Enhanced Tumor-Specific Disulfiram Chemotherapy by In Situ Cu2+ Chelation-Initiated Nontoxicity-to-Toxicity Transition.

Abstract

The antitumor activity of disulfiram (DSF), a traditional US Food and Drug Administration-approved drug for the treatment of "alcohol-dependence", is Cu2+-dependent, but the intrinsic anfractuous biodistribution of copper in the human body and copper toxicity induced by exogenous copper supply have severely hindered its in vivo application. Herein, we report an in situ Cu2+ chelation-enhanced DSF-based cancer chemotherapy technique, using a tumor-specific "nontoxicity-to-toxicity" transition strategy based on hollow mesoporous silica nanoparticles as the functional carrier. Cu2+-doped, DSF-loaded hollow mesoporous silica nanoparticles were constructed for the rapid release of Cu2+ ions induced by the mild acidic conditions of the tumor microenvironment. This resulted in the rapid biodegradation of the nanoparticles and accelerated DSF release once the particles were endocytosed into tumor cells. The resulting in situ chelation reaction between the coreleased Cu2+ ions and DSF generated toxic CuET products and concurrently, Fenton-like reactions between the generated Cu+ ions and the high levels of H2O2 resulted in the production of reactive oxygen species (ROS) in the acidic tumor microenvironment. Both in vitro cellular assays and in vivo tumor-xenograft experiments demonstrated the efficient Cu-enhanced and tumor-specific chemotherapeutic efficacy of DSF, with cocontributions from highly toxic CuET complexes and ROS generated within tumors. This work provides a conceptual advancement of nanoparticle-enabled "nontoxicity-to-toxicity" transformation in tumors, to achieving high chemotherapeutic efficacy and biosafety.

• Authors: Wencheng Wu, Luodan Yu, Quzi Jiang, Minfeng Huo, Han Lin, Liying Wang, Yu Chen, Jianlin Shi
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 141 Issue 29 Pg. 11531-11539 (07 24 2019) ISSN: 1520-5126 [Electronic] United States
• PMID: 31251050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chelating Agents
• Drug Carriers
• Silicon Dioxide
• Copper
• Hydrogen Peroxide
• Disulfiram

Topics

• Animals
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology)
• Cell Line, Tumor
• Chelating Agents (pharmacokinetics, pharmacology)
• Copper (pharmacokinetics)
• Disulfiram (administration & dosage, adverse effects, pharmacology)
• Drug Carriers (administration & dosage, chemistry)
• Drug Liberation
• Endocytosis (drug effects)
• Female
• Humans
• Hydrogen Peroxide (metabolism)
• Mice, Inbred BALB C
• Nanoparticles (administration & dosage, chemistry)
• Silicon Dioxide (chemistry)
• Tissue Distribution
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays