a College of Science, Nanjing Forestry University , Nanjing , PR China.
b College of Life Science, Nanjing Normal University , Nanjing , PR China.
Drug Deliv. 2019 Dec;26(1):262-272. doi: 10.1080/10717544.2019.1580797.
Multidrug resistance (MDR) remains one of the major reasons for inefficiency of many chemotherapeutic agents in cancer therapy. In this study, a D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and polylysine-deoxycholic acid copolymer (PLL-DA) co-modified cationic liposome coating with hyaluronic acid (HA) was constructed for co-delivery of paclitaxel (PTX) and chemosensitizing agent, sorafenib (SOR) to treat the MDR cancer. The multifunctional liposome (HA-TPD-CL-PTX/SOR) presented good stability against rat plasma and was capable of reversing surface zeta potential under acidic conditions in the presence of HAase. Additionally, experimental result confirmed that the PLL-DA copolymer would facilitate the endo-lysosomal escape of the liposome. In vitro study demonstrated that HA-TPD-CL-PTX/SOR could significantly enhance drug accumulation in resistant MCF-7/MDR cells by inhibiting the P-gp efflux, and effectively inhibited growth of tumor cells. Furthermore, the liposome showed an enhanced anticancer activity in vivo, with a tumor growth inhibition rate of 78.52%. In summary, HA-TPD-CL-PTX/SOR exhibited a great potential for effective therapy of resistant cancers by combining with chemotherapeutic agents and could be a promising nano-carrier for reversing MDR and improving the effectiveness of chemotherapy.
多药耐药（MDR）仍然是许多癌症化疗药物疗效不佳的主要原因之一。在这项研究中，构建了一种 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）和聚赖氨酸-去氧胆酸共聚物（PLL-DA）共修饰的带有透明质酸（HA）的阳离子脂质体涂层，用于共递送紫杉醇（PTX）和化疗增敏剂索拉非尼（SOR）以治疗多药耐药性癌症。多功能脂质体（HA-TPD-CL-PTX/SOR）在大鼠血浆中具有良好的稳定性，并且在存在 HAase 的情况下能够在酸性条件下逆转表面 zeta 电位。此外，实验结果证实 PLL-DA 共聚物将有助于脂质体的内体-溶酶体逃逸。体外研究表明，HA-TPD-CL-PTX/SOR 通过抑制 P-糖蛋白外排可显著增加耐药 MCF-7/MDR 细胞中药物的积累，并有效抑制肿瘤细胞的生长。此外，该脂质体在体内显示出增强的抗癌活性，肿瘤生长抑制率为 78.52%。总之，HA-TPD-CL-PTX/SOR 通过与化疗药物联合使用显示出治疗耐药性癌症的巨大潜力，并且可以作为一种有前途的逆转多药耐药性和提高化疗效果的纳米载体。
