Beyond Antibodies: Glypican-3-Targeting Peptides for Precision Hepatocellular Carcinoma Theranostics

Glypican-3 (GPC-3) is a cell-surface glycoprotein, highly expressed in hepatocellular carcinoma (HCC) but largely absent in normal adult liver tissues, making it a clinically compelling biomarker and therapeutic target. Although monoclonal antibodies and antibody-drug conjugates have proven to be GPC-3-targeted therapies, their large molecular size, slow pharmacokinetics, and potential immunogenicity limit their diagnostic applications. Peptide ligands offer an attractive alternative owing to their low molecular weight, rapid tumor penetration, favorable clearance profiles, synthetic accessibility, and ease of chemical modification. This topical review highlights the development of linear and cyclic GPC-3-binding peptides over the past two decades, developed primarily via phage display, rational optimization, and structure-guided approaches, enabling PET, SPECT, and fluorescence imaging of HCC in preclinical models. Recent refinements, including albumin-binding modifications and cyclization strategies, have improved tumor-to-liver contrast and in vivo stability. This review summarizes the biological significance of GPC-3, compares peptides and peptide probes as targeting modalities, and critically analyzes recent advances in linear and cyclic peptide-based GPC-3 imaging probes. We also emphasized the importance, current challenges, and future opportunities in AI/ML-based design of peptide ligands for HCC theranostics.