A 177Lu-Labeled Circular Bivalent Aptamer for PTK7-Targeting Radionuclide Therapy in Ovarian Cancer and Orthotopic Hepatoblastoma

Abstract Targeted radionuclide therapy (TRT) is a promising strategy for precision oncology but is limited by the lack of high-performance targeting ligands. Here, we report a lutetium-177 (177Lu)-labeled PTK7-targeted cyclized bivalent aptamer (CBSgc8) for treating an orthotopic hepatoblastoma. The cyclized multivalent design enhances biostability and binding affinity, while 177Lu labeling preserves its functional properties. The resulting 177Lu-CBSgc8 exhibited high serum stability, strong specificity for PTK7-positive cells, efficient internalization, and dose-dependent cytotoxicity in vitro. In vivo, 177Lu-CBSgc8 inhibited tumor growth in an OVCAR3 ovarian cancer model, although tumor accumulation remained limited. Given its PTK7-targeting capability and preferential hepatic distribution, we further evaluated its therapeutic potential in an orthotopic HepG2 hepatoblastoma model. In this setting, 177Lu-CBSgc8 achieved 76.6% tumor growth inhibition with a favorable safety. These findings demonstrate the potential of exploiting tissue distribution characteristics together with molecular targeting to expand the applicability of aptamer-based TRTs.