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

<b>Background:</b> 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. <b>Objective:</b>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. <b>Methods</b>The 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. <b>Results:</b>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. <b>Conclusions:</b> 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，甲磺嘌呤司他（Purinostat Mesylate，PM）是一种新型组蛋白去乙酰化酶（HDAC）抑制剂，具备显著的抗肿瘤活性。然而，甲磺嘌呤司他水溶性较差且生物利用度低，极大限制了其临床应用。
**研究目的：** 本研究旨在通过药剂学研究提升PM的溶解度，制备符合静脉给药需求的注射剂，以推动其临床转化与应用。
**研究方法：** 对所制备的PM/羟丙基-β-环糊精（HP-β-CD）包合物，采用计算机模拟、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）进行表征分析。随后通过体外细胞毒性实验、细胞凋亡实验、药代动力学研究及体内抗肿瘤实验，评估PM/HP-β-CD包合物的抗肿瘤效果。
**研究结果：** 相溶解度分析结果显示，PM与HP-β-CD具有良好的相容性，PM的溶解度提升了近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的空腔内。细胞活力与细胞凋亡实验证实，PM/HP-β-CD包合物保留了PM优异的抗癌活性；体内实验结果显示，该包合物相较于LBH589与Hyper-CVAD/RTX，具备更优的抗肿瘤效果与更低的毒性。所有研究结果均表明，HP-β-CD可有效解决PM的给药难题，为其临床应用提供了可行路径。
**研究结论：** 本研究成功制备了10% w/v的HP-β-CD载PM注射剂，显著改善了其水溶性。本研究为PM的临床给药提供了可行方案，目前该制剂已在中国与美国开展治疗复发/难治性B细胞相关血液系统恶性肿瘤的I期临床试验。
**核心要点：**
1. 本研究开发了可静脉给药的甲磺嘌呤司他制剂，降低了口服给药相关的毒性反应。
2. 该制剂对SU-DHL-6异种移植瘤具有优异的治疗效果，具备潜在临床应用价值，目前已在中国与美国开展治疗复发/难治性B细胞相关血液系统恶性肿瘤的I期临床试验。