Therapeutic efficacy of an injectable formulation of purinostat mesylate in SU-DHL-6 tumour model

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. We 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.

背景：既往研究证实，甲磺酸普立诺司他(Purinostat Mesylate, PM)是一种新型组蛋白去乙酰化酶(HDAC)抑制剂，具有显著的抗肿瘤活性。然而，该化合物水溶性较差、生物利用度低，极大限制了其临床应用。目的：本研究旨在通过药物制剂研究提升PM的水溶性，并将其制备为符合静脉给药要求的注射剂，以推动其临床应用。方法：本研究通过计算机模拟、傅里叶变换红外光谱(FT-IR)、核磁共振氢谱(1H-NMR)以及扫描电子显微镜(SEM)，对制备得到的PM/羟丙基-β-环糊精(HP-β-CD)包合物进行表征分析；随后通过体外细胞毒性实验、细胞凋亡实验、药代动力学研究以及体内抗肿瘤实验，考察PM/HP-β-CD包合物的抗肿瘤效果。结果：相溶解度分析结果显示，PM与HP-β-CD具有良好的相容性，PM的水溶性提升了近220倍，达到2.02 mg/mL。相互作用机制研究表明，PM可通过氨基苯环一侧嵌入HP-β-CD的空腔结构中。细胞活力与凋亡实验结果证实，PM/HP-β-CD包合物保留了PM优异的抗癌活性，且在体内的抗肿瘤效果优于LBH589与Hyper-CVAD/RTX，同时毒性更低。上述结果表明，HP-β-CD可解决PM的给药难题，为其临床应用提供了可行路径。结论：本研究制备了以HP-β-CD(10% w/v)为载体的PM注射剂，以提升其水溶性。本研究为PM的临床给药提供了可行方案，该制剂目前已在中国与美国开展复发或难治性B细胞相关血液系统恶性肿瘤治疗的I期临床试验。核心要点：本研究开发了可静脉给药的甲磺酸普立诺司他制剂，降低了口服给药相关的毒性反应。该制剂对SU-DHL-6异种移植瘤具有优异的治疗效果，彰显了其临床应用价值，目前已在中国与美国开展复发或难治性B细胞相关血液系统恶性肿瘤治疗的I期临床试验。本研究开发了可静脉给药的甲磺酸普立诺司他制剂，降低了口服给药相关的毒性反应。该制剂对SU-DHL-6异种移植瘤具有优异的治疗效果，彰显了其临床应用价值，目前已在中国与美国开展复发或难治性B细胞相关血液系统恶性肿瘤治疗的I期临床试验。