Integrating the drug, disulfiram into the vitamin E-TPGS-modified PEGylated nanostructured lipid carriers to synergize its repurposing for anti-cancer therapy of solid tumors
Integrating the drug, disulfiram into the vitamin E-TPGS-modified PEGylated nanostructured lipid carriers to synergize its repurposing for anti-cancer therapy of solid tumors
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DOI：
10.1016/j.ijpharm.2018.12.051
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发表时间：
2019-02-25
影响因子：
5.8
通讯作者：
Wang, Bo
中科院分区：
文献类型：
--
作者：
Banerjee, Parikshit;Geng, Tianjiao;Wang, Bo
这种被重新利用的药物，双硫仑（DSF），是一种廉价的FDA批准的具有多靶点抗癌作用的抗酒精中毒药物。然而，由于DSF在血液中的高度不稳定性，其在临床环境中的使用仍然有限。在本研究中，我们创建了纳米结构脂质载体（NLC）封装DSF与D-α-生育酚聚乙二醇1000琥珀酸酯（维生素E-TPGS）改性。通过TEM、XRD和DSC分析证实了DSF的球形形状、上级药物包封率（80.7%）和结晶度降低。TPGS的添加显著改善了NLC包封的DSF在本文测试的不同条件下的物理化学稳定性。此外，TPGS-DSF-NLC通过具有显著更高的细胞毒性、更低的IC 50值（4 T1：263.2 nM和MCF 7：279.9 nM）以及在MCF 7和4 T1细胞系中增强的细胞摄取而优于未修饰的DSF-NLC和游离DSF溶液。在4 T1鼠异种移植模型小鼠中的体内抗肿瘤分析显示，与游离DSF溶液（8.49%）和DSF-NLC制剂（29.2%）相比，用TPGS-DSF-NLC处理的肿瘤体积显著（p值< 0.05）减小并且肿瘤生长抑制率更高（48.24%）。肿瘤组织的组织学分析进一步证实了TPGS-DSF-NLC通过增强实体瘤中的细胞坏死而具有显著更高的抗肿瘤活性。因此，本研究确定，添加TPGS可以协同NLC包封的DSF制剂的抗癌活性，从而为DSF提供有希望的抗癌递送系统。
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-alpha-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 MCF7: 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.