Tumor-Targeted Oxaliplatin(IV) Prodrug Delivery Based on ROS-Regulated Cancer-Selective Glycan Labeling

Platinum-drug-based chemotherapy in clinics has achieved
great
success in clinical malignancy therapy. However, unpredictable off-target
toxicity and the resulting severe side effects in the treatment are
still unsolved problems. Although metabolic glycan labeling-mediated
tumor-targeted therapy has been widely reported, less selective metabolic
labeling in vivo limited its wide application. Herein, a novel probe
of B–Ac3ManNAz that is regulated by reactive oxygen
species in tumor cells is introduced to enhance the recognition and
cytotoxicity of DBCO-modified oxaliplatin(IV) via bioorthogonal chemistry.
B–Ac3ManNAz was synthesized from Ac4ManNAz
by incorporation with 4-(hydroxymethyl) benzeneboronic acid pinacol
ester (HBAPE) at the anomeric position, which is confirmed to be regulated
by ROS and could robustly label glycans on the cell surface. Moreover,
N3-treated tumor cells could enhance the tumor accumulation
of DBCO-modified oxaliplatin(IV) via click chemistry meanwhile reduce
the off-target distribution in normal tissue. Our strategy provides
an effective metabolic precursor for tumor-specific labeling and targeted
cancer therapies.