Utilizing biorecognition to prime tumors for enhanced nanomedicine delivery of alpha therapies.

Targeted Radionuclide Therapy (TRT) enables selective delivery of radionuclides for cancer treatment. Alpha particle emitters such as Pb are emerging as potential gamechangers, representing highly potent payloads for precision therapy and refractory cancer treatment. While small-molecule carriers are widely explored due to favorable pharmacokinetics, nanoparticle-based TRT remains less studied due to perceived non-ideal pharmacokinetics. We report a unique nanoparticle-TRT pretargeting approach using bispecific antibodies (BsAbs) which "prime" tumor surfaces, enhancing tumor-specific delivery and minimizing off-target deposition of Pb. We developed a poly(ethylene glycol) (PEG)-based nanomedicine platform to carry Pb, and employed in-house designed and manufactured BsAb (α-epidermal growth factor receptor (EGFR)/α-PEG) to prime tumors to receive the nanocarrier. Sequential administration of each component to EGFR-expressing cells produced enhanced receptor-mediated internalization of the BsAb upon nanomedicine binding, resulting in improved radionuclide delivery and efficacy in a series of in vitro assays. The pretargeting approach more than tripled tumor retention of the Pb-nanomedicine compared to the untargeted nanomaterial in a murine EGFR breast cancer xenograft model, evidenced by single-photon emission computed tomography (SPECT) imaging of Pb-loaded nanomaterials and gamma analysis of the excised organs. Therapeutic studies demonstrated the Pb-nanomedicine to produce well-tolerated and statistically-enhanced therapeutic outcomes for the pretargeting versus conventional Pb-nanomedicine, with no observed long term hematological effects. This work establishes a modular strategy for targeted TRT nanomedicine delivery. The platform has potential for broad applicability, including simultaneous delivery of diverse or synergistic payloads. These findings represent an important advance toward precision nanomedicine approaches in radionuclide therapy.