Chrysin directing an enhanced solubility through the formation of a supramolecular cyclodextrin-calixarene drug delivery system: a potential strategy in antifibrotic diabetes therapeutics

Abstract

BackgroundCalixarene OTX008 and chrysin (CHR) are promising molecules for the treatment of fibrosis and diabetes complications, however, a suitable drug delivery system is required for their combined application due to their low solubility and bioavailability.Research design and methodsSulfobutylated β-cyclodextrin (SBECD) and its polymeric derivative were tested to solubilize CHR through the formation of a ternary complex in presence of calixarene OTX008. Phase-solubility studies revealed the solubility enhancement and complexation mechanisms, and dynamic light-scattering was used to measure the molecular association in the cyclodextrin-calixarene-CHR ternary system. Nuclear magnetic resonance, differential scanning calorimetry, and computational studies discovered the molecular interactions in the complex, while cellular studies tested the biocompatibility of the system.ResultsUsing SBECD and OTX008 together proved more efficient in solubilizing CHR than using SBECD by itself. The ternary complex forms molecular associates in water, which contributes to the solubilization and delivery of both CHR and OTX008. Structural analysis identified non-covalent interactions involved in the formation of the complex, which was not cytotoxic in vitro under hyperglycemic conditions.ConclusionsA novel ternary complex was developed for administering potential antifibrotic compounds in diabetes complications, with OTX008 serving as a pivotal structural and pharmacological element within the complex.

Chrysin-based supramolecular cyclodextrin-calixarene drug delivery system: a novel approach for attenuating cardiac fibrosis in chronic diabetes

“…The experimental methods used to obtain the novel CHR complex in OTX-SBECD have been previously detailed and established ( Hermenean et al, 2023 ). Comprehensive phase-solubility evaluations elucidated the mechanisms behind solubility augmentation and complexation.…”

“…Comprehensive phase-solubility evaluations elucidated the mechanisms behind solubility augmentation and complexation. Molecular associations within the cyclodextrin-calixarene-CHR ternary system were assessed via dynamic light-scattering, as well as nuclear magnetic resonance, differential scanning calorimetry, and computational studies, as documented by Hermenean et al (2023) .…”

“…Therefore, both OTX008 and CHR could have anti-fibrotic effects even in cardiac damage induced by high glucose levels. However, their low solubility in water could affect their in vivo administration ( Dong et al, 2021 ; Hermenean et al, 2023 ).…”

“…In this context, we previously formulated a dual-action supramolecular system to improve CHR and OTX008 solubility, aiming at reducing fibrosis in chronic diabetes. Particularly, we first combined CHR with sulfobutylated β-cyclodextrin (SBECD) to improve its limited solubility in water; then we integrated calixarene OTX008, known for its Gal-1 inhibitory properties, into our drug delivery system ( Hermenean et al, 2023 ). This CHR-based supramolecular cyclodextrin-calixarene delivery system was characterized in the context of rat embryonic cardiomyocytes (H9c2) cell viability, ascertaining its safety.…”

“…This CHR-based supramolecular cyclodextrin-calixarene delivery system was characterized in the context of rat embryonic cardiomyocytes (H9c2) cell viability, ascertaining its safety. Therefore, it could be considered as a promising therapeutic candidate for addressing cardiac fibrosis in chronic diabetes ( Hermenean et al, 2023 ).…”