Anti-COVID multi-therapy by Immune/Chemo-active nanoMOFs
B. Fodor, I. Álvarez-Miguel, G. Gutiérrez, C. Biglione, T. Hidalgo* and P. Horcajada*
Advanced Porous Materials Unit, IMDEA Energy Institute, 28935 Móstoles-Madrid, Spain
The pandemic situation with the SARS-CoV-2 (COVID-19) had global epic social repercussions in the past years: so far, >755 million of infections, resulting in 7 million deaths; being imperative to design new therapies.1 In this context, nanomedicine has risen as a promising tool to treat challenging diseases (eg. cancer), including viral/bacterial infections.2 In particular, Metal-organic frameworks-MOFs, built by metal centers bonded to polydentate ligands, have emerged as alternative drug delivery systems.3 Despite their interest as attractive nanocarriers and their recent approach in COVID-19 sensing,4 MOFs have not been proposed for this viral therapy. Hence, we propose here a pioneer anti-COVID multitherapy (3-in-1 effect-E) for the pulmonary route. In this sense, 7 MOFs with potential intrinsic antiviral activity (E1) were prepared. By screening their biocompatibility & antiviral activity against human infected cell lines (A549-ACE2), the best performing MOF with significant antiviral effect (IC50: <2 µM) and biosafety (cell viability >99%) was selected. In a 2º step, a successful favipiravir encapsulation by a simple impregnation method (21±3%) was obtained. A complementary anti-COVID effect was observed, providing an additional chemotherapeutic approach, related to its RNA polymerase inhibition effect (E2)5. To fulfil our strategy, a heparin grafting with proven immune/chemotherapeutic anti-COVID activity6 has been developed achieving greater antiviral effect at lower concentrations (IC50:<1 µM; E3). Ultimately, a spray-dried mannitol-based microspheres7 were prepared as an efficient formulation adapted to the pulmonary administration, reaching even deep lung zones. Their toxicity & biodistribution is currently being investigated using a murine model. These promising outcomes pave the way towards future (pre)clinical research for the COVID therapy &/or other pulmonary pathologies.
Acknowledgment: Comunidad de Madrid & European Regional Development Fund—2014-2020-OE REACT-UE 1. TH, CB & PH: EU Horizon Europe Research & Innovation, MSCA grant agreements (Nº 897678, 101061833; 860942).
References
1. WHO (COVID-19) Dashboard 2023
2. Athar et al. Adv.Mater.Rev. 2014, 1, 25
3. Horcajada, et al. Chem.Rev. 2012, 112, 1232.
4. Rabiee, et al. Sci.Total Environ. 2022, 825, 153902.
5. Ghasemnejad et al. Drug Res.2021, 71, 166.
6. Gelbach, et al. Front.Mol.Biosci. 2022, 9, 912887
7. Fernández-Paz, et al. ACS Appl.Mater.bInterfaces, 2020, 12, 25676