4.6 Article

DNA-Scaffolded Disulfide Redox Network for Programming Drug-Delivery Kinetics

Journal

CHEMISTRY-A EUROPEAN JOURNAL
Volume 27, Issue 34, Pages 8745-8752

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202100149

Keywords

covalent chemistry; disulfide bonds; disulfide redox network; DNA scaffolds; drug delivery

Funding

  1. National Science Foundation of China [21722502]
  2. National Key Research and Development Program of China for International Science & Innovation Cooperation Major Project between Governments [2018YFE0113200]
  3. Shanghai Rising-Star Program [19QA1403000]
  4. Shanghai Science and Technology Committee (STCSM) [18490740500]
  5. China Postdoctoral Science Foundation [2020TQ0097]

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This study presents a DNA-scaffolded disulfide redox network for selective cargo release within cancer cells and programmable drug-delivery kinetics. By tuning the density of disulfide bonds, drug-release kinetics can be controlled effectively, enhancing the therapeutic effect on multidrug-resistant cancer.
In response to specific stimuli, dynamic covalent materials enable the generation of new structures by reversibly forming/breaking chemical bonds, thus showing great potential for application in controlled drug release. However, using dynamic covalent chemistry to program drug-delivery kinetics remains challenging. Herein, an in situ polymerization-generated DNA-scaffolded disulfide redox network (DdiSRN) is reported in which nucleic acids are used as a scaffold for dynamic disulfide bonds. The constructed DdiSRN allows selective release of loading cargos inside cancer cells in response to redox stimuli. Moreover, the density of disulfide bonds in network can be tuned by precise control over their position and number on DNA scaffolds. As a result, drug-delivery kinetics can be programmed with a half-life, t(1/2), decreasing from 8.3 to 4.4 h, thus facilitating keeping an adequate drug concentration within the therapeutic window. Both in vitro and in vivo studies confirm that co-delivery of DOX and siRNA in combination with fast drug release inside cells using this DdiSRN enhances the therapeutic effect on multidrug-resistant cancer. This nontrivial therapeutic platform enabling kinetic control provides a good paradigm for precision cancer medicine.

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