Polyamine-Based Pt(IV) Prodrugs as Substrates for Polyamine Transporters Preferentially Accumulate in Cancer Metastases as DNA and Polyamine Metabolism Dual-Targeted Antimetastatic Agents.

Diverse platinum drug candidates have been designed to improve inhibitory potency and overcome resistance for orthotopic tumors. However, the antimetastatic properties have rarely been reported. We herein report that homospermidineplatin (4a), a polyamine-Pt(IV) prodrug, can potently inhibit tumor growth in situ and reverse cisplatin resistance as expected, and more importantly, 4a displays remarkably elevated antimetastatic activity in vivo (65.7%), compared to those of cisplatin (27.0%) and oxaliplatin (19.6%). The underlying molecular mechanism indicates that in addition to targeting nuclear DNA, 4a can modulate polyamine metabolism and function in a manner different from that of cisplatin. By upregulating SSAT and PAO, 4a downregulates the concentrations of Put, Spd, and Spm, which favors the suppression of fast-growing tumor cells. Moreover, the p53/SSAT/β-catenin and PAO/ROS/GSH/GSH-Px pathways are involved in the inhibition of 4a-induced tumor metastasis. Our study implies a promising strategy for the design of platinum drugs for the treatment of terminal cancer.