Amidoxime-based radio-microspheres for Internal Irradiation combined with a checkpoint-blocking nanobody boost antitumor immunity

Trans-arterial radioembolization (TARE) therapy confronts significant technical challenges in the preparation of metal nuclide-labeled microsphere carriers, the development of stable and efficient radionuclide labeling strategies, and the ability to treat multiple small lesions in solid tumors. In this study, we synthesized ¹⁷⁷Lu-labeled amidoxime-based polyvinyl alcohol microspheres (¹⁷⁷Lu-PVA-g-PAO-Ms) using in situ synthesis of trunk compounds with chem-induced grafting polymerization. The resulting ¹⁷⁷Lu-PVA-g-PAO-Ms showed excellent stability in radiolabeling and demonstrated high accumulation and prolonged retention in various preclinical rodent models, as observed through SPECT/CT imaging. The cumulative radioactivity uptake in the tumor reached as high as 12.27 %ID/g. In a mouse subcutaneous metastatic tumor model, we observed a significant abscopal effect of radioimmunotherapy after administering a combination of ¹⁷⁷Lu-PVA-g-PAO-Ms and an anti-PD-L1 nanobody. These findings highlight the ability of PVA-g-PAO-Ms to chelate radionuclides efficiently and securely. Furthermore, when combined with nanobodies with enhanced tissue penetration capabilities, these microspheres hold great potential as innovative carrier platforms, offering new therapeutic strategies for integrating TARE with systemic immunotherapy.