Facile engineering of β-cyclodextrin (β-CD)-based supramolecular nanocontainers with simultaneous enhanced extracellular stability and efficient intracellular biosignals-triggered destabilization generally suffers from multistep synthesis and tedious purification process, thus remains a significant challenge for the scale-up production and clinical translation of β-CD-based supramolecular nanomedicine. To address these issues, we reported in this study a one-pot preparation of dual-redox sensitive, stabilized supramolecular nanocontainers for potential programmable drug release by self-crosslinking of a multifunctional β-CD unit that integrates a host cavity for oxidation-mediated reversible complexation with ferrocence (Fc) guest molecule and lipoic acids (LAs)-decorated primary and secondary faces for reversible in-situ crosslinking by the reducible disulfide links. The resulting doxorubicin (DOX)-loaded nanoparticles showed, on one hand, enhanced colloidal stability and high DOX loading capacity with a drug loading content (DLC) of approximately 11.3% due to the crosslinked structure, and on the other hand, a programmable destruction of the supramolecular micelles triggered by a simultaneous adoption of intracellular glutathione (GSH) and reactive oxygen species (ROS) toward a complete structural destruction for promoted drug release with enhanced therapeutic efficiency. Notably, an optimized DOX-loaded micelle formation, DOX@CL P1 showed greater cytotoxicity with an IC of 2.94 ± 0.25 μg/mL than free DOX (6.00 ± 0.56 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free DOX in L02 normal liver cells. In vivo animal study in Bel-7402 tumor-bearing BALB/c mice further confirmed prolonger elimination half-life time, efficient tumor accumulation, enhanced therapeutic efficiency and compromised systemic toxicity of this micelle construct. Therefore the multifunctional CD unit developed in this study offers an extremely straightforward and robust strategy with respect to dual-redox responsive, stabilized supramolecular nanocontainers with potential programmable controlled release properties for clinical translations.
Copyright © 2021. Published by Elsevier B.V.

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