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首页> 外文期刊>ACS applied materials & interfaces >MMP2-Sensitive PEG-Lipid Copolymers: A New Type of Tumor-Targeted P-Glycoprotein Inhibitor
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MMP2-Sensitive PEG-Lipid Copolymers: A New Type of Tumor-Targeted P-Glycoprotein Inhibitor

机译：MMP2敏感的PEG脂质共聚物：一种新型的肿瘤靶向的P糖蛋白抑制剂。

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Low tumor targetability and multidrug resistance (MDR) are two major impediments to the success of cancer treatments. Nanomaterials which possess high tumor targetability and the ability to reverse the MDR are rare. This report describes a new type of self-assembling polyethylene glycol-phosphoethanolamine-based copolymers (PEG-pp-PE) which showed both the matrix metalloproteinase 2 (MMP2)-sensitive tumor-targeted drug delivery and ability to inhibit the P-glycoprotein (P-gp)-mediated drug efflux. In this study, we synthesized a series of the homologous analogues of PEG-pp-PE copolymers and investigated the influence of their structures, including PEG lengths and peptide linkers, on the drug efflux, and identified the underlying mechanisms. We found that the whole structure (PEG-peptide-lipid) rather than any parts of the copolymers was key for the P-gp inhibition and a delicate balance between the hydrophilic and lipophilic segments of the PEG pp-PE copolymers was needed for better modulating the P-gp-mediated drug efflux. The best copolymer, PEG2k-pp-PE, showed even higher P-gp inhibition effect than the D-a-tocopherol polyethylene glycol 1000 succinate (TPGS1k). We also found that the P-gp inhibition capability of PEG-pp-PE copolymers was highly associated with the P-gp down-regulation, the increase in the plasma membrane fluidity, and the inhibition of the P-gp ATPase activity. Besides, the excellent physicochemical properties, high drug loading, MMP2-dependent drug release, and improved drug efficacy in the MDR cancer cells suggested that the PEG-pp-PE copolymers might have great potential for building tumor-targeted drug delivery systems for treating drug-resistant cancers.
机译：低的肿瘤靶向性和多药耐药性（MDR）是成功治疗癌症的两个主要障碍。具有高肿瘤靶向性和逆MDR能力的纳米材料很少见。本报告介绍了一种新型的自组装聚乙二醇-磷酸乙醇胺基共聚物（PEG-pp-PE），该共聚物既显示基质金属蛋白酶2（MMP2）敏感的肿瘤靶向药物传递，又具有抑制P-糖蛋白（ P-gp）介导的药物外排。在这项研究中，我们合成了一系列PEG-pp-PE共聚物的同源类似物，并研究了其结构（包括PEG长度和肽接头）对药物外排的影响，并确定了潜在的机制。我们发现，整个结构（PEG-肽-脂质）而不是共聚物的任何部分是抑制P-gp的关键，而PEG pp-PE共聚物的亲水链段和亲脂链段之间需要微妙的平衡，以便更好地调节P-gp介导的药物外排。最好的共聚物PEG2k-pp-PE显示出比D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS1k）更高的P-gp抑制作用。我们还发现，PEG-pp-PE共聚物的P-gp抑制能力与P-gp的下调，质膜流动性的增加以及P-gp ATPase活性的抑制高度相关。此外，优异的理化性质，高载药量，MMP2依赖性药物释放以及在MDR癌细胞中改善的药物功效表明PEG-pp-PE共聚物在构建靶向肿瘤的药物递送系统以治疗药物方面可能具有巨大潜力。耐药性癌症。

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