Molecular Self-Assembly of Bioorthogonal Aptamer-Prodrug Conjugate Micelles for Hydrogen Peroxide and pH-Independent Cancer Chemodynamic Therapy

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 rad...

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Published in:Journal of the American Chemical Society 2020-01, Vol.142 (2), p.937-944
Main Authors: Xuan, Wenjing, Xia, Yinghao, Li, Ting, Wang, Linlin, Liu, Yanlan, Tan, Weihong
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - therapeutic use
Aptamers, Nucleotide - chemistry
Electron Spin Resonance Spectroscopy
Hep G2 Cells
Humans
Hydrogen Peroxide - chemistry
Hydrogen-Ion Concentration
Micelles
Neoplasms - drug therapy
Prodrugs - chemistry
Spectrometry, Mass, Electrospray Ionization
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Summary: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): aptamer-prodrug 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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.9b10755