Annals of Medicine (Dec 2022)
Therapeutic efficacy of an injectable formulation of purinostat mesylate in SU-DHL-6 tumour model
Abstract
Background: Previous studies have proven that Purinostat Mesylate (PM) is a new HDAC inhibitor and exhibits significant antitumor efficacy. However, the clinical application of PM was greatly limited by its poor solubility in water and low bioavailability.Objective:To increase the solubility of PM through pharmaceutical research, and prepare it into an injection that meets the needs of intravenous use to promote its clinical application.MethodsThe prepared PM/HP-β-CD inclusion complex was studied by computer simulation, fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (1H-NMR spectroscopy), and scanning electron microscopy (SEM). Then, the antitumor effects of PM/HP-β-CD inclusion complex were studied by in vitro cytotoxicity assay, apoptosis assay, pharmacokinetic study and in vivo antitumor assay.Results:Phase Solubility Analysis revealed that PM and HP-β-CD were compatible and the solubility of PM increased almost 220 times, to 2.02 mg/mL. The interaction mechanism studies revealed that PM could be embedded into the cavity of HP-β-CD through the side of the aminobenzene ring. Cell viability and apoptosis assays showed that PM/HP-β-CD complex maintained the good anti-cancer activity of PM, and PM/HP-β-CD complex has a better anti-tumor effect and lower toxicity than LBH589 and Hyper-CVAD/RTX in vivo. All the results suggest that HP-β-CD can solve the problem of PM administration and provide a way for clinical application of PM.Conclusions: In this study, an injectable formulation of PM in HP-β-CD (10% w/v) was prepared to improve its water solubility. Our research provides a way for clinical administration of PM, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related hematologic malignancies in China and the USA.KEY MESSAGESWe developed a preparation of Purinostat Mesylate that can be administered intravenously, reducing the toxicity associated with oral administration.This preparation has an outstanding therapeutic effect on SU-DHL-6 xenograft tumour, indicating its clinical value, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related haematologic malignancies in China and the USA.
Keywords
