Targeted delivery of activatable 131I-radiopharmaceutical for sustained radiotherapy with improved pharmacokinetics

Abstract

Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering legumain is overexpressed in several types of human cancers, we have reported a 131I-labeled radiopharmaceutical ([131I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) for treatment of legumain-overexpressed tumors in vivo. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [131I]IM(HE)3AAN was synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)3) into [131I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [131I]IM(HE)3AAN could react with its precursor to form heterologous dimer ([131I]H-Dimer) that is highly hydrophobic. Cerenkov imaging reveals that [131I]IM(HE)3AAN displayed superior tumor selectivity and longer tumor retention time as compared with [131I]MAAN, with a significant reduction in liver uptake. After an 18-day treatment with [131I]IM(HE)3AAN, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs during treatment. These findings suggest [131I]IM(HE)3AAN emerges as a promising candidate for treatment of legumain-overexpressed tumors.