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Characterization and In Vivo Antiangiogenic Activity Evaluation of Morin-Based Cyclodextrin Inclusion Complexes
Federica De Gaetano1, Fatima Margani2, Vincenzina Barbera2
1Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Università di Messina, Viale Ferdinando Stagno d'Alcontres 31, I-98166 Messina, Italy.
Abstract:
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-β-cyclodextrin (SBE-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-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-β-CD and 115 times for MRN/SBE-β-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-β-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-β-CD and 2870 M-1 for MRN/SBE-β-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.
Insights
This study enhances morin (MRN) solubility and antiangiogenic activity by creating inclusion complexes with cyclodextrins (HP-β-CD and SBE-β-CD). The resulting complexes show significantly improved solubility and potent biological effects in vivo.
Area of Science:
- Pharmacology
- Materials Science
- Biochemistry
Background:
- Morin (MRN) is a natural compound with promising antiangiogenic, antioxidant, anti-inflammatory, and anticancer properties.
- However, its poor water solubility (28 μg/mL) severely limits oral absorption and bioavailability.
- Enhancing MRN solubility is crucial for improving its therapeutic potential, especially its antiangiogenic effects.
Purpose of the Study:
- To improve the water solubility and antiangiogenic activity of morin (MRN) by forming inclusion complexes.
- To investigate the complexation of MRN with hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD).
- To characterize the inclusion complexes and evaluate their biological efficacy in vivo.
Main Methods:
- Preparation of inclusion complexes using the freeze-drying method.
- Characterization of complexes in solution (phase-solubility, UV-Vis titration, NMR spectroscopy) and solid state (TGA, DSC, WAXD).
- In vivo antiangiogenic activity assessment using chick embryo chorioallantoic membrane (CAM) and zebrafish embryo models.
Main Results:
- Complexation with HP-β-CD and SBE-β-CD increased MRN water solubility by approximately 100 and 115 times, respectively.
- Quantitative dissolution of complexes occurred within 60 min, a significant improvement over free MRN.
- NMR and UV-Vis studies confirmed the inclusion of the benzoyl moiety of MRN within both cyclodextrins, with SBE-β-CD also interacting with the cinnamoyl moiety.
- Complexes demonstrated stability in solution with high association constants (3380 M⁻¹ for MRN/HP-β-CD, 2870 M⁻¹ for MRN/SBE-β-CD).
Conclusions:
- Inclusion complexes of MRN with HP-β-CD and SBE-β-CD effectively enhance morin's water solubility and dissolution rate.
- These complexes exhibit improved antiangiogenic activity in vivo compared to free morin.
- The study demonstrates the potential of cyclodextrin complexation to improve the bioavailability and therapeutic efficacy of morin.
