Impairing Tumor Metabolic Plasticity via a Stable Metal-Phenolic-Based Polymeric Nanomedicine to Suppress Colorectal Cancer

Targeting metabolic vulnerability of tumor cells is a promising anticancer strategy. However, the therapeutic efficacy of existing metabolism-regulating agents is often compromised due to tolerance resulting from tumor metabolic plasticity, as well as their poor bioavailability and tumor-targetability. Inspired by the inhibitive effect of N-ethylmaleimide on the mitochondrial function, a dendronized-polymer-functionalized metal-phenolic nanomedicine (pOEG-b-D-SH@NP) encapsulating maleimide-modified doxorubicin (Mal-DOX) is developed to enable improvement in the overall delivery efficiency and inhibition of the tumor metabolism via multiple pathways. It is observed that Mal-DOX and its derived nanomedicine induces energy depletion of CT26 colorectal cancer cells more efficiently than doxorubicin, and shifts the balance of programmed cell death from apoptosis toward necroptosis. Notably, pOEG-b-D-SH@NP simultaneously inhibits cellular oxidative phosphorylation and glycolysis, thus potently suppressing cancer growth and peritoneal intestinal metastasis in mouse models. Overall, the study provides a promising dendronized-polymer-derived nanoplatform for the treatment of cancers through impairing metabolic plasticity.

Automated summary

Targeting the metabolic vulnerability of tumor cells is a promising anticancer strategy. Researchers have developed a nanomedicine called pOEG-b-D-SH@NP, which encapsulates maleimide-modified doxorubicin (Mal-DOX), to improve overall delivery efficiency and inhibit tumor metabolism through multiple pathways. The nanomedicine effectively depletes energy in colorectal cancer cells and shifts cell death from apoptosis to necroptosis. It also inhibits cellular oxidative phosphorylation and glycolysis, suppressing cancer growth in mouse models.