During the last Marie Curie Alumni Association (MCAA)Conference (6-7 November 2020), it was announced that our project coordinator Daniele Catalucci and a Marie Curie Alumni, got the MCAA Best Innovator Award 2019. This category rewards former Marie Curie Alumni who presented the best innovation approach and Daniele was awarded for his "innovative and therapeutic approach for the treatment of failing heart, which could revolutionize the treatment of cardiac disease". Indeed Daniele, after his Ph.D. in molecular and cellular biology from the University of Rome − Tor Vergata, received support by a Marie Curie Outgoing International Fellowship for his postdoctoral studies at the Department of Medicine, University of California San Diego, USA. After that experience, he came back to Italy and started his own group at the CNR. This recognition from…

Just as CUPIDO is developing inhalable nanoparticles to deliver a drug to the heart, several other European projects — using very different compounds to treat very different ailments — have all turned to nanoparticles for drug delivery. These include the New Deal project, which is developing a nano-formulated RNA based therapy to treat inflammatory bowel disease, the B-Smart project, centered on delivering drugs to the brain to treat neurodegenerative disorders, and the Smart-4-Fabry project, which is applying nanotech to treat the rare Fabry disease. While the field of application differs, similar are the challenges that the projects had to face, especially when dealing with scale-up. For this reason, the 4 projects came together at the European Technology Platform on Nanomedicine conference (ETPN2020, 14-15 Oct) to discuss the lessons learned in…

A picture of our nanoparticles has been selected for NanoArtography2020! The author of the picture is  Lorenzo Degli Esposti from the CNR-ISTEC. One day, while at the microscope he spotted a heart-shaped cluster of nanoparticles, very spot on for our inhalable nanoparticles that deliver to the heart. The 50 nm nanoparticles are indeed loaded with therapeutic molecules for the treatment of cardiovascular diseases. Credits to: Lorenzo Degli Esposti, Institute of Science and Technology for Ceramics – Italian National Research Council, Faenza, Italy

Our partners from CNR, PLUMESTARS and FINCERAMICA have just published a new paper in the Special Issue of the Journal Crystals. In the article, the CUPIDO team applies a promising nanoparticles production process that might improve the reproducibility of conditions from laboratory to industrial scale. The Calcium phosphate nanoparticles (CaP NPs) used in CUPIDO are an efficient class of nanomaterials mainly used for biomedical applications but also very promising in other sectors such as cosmetics, catalysis, water remediation, and agriculture. Unfortunately, as in the case of other nanomaterials, their wide application is hindered by the difficulty to control features like size, morphology, purity and degree of particle aggregation. In this paper, the authors apply a method known as continuous flow precipitation, where reactants are continuously mixed, and the precipitated NPs…

CUPIDO since its beginning has worked to develop synergistic targeting techniques that could maximize nanoparticle delivery to the heart. One of the options considered by the project is the functionalization of the CaP nanoparticles with aptamers, which should enhance the internalization into myocardial cells (http://www.cupidoproject.eu/guidance-to-the-heart/) Aptamers, short single stranded synthetic oligonucleotide, can fold into complex tertiary structures and thus are able to bind with high affinity to a specific target receptor on the surface of the target cells. Furthermore, compared to other targeting ligands and monoclonal antibodies, they show many additional advantages, such as low toxicity, high specificity, and superior stability in biological fluids. Based on these premises, in CUPIDO we first, generated a novel internalizing aptamer targeting cardiac cells, and then we efficiently functionalized the surface of the CaP…

Cupido’s partner CNR, Finceramica and Plumestars have closely collaborated during this period to establish the first proof of concept of the therapeutic efficacy of the ultimate formulation of Cupido nanoparticles: a dry powder of Calcium-Phosphate nanoparticle (dpCaPs) loaded with a known therapeutic molecule. The tests have been performed on mice with a specific cardiac disease and their heart activity has been monitored by a non-invasive technique: echocardiography, which uses sound waves to produce live images of the heart and its valves. Furthermore, the ultimate dpCaP formulation was administered via inhalation by a custom-made inhaler for small animals, which was generated and developed exclusively for CUPIDO. The first prototype of such a dry powder inhaler was improved based on the feedback collected in the first test campaign. The updated inhaler is…

The CUPIDO final product owns a certain technological complexity because it consists of two parts: the calcium phosphate nanoparticles that act as nano-carrier and the cardiac-specific drug, which needs to be encapsulated inside the nanoparticles. To dissect the biodistribution of each component, in Cupido we decided to first assess the features of each component and later to assess the biodistribution of the full loaded-nanoparticle to ensure that it is the whole product that is able to reach the heart. Regarding the carrier, the biodistribution of the CaPs nanocarrier has been studied in-vivo up to large animals: in Landrace pigs, three hundred minutes after inhalation of CaP nanoparticles loaded with a marker peptide, a signal was detected in the myocardium, providing evidence for effective delivery of the cargo to the heart…

Heart tissue is perfused by thousands of very small arteries and capillaries branching off the coronary arteries. Obtaining truthful representations of the exact geometries of the perfusion circulation using state-of-the-art imaging techniques is virtually impossible. Despite being the most fundamental process in maintaining organ health and the major pathway for drug delivery, perfusion has, from a computational point of view, received very little attention. Thanks to the work done by SIMULA in CUPIDO, a computationally efficient and accurate model is now available and provides a framework for the simulation of experimentally relevant time frames for pre-clinical research. In CUPIDO, SIMULA has developed a novel particle tracking-based method to simulate the distribution of nanoparticles in the heart mediated by perfusion. To model blood flow through perfused tissue they follow the approach…

One of the key issues in CUPIDO is to track where and when the inhaled CaP nanoparticles travel in the body in vivo (biodistribution). As a first approach, the imaging studies, performed by our partner BIOEMTECH, has been focused on the spatio-temporal biodistribution of the unloaded nanoparticles (without the drug) in mice, in particular in lungs, heart, intestine and kidneys. Nanoparticles have been labelled with technetium-99m (99mTc), the most common medical radioisotope used in clinical practice, that allows to track the signal of the nanoparticles inside the body through real-time, dynamic scintigraphy and/or tomography. Thanks to a new protocol, the incorporation of radioisotope in the nanoparticles is very high; furthermore, the size and physicochemical properties of the CaP nanoparticles aren’t altered. The stability of the technetium-99m attached to the nanoparticles…

In CUPIDO, the formulation developed within the project shall be tested for pre-clinical efficacy in large animals. As such, mini pigs are used to test first, i) if the inhaled nanoparticles show sufficient cardiac enrichment and then ii) if the drug-loaded nanoparticles restore the normal cardiac activity in a model of systolic heart failure (heart failure with reduced ejection fraction or HFrEF). All the tests are conducted at the facility of Charité – University Medicine Berlin, while the company LIFE designed and developed a dedicated wearable device to non-invasively measure several physiological parameters on mini-pigs. Partners at Charité and LIFE worked closely to understand the usage scenario and the functional requirements for the device. Together, they have already performed the early tests and the official evaluation of the measurements on…