Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5‑Fluorouracil

Overexpression
of glucose transporters (GLUTs) in colorectal cancer
cells is associated with 5-fluorouracil (1, 5-FU) resistance
and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting
drug conjugate, triggered by glutathione in the tumor microenvironment,
that releases 5-FU and GLUTs inhibitor (phlorizin (2)
and phloretin (3)). Using an orthotopic colorectal cancer
mice model, we showed that the conjugate exhibited better antitumor
efficacy than 5-FU, with much lower exposure of 5-FU during treatment
and without significant side effects. Our study establishes a GLUT-targeting
theranostic incorporating a disulfide linker between the targeting
module and cytotoxic payload as a potential antitumor therapy.