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

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 multiple types of human cancers, a 131I-labeled radiopharmaceutical ([ 131 I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [ 131 I]IM(HE) 3 AAN was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE) 3) into [ 131 I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [ 131 I]IM(HE) 3 AAN could react with its precursor to form heterologous dimer [ 131 I]H-Dimer that is highly hydrophobic. Cerenkov imaging revealed that [ 131 I]IM(HE) 3 AAN displayed superior tumor selectivity and longer tumor retention time as compared with [ 131 I]MAAN , with a significant reduction in the liver uptake. After an 18-day treatment with [ 131 I]IM(HE) 3 AAN , the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that [ 131 I]IM(HE) 3 AAN could serve as a promising drug candidate for treating legumain-overexpressed tumors. [Display omitted] [ABSTRACT FROM AUTHOR]