Glypican-3–Targeted PET Imaging for Precise Diagnosis of Hepatocellular Carcinoma: From Bench to Bedside

Abstract Purpose: This study aims to develop and evaluate a novel glypican-3 (GPC3)–targeted, single-chain variable fragment–based PET radiotracer for noninvasive assessment of GPC3 expression and precise diagnosis of hepatocellular carcinoma (HCC) in both preclinical models and a first-in-human clinical study. Experimental Design: The novel anti-GPC3 single-chain variable fragment, namely, XH-06, was labeled with gallium-68 to obtain [68Ga]Ga-XH-06. Cell uptake assays, small-animal PET imaging, and biodistribution studies were performed to evaluate its targeting ability. In the first-in-human study, eight patients with suspected HCC underwent [68Ga]Ga-XH-06 PET/MRI. Radiotracer uptake in tumors and normal tissues was quantified, and tumor-to-blood ratios and tumor-to-liver ratios were calculated. Results: [68Ga]Ga-XH-06 was synthesized with high radiochemical purity and exhibited specific uptake and efficient internalization in GPC3-positive cells. In subcutaneous and orthotopic animal models, [68Ga]Ga-XH-06 effectively visualized HCC tumors. Eight patients underwent [68Ga]Ga-XH-06 PET/MRI scans, and no adverse events were observed. The radiotracer successfully detected HCC lesions, including subcentimeter tumors, with high imaging contrast. Among seven patients with HCC, the median maximum standardized uptake value of the lesions was 16.9 (range, 8.2–51.8), the median tumor-to-liver ratio was 6.2 (range, 2.8–24.7), and the median tumor-to-blood ratio was 16.6 (range, 3.0–57.6) at 2.5 hours after injection. Conclusions: [68Ga]Ga-XH-06 is clinically promising for detecting GPC3-positive HCC with a favorable safety profile. Further investigation is warranted to validate the clinical value of GPC3-targeted PET imaging in HCC management.