Design, Synthesis, and Evaluation of Glucose Transporter Inhibitor-SN38 Conjugates for Targeting Colorectal Cancer

Irinotecan (1), a prodrug of SN38 (2)approved by the US Food and Drug Administration for treating colorectalcancer, lacks specificity and causes many side effects. To increasethe selectivity and therapeutic efficacy of this drug, we designedand synthesized conjugates of SN38 and glucose transporter inhibitors(phlorizin (5) or phloretin (6)), whichcould be hydrolyzed by glutathione or cathepsin to release SN38 inthe tumor microenvironment, as a proof of concept. These conjugates(8, 9, and 10) displayed betterantitumor efficacy with lower systemic exposure to SN38 in an orthotopiccolorectal cancer mouse model compared with irinotecan at the samedosage. Further, no major adverse effects of the conjugates were observedduring treatment. Biodistribution studies showed that conjugate 10 could induce higher concentrations of free SN38 in tumortissues than irinotecan at the same dosage. Thus, the developed conjugatesexhibit potential for treating colorectal cancer.

Automated summary

To enhance the selectivity and therapeutic efficacy of SN38, researchers developed conjugates of SN38 and glucose transporter inhibitors. These conjugates released SN38 in the tumor microenvironment and displayed improved antitumor efficacy with lower systemic exposure.