Bivalent sequential binding of docetaxel to methyl-β-cyclodextrin.

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Physical Chemistry

Background:

• Docetaxel (Dtx) is a potent chemotherapeutic agent with poor water solubility, limiting its clinical application.
• Cyclodextrins (CDs) are widely used as complexing agents to improve the solubility and bioavailability of poorly soluble drugs.
• Understanding the complexation mechanism is crucial for optimizing drug formulation and delivery.

Purpose of the Study:

• To develop novel docetaxel (Dtx) and cyclodextrin (CD) inclusion complexes with enhanced apparent water solubility.
• To investigate the complexation mechanism between Dtx and specific CDs, particularly Me-β-CD.
• To elucidate the binding interactions and thermodynamics governing the Dtx-Me-β-CD complex formation.

Main Methods:

• Phase solubility diagrams were constructed to evaluate solubility enhancements.
• Complexation was studied using circular dichroism (CD) spectrometry and 2D NMR (NOESY).
• Isothermal titration calorimetry (ITC) and molecular docking calculations were employed to determine binding mechanisms and thermodynamics.

Main Results:

• Significant increases in Dtx apparent water solubility were achieved, reaching up to 9.98 mg/mL with Me-β-CD (20% w/w) and 7.43 mg/mL with HP-β-CD (40% w/w).
• CDs like γ-CD and SBE-β-CD showed only minor solubility improvements.
• Circular dichroism and NOESY confirmed non-covalent interactions, with Dtx's tert-butyl and aromatic groups interacting with Me-β-CD.
• ITC and molecular docking revealed an unconventional sequential binding mechanism of Me-β-CD to Dtx, involving two distinct binding events with different affinities (K1: 744 M⁻¹, K2: 202 M⁻¹).
• The first binding event exhibited positive entropy, while the second showed negative entropy, attributed to differences in hydrophobic contact and flexibility.

Conclusions:

• Me-β-CD and HP-β-CD are effective complexing agents for significantly enhancing docetaxel water solubility.
• The study elucidated a novel sequential binding mechanism between Me-β-CD and Dtx, providing insights into the molecular interactions.
• These findings support the potential of CD-based formulations for improving docetaxel's therapeutic efficacy.