesco Paolo lo Muzio, PHD,a Vittoria di Mauro, PHD,d,e Jessica Modica, PHD,d,e Eride Quarta, PHD,f,g Lukas Semmler, MD,a Peter Maximilian Deißler, MD,a Yannic Wanja Berger, MSC, PHD,a Khai Liem Tran, MD,a Beatrice de Marchi, PHD,h Gianluigi Longinotti-Buitoni, PHD,h Lorenzo Degli Esposti, PHD,i Etienne Guillot, PHD,j Didier Bazile, PHD,j Michele Iafisco, PHD,i Alessandro Dotti, PHD,k Marie-Louise Bang, PHD,d,e Claudio de Luca, MBA, PHD,l Christina Brandenberger, PHD,m,n Louise Benazzi, PHD,o Dario di Silvestre, PHD,o Antonella de Palma, PHD,o Uwe Primeßnig, MD, PHD,a,b,c Felix Hohendanner, MD, PHD,a,b,c Simone Perna, PHD,p Francesca Buttini, PHD,f Paolo Colombo, PHD,f,g Christian Mühlfeld, MD, PHD,m,q Paul Steendijk, PHD,r Pierluigi Mauri, PHD,o Carsten Tschöpe, MD,a Barry Borlaug, MD,s Burkert M. Pieske, MD,a,b,c Philipp Attanasio, MD, PHD,t Heiner Post, MD,a Frank R. Heinzel, MD, PHD,a,c Daniele Catalucci, PHDd,e
BACKGROUND The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. OBJECTIVES In this study, the authors sought 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), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. METHODS Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachy- pacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% 8%), animals were randomized and treatment was 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) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. RESULTS DpCaP-MPinhalationrestoredsystolicfunction,asshownbyanabsoluteLVEFincreaseoverthetreatmentperiod of 17% 6%, while reversing cardiac remodeling 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. CONCLUSIONS The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeuticpeptidetothediseasedheart.
2016, Articolo in rivista, ENG
Morphology modulation of gas-foamed, micrometric, hollow polystyrene particles
Contaldi, Vincenzo; Imperato, Luigi; Orsi, Silvia; Di Maio, Ernesto; Netti, Paolo Antonio; Iannace, Salvatore
In this article, we reports the effects of the processing conditions on the morphological and hollow attributes of polystyrene micrometric hollow particles produced by the use of a recently developed technique based on the gas foaming of spherical, dense particles. By modulating the foaming temperature and saturation pressure, we produced hollow particles with different attributes in terms of hollow dimensions, eccentricity, and open-close features. The results from these small systems were compared, and we found agreement with what is typically observed in bulk polymeric foaming, for example, an increase in the foaming efficiency with saturation pressure and the nonmonotonic effect of temperature. Furthermore, we observed an increase in the hollow number when using nucleating agents with respect to the neat polymer and when using nitrogen with respect to carbon dioxide as the blowing agent. The effects of particle manipulation before foaming to achieve hollow elongated or distorted particles are also reported. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 44236.
DOI: 10.1002/app.44236