Jian Cheng-Bang, Yu Xu-En, Gao Hua-De, Chen Huai-An, Jheng Ren-Hua, Chen Chong-Yan, Lee Hsien-Ming
Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan.
Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan.
Nanomaterials (Basel). 2022 Jan 3;12(1):163. doi: 10.3390/nano12010163.
Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome's interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors-vadadustat and roxadustat-to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.
含脯氨酰羟化酶结构域蛋白2（PHD2）抑制可稳定缺氧诱导因子（HIF）-1α，从而触发细胞对缺氧的适应性反应，已成为一个重要的治疗靶点。尽管已证实小分子PHD2抑制剂如IOX2具有高效能，但可能需要纳米制剂以实现良好的生物分布，从而降低脱靶毒性。脂质体制剂可改善包封药物的药代动力学，同时实现靶向递送，是一个可行的选择。本研究旨在开发一种高效装载方法，可将IOX2及其他具有相似药效团特征的PHD2抑制剂包封于纳米脂质体中。在跨膜醋酸钙梯度的驱动下，通过优化脂质体外溶液，实现了IOX2向脂质体近100%的远程装载效率。电子显微镜成像显示，装载后IOX2在脂质体内部隔室中形成纳米沉淀。在细胞实验中，就诱导HIF-1α水平而言，脂质体IOX2的效果优于游离药物，尤其是在使用靶向配体时。该方法还能将两种临床使用的抑制剂——vadadustat和roxadustat——以高包封效率装载到脂质体中，表明其在装载其他杂环甘氨酰胺PHD2抑制剂方面具有通用性。我们认为，PHD2抑制剂的脂质体制剂，特别是与主动靶向相结合时，在治疗更具特异性定位的疾病病变方面具有治疗潜力。
