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

Area of Science:

• Oncology
• Drug Discovery
• Cancer Biology

Background:

• Overexpression of glucose transporters (GLUTs) in colorectal cancer correlates with 5-fluorouracil (5-FU) resistance and poor patient outcomes.
• Targeting GLUTs presents a potential strategy to enhance chemotherapy efficacy in colorectal cancer.

Purpose of the Study:

• To design and synthesize a novel GLUT-targeting drug conjugate for colorectal cancer therapy.
• To evaluate the antitumor efficacy and safety of the developed conjugate in a preclinical model.

Main Methods:

• Synthesis of a GLUT-targeting drug conjugate releasing 5-FU and GLUT inhibitors (phlorizin, phloretin) triggered by tumor microenvironment glutathione.
• Evaluation of the conjugate's efficacy and side effects using an orthotopic colorectal cancer mouse model.

Main Results:

• The novel drug conjugate demonstrated superior antitumor efficacy compared to 5-FU alone.
• Treatment with the conjugate resulted in significantly lower systemic exposure to 5-FU.
• The conjugate exhibited a favorable safety profile with no significant side effects observed.

Conclusions:

• A GLUT-targeting theranostic incorporating a disulfide linker effectively delivers cytotoxic payload and GLUT inhibitors.
• This approach represents a promising strategy for overcoming 5-FU resistance and improving colorectal cancer treatment.
• The developed conjugate offers a potential new therapeutic option with enhanced efficacy and reduced toxicity.