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 [111In]In-MDPEI2
([111In]In-TMDPEI2) or [111In]In-MDPEI4 ([111In]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 [111In]In-TMDPEI2
and [111In]In-TMDPEI4 was enhanced compared with RICs without
PEI scaffolds, and [111In]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.