Department of Biomedical Engineering, University of Houston, Houston, TX, USA.
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, USA.
Colloids Surf B Biointerfaces. 2019 Dec 1;184:110481. doi: 10.1016/j.colsurfb.2019.110481. Epub 2019 Sep 2.
This study aims to develop a new anti-cancer formulation based on the chelator Dp44mT (Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone). Dp44mT has outstanding anti-tumor activity and the unique ability to overcome multidrug-resistance in cancer cells. This highly toxic compound has thus far only been applied in free form, limiting its therapeutic effectiveness. To reach its full therapeutic potential, however, Dp44mT should be encapsulated in a nano-carrier that would enable its selective and controlled delivery to malignant cells. As the first step towards this goal, here we encapsulate Dp44mT in nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA), characterize this nano-formulation, and evaluate its therapeutic potential against cancer cells in vitro. Our results showed that the Dp44mT-loaded NPs were homogenous in shape and size, and had good colloidal stability. These PLGA NPs also showed high encapsulation efficiency and loading capacity for Dp44mT and enabled the sustained and tunable release of this chelator. Dp44mT-NPs were uptaken by cancer cells, showed a strong and dose-dependent cytotoxicity towards these cells, and significantly increased apoptotic cell death, in both monolayer and spheroid tumor models. This formulation had a low-level of toxicity towards healthy control cells, indicating an inherent selectivity towards malignant cells. These results demonstrate the great potential of this novel Dp44mT-based nano-formulation for the use in cancer therapy.
本研究旨在开发一种基于螯合剂 Dp44mT（二吡啶酮-4,4-二甲基-3-硫代缩氨基甲）的新型抗癌制剂。Dp44mT 具有出色的抗肿瘤活性和独特的克服癌细胞多药耐药的能力。这种剧毒化合物迄今为止仅以游离形式应用，限制了其治疗效果。然而，为了发挥其全部治疗潜力，Dp44mT 应封装在纳米载体中，以便能够选择性和控制递送到恶性细胞。作为实现这一目标的第一步，我们将 Dp44mT 封装在聚（乳酸-共-乙醇酸）（PLGA）的纳米颗粒（NPs）中，对这种纳米制剂进行了表征，并评估了其在体外对癌细胞的治疗潜力。我们的结果表明，负载 Dp44mT 的 NPs 形状和大小均匀，具有良好的胶体稳定性。这些 PLGA NPs 对 Dp44mT 具有高包封效率和载药能力，并能够持续和可调控制释放这种螯合剂。Dp44mT-NPs 被癌细胞摄取，对这些细胞表现出强烈的、剂量依赖性的细胞毒性，并在单层和球体肿瘤模型中显著增加细胞凋亡。该制剂对健康对照细胞的毒性较低，表明对恶性细胞具有固有选择性。这些结果表明，这种新型基于 Dp44mT 的纳米制剂在癌症治疗中有很大的应用潜力。
