Abstract
Aim of FEROX project is to study and develop non-conventional redox active systems that use superoxide to target ferroptosis with neurodegenerative conditions as the primary target. The FEROX project will investigate novel non-conventional antioxidant systems and redox-active nano smart materials to target ferroptosis as a key common process involved in the pathophysiology of non-transmissible degenerative conditions. Ferroptosis is associated with neurodegenerative diseases, cardiovascular diseases, and cancer, which represent the most important death causes in developed countries and that are expected to become even more significant in the future with the increase of life expectancy. Inhibition of ferroptosis is considered a prime goal in treating cardiovascular and neurodegenerative diseases, hence the molecules and the materials developed in our project represent possible leads for future drugs in the following areas. The impact of the FEROX project can be summarized as follows: 1) acquisition of fundamental knowledge on the role of cross dismutation of HOO• and ROO• radicals to protect cell membranes form LPO; 2) understanding the role of such chemistry in ferroptosis; 3) acquisition of fundamental knowledge on the role of intra-membrane sources of HOO• as “radical-export” agents and understanding their antioxidant or pro-oxidant action; 4) understanding their potential to inhibit or promote ferroptosis and to modulate the related diseases (i.e. their potential to treat neurodegenerative conditions or cancer; 5) development of biomimetic cell-free and cell-based models to study antioxidants and ferroptosis inhibitors 6) development and optimization of non conventional superoxide-based Q/HOO• and >NO•/HOO• antioxidant systems to protect cells from LPO and ferroptosis 7) development, validation and optimization of nanovectors for biomedical applications 8) development and validation redox active nano smart materials to protect cells from LPO and ferroptosis 9) discovery of novel redox-active drug leads and nano smart materials to target neurodegenerative conditions
Results achieved
The UNIBO unit achieved the following main results. 1) synthesis of a series of lipophilic derivatives of dihydrocaffeic acid (DHCA) of the corresponding quinones (Ox-DHCA); 2) synthesis of lipophilic derivatives of hydroxytyrosol (HT) and 2,2,6,6-Tetramethylpiperidin-1-oxyl radical (TEMPO); 3) testing of the antioxidant activity of DHCA, Ox-DHCA, HT and TEMPO derivatives in solution and in different biomimetic models; 4) synthesis of 1,4-cyclohexadiene (CHD) derivatives as controlled sources of HOO• radicals; 5) study of the antioxidant activity of lipophilic DHCA and Ox-DHCA derivatives, alone and in the presence of CHD derivatives in homogenous autoxidation models and in biomimetic micellar and liposomal systems; 6) study of the antioxidant activity of other natural polyphenols in homogenous and heterogenous biomimetic systems, which might become eligible for future incorporation in nanogels; 7) optimization of the synthetic strategies to obtain biocompatible PEG-PEI nanogels; 8) encapsulation of lipophilic DHCA, HT and TEMPO derivatives in nanogels for drug delivery; 9) synthesis of TEMPO modified polymers as smart materials for the preparation of nanogel with antioxidant activity; 10) study of the antioxidant activity of nanogels encapsulating the lipophilic DHCA derivatives and of nanogels incorporating HT and TEMPO derivatives; 11) preliminary testing of prepared lipophilic polyphenols in cell models for the rescuing from ferroptosis. In brief, a series of natural polyphenolic antioxidants were investigated quantifying their kinetic of peroxyl radical trapping in model homogenous systems in organic solution and model biomimetic micellar and liposomal autoxidizing systems. The scope was to evaluate their suitability for future inclusion in nanogels to build smart redox active materials. In addition, a series of lipophilic catechols and the corresponding quinones were synthesized and tested for their antioxidant activity, both in homogenous and heterogenous biomimetic systems, both in the presence and in the absence of a source of HOO• radical such as cyclohexadiene (CHD) derivatives. This allowed to fully characterize their kinetic behaviour and clarify the mechanism of synergic interaction between polyphenols and the related quinones and HOO• radicals as sacrificial reducing agents. In parallel, optimized CHD derivatives were also synthesized and studied for their antioxidant behaviour in heterogenous biomimetic models in the absence of phenols and polyphenols via a mechanism of “radical export” out of the lipid particle and into the aqueous surrounding environment. Meanwhile, synthetic strategies to obtain biocompatible PEG-PEI nanogels were optimized, followed by the synthesis of HT and TEMPO derivatives able to be linked or incorporated in the nanogels. Incorporation of the lipophilic DHCA derivatives into nanogels was also accomplished. The activated nanomaterials were subsequently tested for their antioxidant activity proving their effectiveness as a controlled-release smart materials to deliver the studied antioxidants. Preparation of nanogels containing HT derivatives and TEMPO derivatives was accomplished matching the initial goals of the project. Finally, preliminary testing of the prepared materials in cell models of artificially induced ferroptosis were also accomplished. This showed the effectiveness of the tested materials in counteracting ferroptosis; however, further testing of some of the nanogels is still in progress, prompted by the promising preliminary results. So far the project’s results have been published in 10 articles in open access mode in international peer-reviewed journals: 1) Antioxidants 2023, 12, 1763 (https://doi.org/10.3390/antiox12091763); 2) Bioorganic Chemistry, 2025, 166, 109194 (https://doi.org/10.1016/j.bioorg.2025.109194); 3) Organic Letters 2025, 27, 14201−14206 (https://doi.org/10.1021/acs.orglett.5c04339); 4) Food Chemistry, 2024, 452, 139289 https://doi.org/10.1016/j.foodchem.2024.139289); 5) J. Agric. Food Chem. 2024, 72, 23832−23843 (https://doi.org/10.1021/acs.jafc.4c04580); 6) Molecules, 2024, 29, 2604 (https://doi.org/10.3390/molecules29112604); 7) J. Org. Chem. 2025, 90, 13467–13476 (https://doi.org/10.1021/acs.joc.5c01140); 8) New J. Chem. 2024, 48, 16047–16056 (https://doi.org/10.1039/d4nj03030c); 9) Food Res. Int. 2024, 198, 115339 (https://doi.org/10.1016/j.foodres.2024.115339); 10) Antioxidants 2024, 13, 1484 (https://doi.org/10.3390/antiox13121484). Additionally, five manuscripts are in preparation or have been submitted for publication. Furthermore results have disseminated via communications at 8 international and 1 national conferences.Project details
Unibo Team Leader: Luca Valgimigli
Unibo involved Department/s:
Dipartimento di Chimica "Giacomo Ciamician"
Coordinator:
ALMA MATER STUDIORUM - Università di Bologna(Italy)
Total Eu Contribution: Euro (EUR) 201.811,00
Total Unibo Contribution: Euro (EUR) 102.079,00
Project Duration in months: 24
Start Date:
16/10/2023
End Date:
28/02/2026
