Periodic Reporting for period 3 - CUPIDO (Cardio Ultraefficient nanoParticles for Inhalation of Drug prOducts)
Reporting period: 2020-02-01 to 2021-01-31
The EU-funded project Cupido, started in February 2017, proposes an innovative solution: inhalable nanoparticles that can rapidly and effectively deliver a therapy directly to the diseased heart. To achieve the goal, the Cupido consortium is working to develop biocompatible and biodegradable nanoparticles that can self-assemble and encapsulate drugs, novel or available, in a suitable format to reach the heart. The nanoparticles should be transformed into a microparticle dry powder that can be easily inhaled and reach the deep lung. Once there, the nanoparticles should cross the alveolar-capillary barrier, rapidly reaching the heart. The heart specificity might be further enhanced by chemical and magnetic guidance while imaging methods and computational simulations is used to monitor, characterize and optimize the nanoparticle journey.
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.
On the other side, inhalation has long been studied for the treatment of pulmonary diseases, but its use for targeting of the heart and management of cardiac failing conditions has not been explored. Inhalation is a viable delivery method to target the heart because oxygenated blood from lungs flows directly there via the pulmonary vein. The first hint on the phenomenon came from combustion-derived ultrafine nanoparticles that, once inhaled through polluted air, were detected in the heart. CUPIDO method exploits the same mechanism, but to deliver a therapeutic instead.
Nanoparticle-based inhalation approach has the potential to provide a faster, more efficient, patient-friendly and heart-specific administration route compared with traditional ones such as intravenous or oral. This might lead to a drastic reduction of drug dose per administration. The therapeutic drug, carried by the nanoparticle, should be protected from adverse systemic and gastric degradation, therefore side-effects due to the targeting of other organs might also be reduced. Overall, these advantages improve the patient comfort.
Furthermore, Cupido multidisciplinary consortium pulls together cutting-edge research with pre-clinical experience and industrial manufacturing, making it an ideal team to transform an idea into a feasible product.