Construction and evaluation of liposomal drug delivery system for an ALK/HDACs dual-targeted inhibitor with sustained release and enhanced antitumor effect.

IF 5.7 3区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Drug Delivery and Translational Research Pub Date : 2025-03-01 Epub Date: 2024-08-07 DOI:10.1007/s13346-024-01647-1

Fang Ren, Zongjie Gan, Qianyu Zhang, Dan He, Baoyan Chen, Xianwei Wu, Xiaolin Zeng, Kexin Wu, Yangchen Xing, Yan Zhang, Huali Chen

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Abstract

ALK/HDACs dual target inhibitor (PT-54) was a 2,4-pyrimidinediamine derivative synthesized based on the pharmacophore merged strategy that inhibits both anaplastic lymphoma kinase (ALK) and histone deacetylases (HDACs), which has demonstrated significant efficacy in treating multiple cancers. However, its poor solubility in water limited its clinical application. In this study, we prepared PT-54 liposomes (PT-54-LPs) by the membrane hydration method to overcome this defect. The encapsulation efficiency (EE) and particle size were used as evaluation indicators to explore the preparation conditions of PT-54-LPs. The morphology, particle size, EE, drug loading content (DLC), drug release properties, and stability of PT-54-LPs were further investigated. In vitro drug release studies showed that PT-54-LPs exhibited significant slow-release properties compared with free PT-54. PT-54-LPs also showed better tumor inhibitory effects than free PT-54 without significant adverse effects. These results suggested that PT-54-LPs displayed sustained drug release and significantly improved the tumor selectivity of PT-54. Thus, PT-54-LPs showed significant promise in enhancing anticancer efficiency.

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构建和评估具有持续释放和增强抗肿瘤效果的 ALK/HDACs 双靶向抑制剂脂质体给药系统。

ALK/HDACs双靶点抑制剂（PT-54）是一种基于药源合并策略合成的2,4-嘧啶二胺衍生物，可同时抑制无性淋巴瘤激酶（ALK）和组蛋白去乙酰化酶（HDACs），在治疗多种癌症方面具有显著疗效。然而，其在水中的溶解性较差，限制了其临床应用。本研究采用膜水合法制备了 PT-54 脂质体（PT-54-LPs），克服了这一缺陷。以包封效率（EE）和粒径为评价指标，探讨了PT-54-LPs的制备条件。进一步研究了 PT-54-LPs 的形态、粒度、EE、载药量（DLC）、药物释放性能和稳定性。体外药物释放研究表明，与游离 PT-54 相比，PT-54-LPs 具有明显的缓释特性。与游离 PT-54 相比，PT-54-LPs 还表现出更好的肿瘤抑制效果，且无明显不良反应。这些结果表明，PT-54-LPs 具有持续的药物释放特性，并显著提高了 PT-54 的肿瘤选择性。因此，PT-54-LPs 在提高抗癌效率方面大有可为。

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来源期刊

Drug Delivery and Translational Research MEDICINE, RESEARCH & EXPERIMENTALPHARMACOL-PHARMACOLOGY & PHARMACY

CiteScore

11.70

自引率

1.90%

发文量

160

期刊介绍： The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions. Research focused on the following areas of translational drug delivery research will be considered for publication in the journal. Designing and developing novel drug delivery systems, with a focus on their application to disease conditions; Preclinical and clinical data related to drug delivery systems; Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes Short-term and long-term biocompatibility of drug delivery systems, host response; Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering; Image-guided drug therapy, Nanomedicine; Devices for drug delivery and drug/device combination products. In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.