Glutathione and Reactive Oxygen Species Dual-Responsive Block Copolymer Prodrugs for Boosting Tumor Site-Specific Drug Release and Enhanced Antitumor Efficacy.,Biomacromolecules

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Glutathione and Reactive Oxygen Species Dual-Responsive Block Copolymer Prodrugs for Boosting Tumor Site-Specific Drug Release and Enhanced Antitumor Efficacy.
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-01-30 , DOI: 10.1021/acs.biomac.9b01578
Wei Yin _{1,

2} , Wendong Ke ₂ , Nannan Lu _{2,

3} , Yuheng Wang ₂ , Abd Al-Wali Mohammed M Japir ₂ , Fathelrahman Mohammed ₂ , Yi Wang ₄ , Yueyin Pan ₃ , Zhishen Ge _{2,

3}

Affiliation

A remarkable hallmark of cancer cells is the heterogeneous coexistence of overproduced intracellular glutathione (GSH) and a high level of reactive oxygen species (ROS) compared with those in normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of the stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g., GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG)- and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide or thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in an aqueous solution with a diameter of ∼50 nm. Compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with the half-inhibitory concentration (IC50) of 6.3 μM, which is much lower than 17.8 μM for G-BCP and 28.9 μM for R-BCP. Moreover, for in vivo antitumor performance, G-BCP, R-BCP, and GR-BCP showed similar efficiencies in blood circulation and tumor accumulation after intravenous injection. However, GR-BCP realized the most efficient tumor suppression with few side effects. Our findings demonstrate that intracellular GSH and ROS dual-responsive BCPs show a more efficient responsive drug release inside tumor cells for boosting the antitumor efficacy as compared with GSH or ROS single-responsive BCPs, which provides novel strategies for designing redox-responsive BCPs.

中文翻译：

谷胱甘肽和活性氧双反应嵌段共聚物前药，用于促进肿瘤部位特异性药物释放和增强的抗肿瘤功效。

癌细胞的一个显着标志是与正常细胞相比，过量产生的细胞内谷胱甘肽（GSH）和高水平的活性氧（ROS）异质共存，它们经常被用作刺激来触发药物从纳米载体上释放。大多数刺激响应性递送载体已被设计成仅对一种氧化还原刺激（例如，GSH或ROS）响应。本文中，我们开发了一种GSH和ROS双反应性两亲性二嵌段共聚物前药（BCP）（GR-BCP），该药物由侧链中的聚乙二醇（PEG）和喜树碱（CPT）共轭的聚（甲基丙烯酸酯）组成硫醚键。相比之下，制备了GSH或ROS单反应BCP（G-BCP或R-BCP），其中CPT药物分别通过二硫键或硫代缩酮键连接。这三种BCP可以在直径约50 nm的水溶液中形成轮廓分明的球形胶束纳米颗粒。与G-BCP和R-BCP相比，GR-BCP对HeLa细胞具有最高的细胞毒性，其半抑制浓度（IC50）为6.3μM，远低于G-BCP的17.8μM和R-的28.9μM。 BCP。此外，对于体内抗肿瘤性能，静脉注射后G-BCP，R-BCP和GR-BCP在血液循环和肿瘤蓄积方面显示出相似的效率。但是，GR-BCP实现了最有效的肿瘤抑制作用，几乎没有副作用。我们的研究结果表明，与GSH或ROS单反应BCP相比，细胞内GSH和ROS双重响应BCP在肿瘤细胞内显示出更有效的响应药物释放，从而增强了抗肿瘤功效，

更新日期：2020-01-31

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