Cyclodextrin Complexation Studies as the First Step for Repurposing of Chlorpromazine

Zhiqiang Wang (1) , David Landy (2) , Christina Sizun (3, 4) , Christine Cézard (5) , Audrey Solgadi (6) , Cédric Przybylski (7) , Luc De Chaisemartin (8, 9) , Lars Herfindal (10) , Gillian Barratt (1) , François-Xavier Legrand (1)

1 IGPS - Institut Galien Paris-Saclay
2 UCEIV - Unité de Chimie Environnementale et Interactions sur le Vivant
3 ICSN - Institut de Chimie des Substances Naturelles
4 CNRS - Centre National de la Recherche Scientifique
5 LG2A - Laboratoire de Glycochimie, des Antimicrobiens et des Agro-ressources - UMR CNRS 7378
6 IPSIT - Ingénierie et Plateformes au Service de l'Innovation Thérapeutique
7 CSOB - Chimie Structurale Organique et Biologique
8 Service d'hématologie et immunologie
9 MI2 - Inflammation, microbiome, immunosurveillance
10 UiB - University of Bergen

The antipsychotic drug chlorpromazine (CPZ) has potential for the treatment of acute myeloid leukemia, if central nervous system side-effects resulting from its passage through the blood-brain barrier can be prevented. A robust drug delivery system for repurposed CPZ would be drug-in-cyclodextrin-in-liposome that would redirect the drug away from the brain while avoiding premature release in the circulation. As a first step, CPZ complexation with cyclodextrin (CD) has been studied. The stoichiometry, binding constant, enthalpy, and entropy of complex formation between CPZ and a panel of CDs was investigated by isothermal titration calorimetry (ITC). All the tested CDs were able to include CPZ, in the form of 1:1, 1:2 or a mixture of 1:1 and 1:2 complexes. In particular, a substituted γ-CD, sugammadex (the octasodium salt of octakis(6-deoxy-6-S-(2-carboxyethyl)-6-thio)cyclomaltooctaose), formed exclusively 1:2 complexes with an extremely high association constant of 6.37 × 10 9 M −2. Complexes were further characterized by heat capacity changes, one-and twodimensional (ROESY) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations. Finally, protection of CPZ against photodegradation by CDs was assessed. This was accelerated rather than reduced by complexation with CD. Altogether these results provide a molecular basis for the use of CD in delayed release formulations for CPZ.

Mots clés: CSOB; Cyclodextrin; Chlorpromazine; Inclusion complex; Sugammadex; Photodegradation; Repurposin

Domaines: Chimie

Zhiqiang Wang, David Landy, Christina Sizun, Christine Cézard, Audrey Solgadi, et al.. Cyclodextrin Complexation Studies as the First Step for Repurposing of Chlorpromazine. International Journal of Pharmaceutics, 2020, 584, pp.119391. ⟨10.1016/j.ijpharm.2020.119391⟩. ⟨hal-02885940⟩