Chrysin Directing an Enhanced Solubility through the Formation of a Supramolecular Cyclodextrin–Calixarene Drug Delivery System: A Potential Strategy in Antifibrotic Diabetes Therapeutics

Author:

Hermenean Anca1ORCID,Dossi Eleftheria2,Hamilton Alex3,Trotta Maria Consiglia4ORCID,Russo Marina56,Lepre Caterina Claudia47,Sajtos Csilla8,Rusznyák Ágnes89ORCID,Váradi Judit10ORCID,Bácskay Ildikó910ORCID,Budai István11ORCID,D’Amico Michele4ORCID,Fenyvesi Ferenc8ORCID

Affiliation:

1. “Aurel Ardelean” Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Revolutiei, 310414 Arad, Romania

2. Centre for Defence Chemistry, Cranfield University, Defence Academy of United Kingdom, Shrivenham, Swindon SN6 8LA, UK

3. Biomolecular Sciences Research Centre (BMRC), Department of Biosciences and Chemistry, College of Health, Wellbeing and Life Sciences, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK

4. Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy

5. Doctoral School of National Interest in Public Administration and Innovation for Disability and Social Inclusion, Department of Mental, Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy

6. School of Pharmacology and Clinical Toxicology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy

7. Doctoral School of Translational Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy

8. Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary

9. Institute of Healthcare Industry, University of Debrecen, Egyetem Square 1, H-4032 Debrecen, Hungary

10. Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary

11. Faculty of Engineering, University of Debrecen, Ótemető Street 2-4, H-4028 Debrecen, Hungary

Abstract

Calixarene 0118 (OTX008) and chrysin (CHR) are promising molecules for the treatment of fibrosis and diabetes complications but require an effective delivery system to overcome their low solubility and bioavailability. Sulfobutylated β-cyclodextrin (SBECD) was evaluated for its ability to increase the solubility of CHR by forming a ternary complex with OTX008. The resulting increase in solubility and the mechanisms of complex formation were identified through phase-solubility studies, while dynamic light-scattering assessed the molecular associations within the CHR-OTX008-SBECD system. Nuclear magnetic resonance, differential scanning calorimetry, and computational studies elucidated the interactions at the molecular level, and cellular assays confirmed the system’s biocompatibility. Combining SBECD with OTX008 enhances CHR solubility more than using SBECD alone by forming water-soluble molecular associates in a ternary complex. This aids in the solubilization and delivery of CHR and OTX008. Structural investigations revealed non-covalent interactions essential to complex formation, which showed no cytotoxicity in hyperglycemic in vitro conditions. A new ternary complex has been formulated to deliver promising antifibrotic agents for diabetic complications, featuring OTX008 as a key structural and pharmacological component.

Funder

Ministry of Research, Innovation, and Digitization, CNCS/CCCDI-UEFISCDI

Ministry of Culture and Innovation of Hungary from the National Research, Development, and Innovation Fund

European Union and the European Regional Development Fund

Publisher

MDPI AG

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