Development of Novel Trifunctional Chelating Agents That Enhance Tumor Retention of Radioimmunoconjugates.

Chelator-containing radioimmunoconjugates (RICs) composed of monoclonal antibodies, chelators, and radiometals exhibit broad potential for cancer diagnosis or therapy. In this study, we developed novel trifunctional chelating agents that enhance the tumor retention of RICs, MDPEI2, and MDPEI4, which contain the metal chelator DOTA, a maleimide moiety, and diethylenetriamine (PEI2) or tetraethylenepentamine (PEI4), respectively, as a poly(ethylenimine) (PEI) scaffold for the addition of positive charges to the radiometabolites of RICs to reduce their release from tumor cells. Trastuzumab radiolabeled by [ 111 In]In-MDPEI2 ([ 111 In]In-TMDPEI2) or [ 111 In]In-MDPEI4 ([ 111 In]In-TMDPEI4) showed high immunoreactivity and lower rates of exportations of their radiometabolites from tumor cells than RICs without PEI scaffolds. The tumor uptake of [ 111 In]In-TMDPEI2 and [ 111 In]In-TMDPEI4 was enhanced compared with RICs without PEI scaffolds, and [ 111 In]In-TMDPEI2 exhibited the highest tumor/blood ratio. These results indicate the utility of MDPEI2 to synthesize RICs with favorable tumor-targeting properties in vivo by controlling the radioactivity distribution in tumor cells.