Anti-recurrence/metastasis and chemosensitization therapy with thioredoxin reductase-interfering drug delivery system

Thioredoxin reductase (TrxR) is an essential mammalian enzyme that possesses a selenocysteine active site. TrxR is overexpressed in many malignant tumors and has a close relationship with apoptosis, drug resistance, recurrence and metastasis of tumors. Recently, TrxR has emerged as a promising target for anticancer therapy. Herein, we developed a TrxR-interfering drug delivery system (DDS) based on RGD-PEG-PUSeSe-PEG-RGD self-assembling micelles for imaging-guided gemcitabine (GEM) chemosensitization and anti-recurrence/metastasis therapy. The diselenide-containing micelles were degraded in response to TrxR stimuli for GEM releasing. In the meantime, the dissociated polymers’ chain segments targeted the active site of TrxR via Se–Se/Se–S dynamic reactions for activity inhibition. This inhibition by the micelles not only provided chemosensitization, but reduced tumor recurrence/metastasis risk via the induction of residual tumor cell apoptosis by triggering ROS production post-chemotherapy. In this work, we took the transformation between Se-containing dynamic covalent bonds developed by our group from in vitro to in vivo, which furthered the knowledge on the biochemistry of selenium and provided aspects to develop new TrxR inhibitors. Overall, the TrxR-interfering DDS combined excellent antitumor effects for primary solid tumors with the inhibition of tumor recurrence/metastasis during post-treatment care, providing new perspectives for efficient cancer therapy.