177 Lu‐labeled amidoxime‐functionalized biodegradable microspheres for transarterial radioembolization of hepatocellular carcinoma

Abstract Purpose Transarterial radioembolization (TARE) is an important locoregional therapy for hepatocellular carcinoma (HCC). However, clinically used yttrium‐90 ( 90 Y) microspheres are non‐biodegradable and provide limited imaging capability, while biodegradable polymeric microspheres prepared using conventional radiolabeling strategies often exhibit poor radionuclide stability. Experimental design We designed a biodegradable radiometal‐chelating microsphere based on amidoxime‐functionalized polylactic acid microspheres (PLA‐g‐PAO‐Ms) engineered via electron beam‐induced graft polymerization. Results The PLA‐g‐PAO‐Ms exhibited a high Lu 3+ loading capacity (33.83 mg g −1 ) and underwent controlled biodegradation in vitro after approximately 20 d. Cell Counting Kit‐8 (CCK‐8) assays confirmed favorable cytocompatibility, with both LO2 and HepG2 cell viabilities exceeding 90% after 72 h, showing no significant difference from the control group ( p > 0.05); by contrast, free Lu 3+ (50 mg·L −1 ) significantly reduced HepG2 viability to 51.4% ( p < 0.001). In a rat orthotopic liver tumor model, the intra‐arterial administration of 177 Lu‐labeled PLA‐g‐PAO‐Ms ( 177 Lu‐PLA‐g‐PAO‐Ms) resulted in pronounced tumor suppression with sustained in vivo radionuclide retention for at least 14 d. Biodistribution analysis revealed selective tumor accumulation of 8.79 ± 1.74 %ID g −1 , significantly higher than that in normal liver ( 1 ± 0.54 %ID g −1 ) and other organs ( P < 0.001 ), whereas free 177 LuCl 3 showed minimal tumor uptake ( 0.30 ± 0.28 %ID g −1 ) with predominant non‐target organ accumulation. Conclusion These findings suggest that PLA‐g‐PAO‐Ms provide a biodegradable microsphere system capable of stable radiometal incorporation and effective tumor suppression following intra‐arterial administration, offering a promising approach for interventional radionuclide therapy for HCC.