Molecular Self-Assembly of Bioorthogonal Aptamer-Prodrug Conjugate Micelles for Hydrogen Peroxide and pH-Independent Cancer Chemodynamic Therapy
Molecular Self-Assembly of Bioorthogonal Aptamer-Prodrug Conjugate Micelles for Hydrogen Peroxide and pH-Independent Cancer Chemodynamic Therapy
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用于过氧化氢和 pH 依赖性癌症化学动力学治疗的生物正交适体-前药缀合物胶束的分子自组装
DOI：
10.1021/jacs.9b10755
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发表时间：
2020-01-15
影响因子：
15
通讯作者：
Tan, Weihong
中科院分区：
文献类型：
--
作者：
Xuan, Wenjing;Xia, Yinghao;Tan, Weihong
化学动力学疗法（CDT）已证明了通过特异性操纵失调的肿瘤自由基稳态来进行选择性和逻辑性癌症干预的新可能性。目前的CDT方法主要依赖于通过经典的芬顿或哈伯韦斯化学将内源性过氧化氢（H2O2）转化为高毒性的羟基自由基。然而，它们的抗癌功效受到有效化学反应所需的强酸性、肿瘤H2O2不足以及上调抗氧化防御以抵消自由基引起的氧化损伤的极大限制。在这里，我们提出了一个新的概念，即生物正交化学和前药相结合，以创建一种新型的适配体药物缀合物（ApDC）：适配体前药缀合物（ApPdC）胶束，用于改善和癌症靶向CDT。疏水性前药碱基不仅可以促进适体的自组装，而且可以通过生物正交化学作为自由基发生器。深入的机理研究表明，与传统的CDT系统不同，ApPdC胶束能够通过级联生物正交反应在癌细胞中原位活化和自循环产生毒性C中心自由基，不依赖于H2O2或pH值，但同时通过GSH耗尽降低癌性抗氧化作用，以实现协同CDT效应。我们希望这项工作能为靶向癌症治疗的设计和自由基相关分子机制的研究提供新的见解。
Chemodynamic therapy (CDT) has demonstrated new possibilities for selective and logical cancer intervention by specific manipulation of dysregulated tumorous free radical homeostasis. Current CDT methods largely rely on conversion of endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals via classical Fenton or Haber Weiss chemistry. However, their anticancer efficacies are greatly limited by the requirement of strong acidity for efficient chemical reactions, insufficient tumorous H2O2, and upregulated antioxidant defense to counteract free radical-caused oxidative damage. Here, we present a new concept whereby bioorthogonal chemistry and prodrug are combined to create a new type of aptamer drug conjugate (ApDC): aptamerprodrug conjugate (ApPdC) micelle for improved and cancer-targeted CDT. The hydrophobic prodrug bases can not only promote self-assembly of aptamers but also act as free radical generators via bioorthogonal chemistry. In depth mechanistic studies reveal that, unlike traditional CDT systems, ApPdC micelles enable in situ activation and self-cycling generation of toxic C-centered free radicals in cancer cells through cascading bioorthogonal reactions, with no dependence on either H2O2 or pH, yet concurrently with diminished cancerous antioxidation by GSH depletion for a synergistic CDT effect. We expect this work to provide new insights into the design of targeted cancer therapies and studies of free radical-related molecular mechanisms.