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一种氧化还原响应性二氢青蒿素二聚体纳米前药，用于增强抗肿瘤活性。

A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity.

机构信息

Jilin Medical University, Jilin, 132013, People's Republic of China.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People's Republic of China.

出版信息

J Nanobiotechnology. 2021 Dec 20;19(1):441. doi: 10.1186/s12951-021-01200-z.

DOI:10.1186/s12951-021-01200-z
PMID:34930288
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8686335/
Abstract

Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug.

摘要

氧化还原响应型药物递送系统作为肿瘤治疗的一种有前途的平台而出现。青蒿素（DHA）已被研究作为一种创新的肿瘤治疗剂。本文设计并合成了一种二硫键作为连接桥的 DHA 二聚前药（DHA-SS）。所制备的前药可以自组装成具有高 DHA 含量（>90%）和强稳定性的纳米颗粒（SS NPs）。这些 SS NPs 表现出敏感的氧化还原响应能力，可以在肿瘤异质性微环境下释放 DHA。与游离 DHA 相比，SS NPs 具有更好的抗肿瘤治疗活性。此外，通过 RNA-seq 分析、生物信息学和分子生物学方法研究了 SS NPs 的可能抗癌机制。SS NPs 可以通过线粒体凋亡途径诱导细胞凋亡，以及与 PI3K/AKT/HIF-1α信号通路的调节相关的糖酵解抑制，这可能为肝癌提供潜在的治疗靶点。我们的研究强调了使用氧化还原响应型前药纳米颗粒治疗癌症的潜力，同时深入了解了 DHA 前药的抗癌机制。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad3a/8686335/f1da524586f0/12951_2021_1200_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad3a/8686335/49b9f78fe16b/12951_2021_1200_Fig1_HTML.jpg
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