Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 92290 Châtenay-Malabry, France.
Unité de Chimie Environnementale et Interactions sur le Vivant (UCEIV, EA 4492), SFR Condorcet FR CNRS 3417, Université du Littoral Côte d'Opale, 59140 Dunkerque, France.
Int J Pharm. 2020 Jun 30;584:119391. doi: 10.1016/j.ijpharm.2020.119391. Epub 2020 May 4.
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 M. Complexes were further characterized by heat capacity changes, one- and two-dimensional (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.
抗精神病药物氯丙嗪(CPZ)有可能用于治疗急性髓系白血病,如果能防止其穿过血脑屏障引起的中枢神经系统副作用。一种用于 CPZ 再利用的强大药物输送系统将是药物-环糊精-脂质体,它将使药物远离大脑,同时避免在循环中过早释放。作为第一步,已经研究了 CPZ 与环糊精(CD)的络合。通过等温滴定量热法(ITC)研究了 CPZ 与一系列 CD 之间的配合物形成的化学计量比、结合常数、焓和熵。所有测试的 CD 都能够以 1:1、1:2 或 1:1 和 1:2 配合物的混合物的形式包含 CPZ。特别是,一种取代的 γ-CD,即八聚(6-脱氧-6-S-(2-羧乙基)-6-硫)环麦芽八聚糖的八钠盐,与 CPZ 形成了仅 1:2 的复合物,具有极高的结合常数 6.37×10 M。通过热容变化、一维和二维(ROESY)核磁共振(NMR)光谱和分子动力学模拟进一步表征了配合物。最后,评估了 CD 对 CPZ 光降解的保护作用。CPZ 与 CD 络合反而加速了光降解。总之,这些结果为 CD 在 CPZ 延迟释放制剂中的应用提供了分子基础。