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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CUPIDO (Cardio Ultraefficient nanoParticles for Inhalation of Drug prOducts)

Teaser

Summary

Cardiovascular diseases, such as angina and heartÂ attack, represent a societal burden, accounting for more than 30% of deaths globally and spending yearly ~190 billion â‚¬ in European healthcare. Today the chronic treatment of patients leads only to short-term benefits due to the limitations of conventional drug-delivery methods. Drugs targeted to heart are currently administrated orally or by injection and circulate systematically in the bloodstream causing several side-effects, reducing the drug efficacy and provoking discomfort to the patient. During the end-stages of the disease, the administration might become even more invasive, employing catheters or implantable pumps. The cardiovascular field needs fresh approaches to discover novel patient-friendly administration routes that are more efficient and heart-specific.

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.

Work performed

The Cupido researchers had already developed biocompatible and biodegradable calcium phosphate nanoparticles composed of a material that closely resembles bone and teeth. During the last year, they demonstrated that inhalation of such nanoparticles, when loaded with a known drug, succeed in restoring cardiac function in small animals (rodents) without causing any major adverse effects. This preliminary result proves that the nanoparticle can readily translocate from the pulmonary tree to the heart, where the drug cargo is finally released. Furthermore, after inhalation, the nanoparticles rapidly accumulate in the heart of healthy pigs, encouraging the application of Cupido approach in large animals too.
In the meantime, the Consortium successfully manufactured and characterized the microparticles powder containing nanoparticles loaded with drugs. The powder is currently under biological assessment and its production is being refined to reach a more industrial-oriented process.
To assess the nanoparticles behaviour with the lungs cells, their first target before translocating to the heart, partners performed several in vitro studies. Overall, the preliminary results showed that cell viability is not affected in the alveolar epithelial type 1-like model cells and inflammatory mediators are not released. However, further studies are required to monitor the inflammatory response and to quantify particle uptake and to analyse the nanoparticles behaviour in more physiological-like conditions. For this reason, the CUPIDO consortium is developing a fluid-flow bioreactor that mimics the gas-blood interface found in the lung.

The fate of the nanoparticles in the body after administration is monitored in vivo by a combination of imaging methods that altogether provide a detailed and clear biodistribution of the tracked nanoparticles 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 will be 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. Two other devices were developed to test the outcomes: a low pulsed electromagnetic bioreactor device to modulate the drug release efficacy of the nanoparticles and a 3D printed micro-fluidic device that mimics the physiological blood velocities in different vessels (from the aorta to capillaries).
In the meantime, progress have been made for the aptamer-mediated guidance to the heart too. Cupido researchers identified and tested promising aptamers that specifically target the myocardium and promote cell-internalization. The first results support the 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 so far open up new avenues to optimize nanomaterials for inhalation as a more efficient and patient-friendly way to deliver therapeutics to the heart.

Final results

Nanomedicine, meaning the application of nanotechnology to the health sector, represents a promising approach for near future health care. Indeed, some nanopharmaceuticals has been approved by the FDA since the late 90sâ€™ leading toÂ remarkable advantages especially in the cancer field. Curiously, only very few attempts have been made to apply nanomedicine to cardiovascular disease area in spite it represents the leading cause of death worldwide.
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.