pH 敏感纳米颗粒共同传递多西紫杉醇和双氢青蒿素通过增强反应性氧化物种介导的线粒体凋亡有效治疗乳腺癌,Molecular Pharmaceutics

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pH 敏感纳米颗粒共同传递多西紫杉醇和双氢青蒿素通过增强反应性氧化物种介导的线粒体凋亡有效治疗乳腺癌
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2020-10-21 , DOI: 10.1021/acs.molpharmaceut.0c00432
Jin Tao _{1,

2} , Lu Diao _{1,

3} , Fangcheng Chen ₁ , Ao Shen ₄ , Shutian Wang ₁ , Hongyan Jin ₁ , Danwei Cai ₁ , Ying Hu _{1,

3}

Affiliation

肿瘤生长和转移是乳腺癌高死亡率的主要原因。我们先前构建了用于多西紫杉醇 (DTX) 和双氢青蒿素 (DHA) 共递送的 pH 敏感纳米粒子 (D/D NPs)，并证明 D/D NPs 在体外乳腺癌细胞中显示出抗癌活性。本研究进一步研究了 D/D NPs 对体内原位乳腺癌的治疗作用，并检查了 D/D NPs 的抗肿瘤机制。D/D NPs 在 DTX 和 DHA 的协同作用下显着增加了 4T1 细胞的凋亡。D/D NPs 增加活性氧，降低线粒体膜电位，增加 p53 的表达，并诱导细胞色素c释放到细胞质中以激活 caspase-3。在源自 4T1 细胞的原位转移性乳腺癌小鼠模型中，由于 DTX 和 DHA 的协同作用，D/D NPs 抑制肿瘤生长并防止肺转移。在主要器官的组织学中没有观察到明显的变化。这些结果表明，基于 pH 敏感 D/D NP 的联合疗法可能是通过 ROS 介导的线粒体凋亡途径治疗转移性乳腺癌的一种有前景的策略。

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pH-Sensitive Nanoparticles Codelivering Docetaxel and Dihydroartemisinin Effectively Treat Breast Cancer by Enhancing Reactive Oxidative Species-Mediated Mitochondrial Apoptosis

Tumor growth and metastasis are the major causes of high mortality in breast cancer. We previously constructed pH-sensitive nanoparticles (D/D NPs) for the codelivery of docetaxel (DTX) and dihydroartemisinin (DHA) and demonstrated that D/D NPs showed anticancer activity in breast cancer cells in vitro. The present study further investigated the therapeutic effect of D/D NPs on orthotopic breast cancer in vivo and examined the antitumor mechanism of D/D NPs. D/D NPs significantly increased the apoptosis of 4T1 cells with a synergistic effect of DTX and DHA. D/D NPs increased reactive oxygen species, reduced mitochondrial membrane potential, increased the expression of p53, and induced cytochrome c release into the cytoplasm to activate caspase-3. In an orthotopic metastatic breast cancer mouse model derived from 4T1 cells, D/D NPs inhibited tumor growth and prevented lung metastasis due to the synergistic effect of DTX and DHA. No distinct changes were observed in the histology of major organs. These results indicate that pH-sensitive D/D NP-based combination therapy may be a promising strategy for the treatment of metastatic breast cancers via the ROS-mediated mitochondrial apoptosis pathway.

更新日期：2020-10-21

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