Glypican-3 targeted radiopharmaceuticals for hepatocellular carcinoma: a review of molecular platforms

Abstract Background Hepatocellular carcinoma (HCC) is characterized by high heterogeneity, making early diagnosis and systemic therapy challenging. Glypican-3 (GPC-3) targeted radiopharmaceuticals are promising tools for HCC. This review summarizes the development of this field from a platform-centric perspective, comparing various molecular targeting vectors designed against GPC-3. Main body The development of GPC-3 radiopharmaceuticals has evolved from slow-clearing monoclonal antibodies (mAbs) to rapidly excreted antibody fragments, peptides and other promising platforms. Early platform selection faced a compromise between molecular size and tumor retention. Current strategies tend to optimize pharmacokinetic profiles through chemical modifications, including the application of albumin-binding groups, PEGylation (polyethylene glycol modification), cyclization and integrating these strategies. These engineering approaches aim to provide an optimal signal-to-noise ratio in same-day imaging for diagnosis, while ensuring sustained tumor retention required for targeted radionuclide therapy. Conclusion Future clinical translation will require further exploration of optimal pharmacokinetic properties to achieve a better balance between diagnostic and therapeutic capabilities, which is essential to promote GPC-3 theranostics into routine clinical practice. Furthermore, emerging strategies such as shifting towards more potent alpha-radionuclides; moving from single-targeting to multi-targeting strategies, such as GPC-3 and prostate-specific membrane antigen (PSMA); and synergizing radionuclide therapy with immunotherapy (e.g., immune checkpoint inhibitors) are expected to become key to overcoming tumor heterogeneity and prolonging patient survival.