PeptoBrush Enables Sustained Release of Auger Radiotherapeutic [¹²⁵I]Iododeoxyuridine for Glioblastoma Treatment

Glioblastoma continues to be one of the most lethal and treatment-refractory forms of brain cancer. In this study, we report the development of a novel nanocarrier ("PeptoBrush") for the sustained release of the Auger-emitting radiotherapeutic agent [¹²⁵I]iododeoxyuridine ([¹²⁵I]IUdR). The PeptoBrush scaffold, consisting of a polyglutamic acid backbone with degree of polymerization (DP) of 100 grafted with polysarcosine with DP of 82 (30% grafting density with respect to pGlu) and DBCO units (16% grafting density with respect to pGlu), was synthesized, and [¹²⁵I]IUdR was conjugated via strain-promoted azide-alkyne cycloaddition (SPAAC). The resulting radioconjugate exhibited a defined spherical morphology with a hydrodynamic diameter of 12.1 ± 1.9 nm and ξ-potential of -4.0 ± 1.4 mV. In vitro release studies demonstrated esterase-responsive release of [¹²⁵I]IUdR, supporting a sustained release profile. DNA incorporation assays and viability studies in glioblastoma cells confirmed the biological activity and radiotoxicity of the released compound. This work highlights the potential of PeptoBrushes for controlled radionuclide delivery of Auger-emitting radiotherapeutic agents, laying the foundation for an innovative strategy in glioblastoma therapy.