Breaking down barriers to foster new Cyclodextrin-based applications for healthcare by implementing sustainable design principles

Informations projet

Bicyclos

N° de convention de subvention: 101130235

DOI

10.3030/101130235

Date de signature de la CE 28 Juillet 2023

Date de début 1 Septembre 2023

Date de fin 31 Août 2027

Financé au titre de

• Marie Skłodowska-Curie Actions (MSCA)

Coût total

Aucune donnée

Contribution de l’UE

€ 1 297 200,00

Coordonné par

CONSIGLIO NAZIONALE DELLE RICERCHE
Italy

Periodic Reporting for period 1 - Bicyclos (Breaking down barriers to foster new Cyclodextrin-based applications for healthcare by implementing sustainable design principles)

Période du rapport: 2023-09-01 au 2025-08-31

Résumé du contexte et des objectifs généraux du projet

Cyclodextrins (CD) are circular "sugar" molecules with a truncated cone shape and have found applications in different sectors: pharmaceutical sector, food, agriculture, environment, separation processes, etc They have a “green” origin, as they can be obtained from enzymatic degradation of starch, a natural product. They are also low cost which makes them the ideal class of compounds for further fields of exploitation. However, depending on the selected application they still suffer limits of various nature, and in the field of biomedical applications some problems need to be faced:
• Synthetic protocols to produce new modified cyclodextrins starting from the natural cyclodextrins afford mixtures of cyclodextrins isomers; these methods are not sustainable neither upgradable;
• Purification of cyclodextrin isomer mixtures is difficult and expensive;
• There is little knowledge about cyclodextrin biology and their behaviour in the human body and overall in living organisms;
• Inclusion by cyclodextrins of, for example, drugs, in the cavity of the truncated cone can be unique but is still underexploited;
• Cyclodextrin polymers are easily prepared with green methods but there is still little control on the molecular weight of the polymer and batch-to-batch reproducibility has not yet been achieved. This is a strong limit in their application for drug delivery as very rigid regulatory rules must be met to be approved by the drug agencies.
The goal of the Bicyclos project is to find solutions to some of these problems in order to bring cyclodextrin-based medical systems closer to clinical applications. New discoveries on the sustainable production on Cyclodextrin-based molecules conform to production requirements for pharmaceuticals are expected and they will open a wide range of new applications. Most importantly, as cyclodextrin systems can be combined with different drugs that are already approved by food and drug agencies, we expect to find solutions for different diseases according to the chosen drug or combination of drugs. Not only, the new cyclodextrin molecules will be exploited also to develop new sensing applications in clinical settings as well as beyond.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Part of the work of the project focuses on the "Design, Synthesis and Characterization of new CD derivatives; establishment of sustainable preparation protocols; development of delivery and sensor systems". The first results are contained in a report with new sustainable Routes of Synthesis and 2 protocols are particularly relevant:
a) 1 viable protocol for the regioselective allylation of CD monomers and dimers and 1 for the regioselective installation of alkylamine groups onto CD monomers and dimers;
b) 1 sustainable protocol for the synthesis and characterization of esters cross-linked CD polymers.
We have also optimized protocols for the synthesis of citric acid-crosslinked polymers. Specifically, we focused on cysteamine-modified β- and γ-cyclodextrins (cyst-β/γCDs) and investigated their polymerization with citric acid, 3,3′-dithiodipropionic acid, and toluene diisocyanate.
We also obtained the first set of results on CD hydrogels. Specifically, the design and synthesis of biocompatible and biodegradable hydrogel matrices focused on developing crosslinked pullulan-based hydrogels, leveraging pullulan’s biocompatibility, sustainability, and water solubility to create versatile materials for sensor applications.
Another part of the project work deals with (i) the rationalisation of molecular mechanisms underlying interaction of CDs with different cell types, and (ii) the assessment of the biological activity of new CD-based APIs and multicargo delivery systems in 2D and 3D models. The main achievements concern nucleic acid delivery, a very challenging goal, with potential applications in different fields going from cancer treatment to vaccine development: in aqueous environments, innovative βCD with cationic centers and hydrophobic tails self-assembly into bilayer vesicles, with their stability influenced by pH. They are able to co-assembly with plasmid DNA (pDNA), leading to the formation of DNA formulations upon a simple mixing process. Different short CD polymers were tested as delivery tool for nucleic acid molecular beacons and the first results on their intrinsic toxicity were obtained. The less toxic ones displayed transfection efficiency for the selected molecular beacon that was comparable with transfectamine protocols.
Finally, Folate-modified CDs functionalizing the primary face with aliphatic chains were obtained that self-assembly into small nanoparticles. Insight were obtained for these nanoparticles undergoing folate receptor-mediated endocytosis in selected cancer cell lines.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Innovative outcomes of the project include novel synthetic protocols with potential application in industrial contexts. While still at an early stage, these results carry promising implications for EU policy priorities, especially in relation to sustainability and innovation. The presence of the company Carbohyde with interest in CD synthesis at industrial scale is expected to promote further industrial uptake.