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 colorectal
cancer, lacks specificity and causes many side effects. To increase
the selectivity and therapeutic efficacy of this drug, we designed
and synthesized conjugates of SN38 and glucose transporter inhibitors
(phlorizin (5) or phloretin (6)), which
could be hydrolyzed by glutathione or cathepsin to release SN38 in
the tumor microenvironment, as a proof of concept. These conjugates
(8, 9, and 10) displayed better
antitumor efficacy with lower systemic exposure to SN38 in an orthotopic
colorectal cancer mouse model compared with irinotecan at the same
dosage. Further, no major adverse effects of the conjugates were observed
during treatment. Biodistribution studies showed that conjugate 10 could induce higher concentrations of free SN38 in tumor
tissues than irinotecan at the same dosage. Thus, the developed conjugates
exhibit potential for treating colorectal cancer.