Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China.
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, PR China; State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Int J Pharm. 2019 Feb 25;557:374-389. doi: 10.1016/j.ijpharm.2018.12.051. Epub 2019 Jan 3.
The 'repurposed drug,' disulfiram (DSF), is an inexpensive FDA-approved anti-alcoholism drug with multi-target anti-cancer effect. However, the use of DSF in clinical settings remains limited due to its high instability in blood. In the present study, we created nanostructured lipid carriers (NLC) encapsulated DSF modified with d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E-TPGS). A spherical shape, superior drug encapsulation (80.7%), and decreased crystallinity of DSF were confirmed with results obtained from TEM, XRD, and DSC analysis. Addition of TPGS considerably improved the physicochemical stability profile of NLC-encapsulated DSF under the different conditions tested here. Furthermore, TPGS-DSF-NLCs outperformed unmodified DSF-NLCs and the free DSF solution by having significantly higher cytotoxicity, lower IC50 value (4T1: 263.2 nM and MCF-7: 279.9 nM), and an enhanced cellular uptake in MCF7 and 4T1 cell lines. In vivo anti-tumor analysis in 4T1 murine xenograft model mice revealed a significant (p-value < 0.05) decrease in tumor volume and higher tumor growth inhibition rate (48.24%) with TPGS-DSF-NLC treatment as compared to both the free DSF solution (8.49%) and DSF-NLC formulations (29.2%). Histopathology analysis of tumor tissues further confirmed a noticeably higher anti-tumor activity of TPGS-DSF-NLC through augmented cell necrosis in solid tumors. Hence, the present study established that addition of TPGS can synergize the anti-cancer activity of NLC-encapsulated DSF formulations, and thus, offer a promising anti-cancer delivery system for DSF.
“再利用药物”双硫仑（DSF）是一种廉价的美国食品和药物管理局（FDA）批准的抗酒精中毒药物，具有多靶点抗癌作用。然而，由于其在血液中的高不稳定性，DSF 在临床中的应用仍然有限。在本研究中，我们创建了纳米结构脂质载体（NLC）封装的 DSF，并用 d-α-生育酚聚乙二醇 1000 琥珀酸酯（维生素 E-TPGS）进行了修饰。通过 TEM、XRD 和 DSC 分析，证实了 DSF 的球形形状、优异的药物包封（80.7%）和结晶度降低。TPGS 的添加大大改善了 NLC 包封 DSF 在本研究中测试的不同条件下的物理化学稳定性。此外，TPGS-DSF-NLC 在具有更高的细胞毒性、更低的 IC50 值（4T1：263.2 nM 和 MCF-7：279.9 nM）和增强的 MCF7 和 4T1 细胞系摄取方面，优于未修饰的 DSF-NLC 和游离 DSF 溶液。在 4T1 小鼠异种移植模型小鼠中的体内抗肿瘤分析表明，与游离 DSF 溶液（8.49%）和 DSF-NLC 制剂（29.2%）相比，用 TPGS-DSF-NLC 治疗可显著（p 值<0.05）降低肿瘤体积和提高肿瘤生长抑制率（48.24%）。肿瘤组织的组织病理学分析进一步证实，通过增加实体瘤中的细胞坏死，TPGS-DSF-NLC 具有更高的抗肿瘤活性。因此，本研究表明，添加 TPGS 可以协同增强 NLC 包封的 DSF 制剂的抗癌活性，从而为 DSF 提供了一种有前途的抗癌输送系统。
