Rutin/Sulfobutylether-ß-Cyclodextrin as a Promising Therapeutic Formulation for Ocular Infection.

Ocular pathologies present significant challenges to achieving effective therapeutic results due to various anatomical and physiological barriers. Natural products such as flavonoids, alone or in association with allopathic drugs, present many therapeutic actions including anticancer, anti-inflammatory, and antibacterial action. However, their clinical employment is challenging for scientists due to their low water solubility. In this study, we designed a liquid formulation based on rutin/sulfobutylether-ß-cyclodextrin (RTN/SBE-ß-CD) inclusion complex for treating ocular infections. The correct stoichiometry and the accurate binding constant were determined by employing SupraFit software (2.5.120) in the UV-vis titration experiment. A deep physical-chemical characterization of the RTN/SBE-ß-CD inclusion complex was also performed; it confirmed the predominant formation of a stable complex (Kc, 9660 M-1) in a 1:1 molar ratio, with high water solubility that was 20 times (2.5 mg/mL) higher than the free molecule (0.125 mg/mL), permitting the dissolution of the solid complex within 30 min. NMR studies revealed the involvement of the bicyclic flavonoid moiety in the complexation, which was also confirmed by molecular modeling studies. In vitro, the antibacterial and antibiofilm activity of the formulation was assayed against Staphylococcus aureus and Pseudomonas aeruginosa strains. The results demonstrated a significant activity of the formulation than that of the free molecules.

Characterization and In Vivo Antiangiogenic Activity Evaluation of Morin-Based Cyclodextrin Inclusion Complexes.

Morin (MRN) is a natural compound with antiangiogenic, antioxidant, anti-inflammatory, and anticancer activity. However, it shows a very low water solubility (28 µg/mL) that reduces its oral absorption, making bioavailability low and unpredictable. To improve MRN solubility and positively affect its biological activity, particularly its antiangiogenic activity, in this work, we prepared the inclusion complexes of MNR with sulfobutylether-ß-cyclodextrin (SBE-ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The inclusion complexes obtained by the freeze-drying method were extensively characterized in solution (phase-solubility studies, UV-Vis titration, and NMR spectroscopy) and in the solid state (TGA, DSC, and WAXD analysis). The complexation significantly increased the water solubility by about 100 times for MRN/HP-ß-CD and 115 times for MRN/SBE-ß-CD. Furthermore, quantitative dissolution of the complexes was observed within 60 min, whilst 1% of the free drug dissolved in the same experimental time. 1H NMR and UV-Vis titration studies demonstrated both CDs well include the benzoyl moiety of the drug. Additionally, SBE-ß-CD could interact with the cinnamoyl moiety of MRN too. The complexes are stable in solution, showing a high value of association constant, that is, 3380 M-1 for MRN/HP-ß-CD and 2870 M-1 for MRN/SBE-ß-CD. In vivo biological studies on chick embryo chorioallantoic membrane (CAM) and zebrafish embryo models demonstrated the high biocompatibility of the inclusion complexes and the effective increase in antiangiogenic activity of complexed MRN with respect to the free drug.

Progress in the development of selective heme oxygenase-1 inhibitors and their potential therapeutic application.

Heme oxygenases (HOs) are a family of enzymes involved in the selective catabolism of free circulating heme. While HO-2 is constitutively expressed, HO-1 is strongly overexpressed under stressful stimuli (e.g., oxidative stress). Under these conditions, HO-1 exerts its strong cytoprotective activities and plays a crucial role in stimulating cell survival by removing the pro-oxidant heme and by producing carbon monoxide and biliverdin (promptly reduced to bilirubin). Unfortunately, the broad spectrum of HO-1 cytoprotective effects has been well experimentally documented both in normal and tumor cells, where the enzyme can be overexpressed, making it an exciting target in the management of some type of tumors. Development of non-competitive HO-1 inhibitors dates back in 2002 with the discovery of Azalanstat. Since then, many efforts have been devoted to the identification of selective HO-1 and HO-2 inhibitors and to unravel the molecular determinants responsible for selectivity. Molecular modeling studies supported the identification of chemical features involved in the recognition and inhibition of these enzymes. Herein, medicinal chemistry aspects and in silico studies related to the development of HO inhibitors will be discussed. The purpose of this review is to highlight recent advances in the development of new selective HO-1 and HO-2 inhibitors and covers the last six years (2013-2018).