The Cupido researchers had developed biocompatible and biodegradable calcium phosphate nanoparticles composed of a material that closely resembles bone and teeth. During the last years, they demonstrated that inhalation of such nanoparticles, when loaded with a known drug, succeed in restoring cardiac function in small animals (rodents) and large animals (pigs) without causing any major adverse effects. The selected drug is the Mimetic Peptide that has the ability to improve cardiac contractility in some pathological heart conditions. This result proved that the nanoparticle can readily translocate from the pulmonary tree to the heart, where the drug cargo is finally released. Other evaluations confirmed that the restoring effect on cardiac contractions is related to the nanoparticle delivery, excluding any placebo effect. For the study in large animals, the Consortium designed and developed a dedicated wearable device to non-invasively measure several physiological parameters on mini pigs.
In the meantime, the Consortium successfully characterized the microparticles powder containing nanoparticles loaded with drugs. Partners have refined the synthesis protocol of the microparticles powder to meet the intrinsic requirements of the industrial facilities. A project manufacturing supply chain was identified, delineating the evolution from peptide-loaded nanoparticles to inhalable microparticles, with the underlying physicochemical rationale of the scaled-up synthesis and associated target product profiles.
To assess the behaviour of the nanoparticles with the lungs cells, their first target before translocating to the heart, partners performed several in vitro studies to monitor the immune response, to quantify particle uptake and to analyze their behavior in more physiological-like conditions. The immunoreactivity remains low when the scale up formulations were put in contact with human blood cells, while higher concentration might deserves further investigations. Further histopathological and molecular analyses are still ongoing.
The fate of the nanoparticles in the body after administration is monitored in vivo by a combination of imaging methods that all together provide information on the biodistribution up to 24 hours. In parallel, the consortium has successfully implemented simulations of the nanoparticles distribution in the myocardium throughout the entire cardiac cycle. This tool is used to predict and assess the nanoparticles delivery to the heart.
Experimentally validated simulations supported also the feasibility assessment of the electromagnetic-mediated guidance to the heart. To evaluate in vitro the interactions between the nanoparticles functionalized with iron and endothelial cells under combined fluidic and magnetic stimuli, the CUPIDO consortium has developed a microfluidic bioreactor. In the meantime, progress has been made for the aptamer-mediated guidance to the heart too. After having identified promising aptamers, the Consortium collected evidence that the nanoparticles functionalized with these aptamers retain the cell-internalizing feature and therefore facilitate the drug delivery inside the cardiac cells.
The preliminary results reached open up new avenues to optimize nanomaterials for inhalation as a more efficient and patient-friendly way to deliver therapeutics to the heart.
