Cyclodextrin complexation studies as the first step for repurposing of chlorpromazine

Area of Science:

• Pharmaceutical Chemistry
• Drug Delivery Systems
• Supramolecular Chemistry

Background:

• Chlorpromazine (CPZ), an antipsychotic, shows promise for acute myeloid leukemia treatment.
• Preventing CPZ's central nervous system side effects requires advanced drug delivery, like cyclodextrin-liposome systems.
• Complexation with cyclodextrins (CDs) is a key step for developing such systems.

Purpose of the Study:

• To investigate the complexation of CPZ with various CDs.
• To characterize the stoichiometry, binding affinity, and thermodynamic parameters of CPZ-CD complexes.
• To evaluate the photoprotective effects of CDs on CPZ.

Main Methods:

• Isothermal titration calorimetry (ITC) to determine binding constants and thermodynamics.
• Nuclear magnetic resonance (NMR) spectroscopy (1D and ROESY) for structural analysis.
• Molecular dynamics simulations to model complex formation.

Main Results:

• All tested CDs formed 1:1, 1:2, or mixed complexes with CPZ.
• Sugammadex, a modified gamma-cyclodextrin, formed exclusive 1:2 complexes with a high association constant (6.37 × 10^9 M^-2).
• CD complexation accelerated, rather than protected against, CPZ photodegradation.

Conclusions:

• CDs can form stable complexes with CPZ, providing a foundation for drug delivery systems.
• Sugammadex exhibits exceptionally strong binding, suitable for targeted drug delivery.
• Further research is needed to optimize CPZ delivery and address photodegradation issues.