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Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery

机译：触发释放的聚合共轭胶束，用于按需细胞内药物递送

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Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 +/- 5.9 (nm) with a zeta potential of -10.6 +/- 0.7 (mV). The critical micelle concentration was determined at 6.7 +/- 0.4 (mu gmL(-1)). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5 +/- 1.4 (mu gmL(-1)), whereas the IC50 of control micelles was 41.0 +/- 2.4 (mu gmL(-1)). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice.
机译：在过去的四十年中，已经开发出了纳米级药物递送平台，在多种类型的癌症和炎症性疾病中显示出令人鼓舞的临床结果。这些携带治疗有效载荷的纳米载体可最大程度地提高治疗效果，同时最大程度减少不良影响。然而，药物开发人员面临的主要挑战之一是过早与按需释放药物的困境，这影响了治疗方案，疗效和潜在的毒性。在此，我们报道了氧化还原敏感的聚合物-药物共轭胶束，用于模型活性剂姜黄素的按需细胞内递送。将可生物降解的甲氧基聚（乙二醇）-聚（乳酸）共聚物（mPEG-PLA）分别通过二硫键或酯键（对照）与姜黄素结合。自组装的氧化还原敏感胶束的流体力学尺寸为115.6 +/- 5.9（nm），ζ电位为-10.6 +/- 0.7（mV）。临界胶束浓度确定为6.7 +/- 0.4（mu gmL（-1））。在模拟氧化还原环境（10 mM二硫苏糖醇）的洗涤条件下，姜黄素在48小时时从二硫键连接的胶束中释放的程度是对照胶束的近三倍。这种快速释放导致HeLa细胞的半数最大抑制浓度（IC50）降低至18.5 +/- 1.4（mu gmL（-1）），而对照胶束的IC50为41.0 +/- 2.4（mu gmL（-1） ））。细胞摄取研究还显示出对氧化还原敏感的胶束更高的荧光强度。总之，氧化还原敏感的聚合物共轭胶束可以增强姜黄素的输送，同时避免过早释放，并在细胞质中高谷胱甘肽浓度下实现按需释放。该策略为纳米级细胞内递送平台的按需药物释放开辟了新途径，最终可以转化为临床前和未来的临床实践。

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