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首页> 外文期刊>Nanotechnology >Alpha-tocopheryl polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles for reversal of multidrug resistance in vitro
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Alpha-tocopheryl polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles for reversal of multidrug resistance in vitro

机译：α-生育酚聚乙二醇琥珀酸酯乳化的聚乳酸-乙醇酸纳米粒子在体外逆转多药耐药性

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Multidrug resistance (MDR) is one of the factors in the failure of anticancer chemotherapy. In order to enhance the anticancer effect of P-glycoprotein (P-gp) substrates, inhibition of the P-gp efflux pump on MDR cells is a good tactic. We designed novel multifunctional drug-loaded alpha-tocopheryl polyethylene glycol succinate (TPGS)/poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TPGS/PLGA/SN-38 NPs; SN-38 is 7-ethyl-10-hydroxy- camptothecin), with TPGS-emulsified PLGA NPs as the carrier and modulator of the P-gp efflux pump and SN-38 as the model drug. TPGS/PLGA/SN-38 NPs were prepared using a modified solvent extraction/evaporation method. Physicochemical characterizations of TPGS/PLGA/SN-38 NPs were in conformity with the principle of nano-drug delivery systems (nDDSs), including a diameter of about 200 nm, excellent spherical particles with a smooth surface, narrow size distribution, appropriate surface charge, and successful drug-loading into the NPs. The cytotoxicity of TPGS/PLGA/SN-38 NPs to MDR cells was increased by 3.56 times compared with that of free SN-38. Based on an intracellular accumulation study relative to the time-dependent uptake and efflux inhibition, we suggest novel mechanisms of MDR reversal of TPGS/PLGA NPs. Firstly, TPGS/PLGA/SN-38 NPs improved the uptake of the loaded drug by clathrin-mediated endocytosis in the form of unbroken NPs. Simultaneously, intracellular NPs escaped the recognition of P-gp by MDR cells. After SN-38 was released from TPGS/PLGA/SN-38 NPs in MDR cells, TPGS or/and PLGA may modulate the efflux microenvironment of the P-gp pump, such as mitochondria and the P-gp domain with an ATP-binding site. Finally, the controlled-release drug entered the nucleus of the MDR cell to induce cytotoxicity. The present study showed that TPGS-emulsified PLGA NPs could be functional carriers in nDDS for anticancer drugs that are also P-gp substrates. More importantly, to enhance the therapeutic effect of P-gp substrates, this work might provide a new insight into the design of pharmacologically inactive excipients that can serve as P-gp modulators instead of drugs that are P-gp inhibitors.
机译：多药耐药（MDR）是抗癌化疗失败的因素之一。为了增强P-糖蛋白（P-gp）底物的抗癌作用，抑制P-gp外排泵对MDR细胞是一种很好的策略。我们设计了新颖的多功能载药α-生育酚聚乙二醇琥珀酸酯（TPGS）/聚乳酸-乙醇酸共聚物（PLGA）纳米粒子（TPGS / PLGA / SN-38 NPs; SN-38是7-乙基-10-羟基喜树碱），以TPGS乳化的PLGA NP为载体和P-gp外排泵的调节剂，而SN-38为模型药物。 TPGS / PLGA / SN-38 NP使用改良的溶剂萃取/蒸发方法制备。 TPGS / PLGA / SN-38 NP的理化特性符合纳米药物递送系统（nDDSs）的原理，包括直径约200 nm，具有光滑表面，尺寸分布窄，表面电荷适中的优异球形颗粒，并成功将药物加载到NP中。 TPGS / PLGA / SN-38 NPs对MDR细胞的毒性是游离SN-38的3.56倍。基于相对于时间依赖性摄取和外排抑制的细胞内积累研究，我们提出了TPGS / PLGA NPs MDR逆转的新机制。首先，TPGS / PLGA / SN-38 NPs以不间断的NPs形式通过网格蛋白介导的内吞作用改善了负载药物的摄取。同时，细胞内NP逃脱了MDR细胞对P-gp的识别。 SN-38从MDR细胞中的TPGS / PLGA / SN-38 NPs释放后，TPGS或/和PLGA可以调节P-gp泵的外排微环境，例如线粒体和具有ATP结合的P-gp结构域现场。最后，控释药物进入MDR细胞核以诱导细胞毒性。本研究表明，TPGS乳化的PLGA NPs可以作为nDDS中的功能载体，用于抗癌药物，也是P-gp底物。更重要的是，为了增强P-gp底物的治疗效果，这项工作可能为药理学上无活性的赋形剂的设计提供新的见解，这些赋形剂可以用作P-gp调节剂，而不是作为P-gp抑制剂的药物。

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