It is discovered that sustained cytosolic drug release at a sufficient concentration is an effective mechanism to circumvent multidrug resistance and consequently enhance antitumor drug efficacy. It is showed that a simple way to enable this mechanism is to reach an intracellular kinetic balance of the drug movement between the drug released from the carrier into the cytosol and the one removed from the cell interior. By adopting nanoparticle (NP) as the drug carrier, a reservoir of drug can be maintained inside the cells upon effective cellular uptake of these NPs via endocytosis. This study shows that gradual release of the drug from the NP carrier provides a feasible scheme for sustained drug release in cells, resulting in relatively stable cytosolic drug concentration level, particularly in the drug resistant case. By implementing an “optical switch” with light irradiation on photosensitizer in the same nanoparticle carrier, cytosolic drug release is further promoted, which increases cytosolic drug concentration with good concentration retention. Enhanced drug efficacy in drug sensitive as well as resistant models is demonstrated both in vitro and in vivo. Such a mechanism is shown to efficiently circumvent multidrug resistance, and at the same time largely reduce the systemic toxicity of the anticancer drug.

中文翻译：

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使用细胞溶质药库规避癌症的多药耐药性

发现以足够的浓度持续释放胞质药物是避免多药耐药性并因此增强抗肿瘤药功效的有效机制。结果表明，实现这种机制的一种简单方法是，在从载体释放到细胞质中的药物与从细胞内部移出的药物之间达到药物运动的细胞内动力学平衡。通过采用纳米颗粒（NP）作为药物载体，通过内吞作用有效吸收这些NP后，可以在细胞内部维持药物储库。这项研究表明，从NP载体逐渐释放药物为在细胞中持续释放药物提供了可行的方案，从而导致相对稳定的胞质药物浓度水平，特别是在耐药情况下。通过在同一纳米颗粒载体中的光敏剂上实施光照射的“光学开关”，可进一步促进细胞溶质药物的释放，从而增加细胞溶质药物的浓度，并保持良好的浓度。在药物敏感性和耐药性模型中均在体外和体内均显示出增强的药物功效。已显示出这种机制有效地规避了多药耐药性，同时大大降低了抗癌药的全身毒性。