Gallium-68 Labeled\nPositron Emission Computed Tomography\nTracer Targeting Glypican‑3 with High Contrast for Hepatocellular\nCarcinoma Imaging

Hepatocellular\ncarcinoma (HCC) represents the predominant\nform\nof primary liver cancer, yet early, precise, and noninvasive detection\ncontinues to pose a considerable clinical challenge. Glypican-3 (GPC3),\na membrane-bound proteoglycan, is markedly overexpressed in most HCC\ncases, while exhibiting low expression in normal and hepatitis-affected\nliver tissues. Given its crucial role in malignant transformation\nand tumor progression, GPC3 emerges as a compelling target for imaging.\nIn this study, we developed and evaluated 2 <sup>68</sup>Ga-labeled\nGPC3-targeted positron emission tomography (PET) probes, each incorporating\neither polyethylene glycol (PEG) or 4-(<i>p</i>-methylphenyl)butanoic\nacid (an albumin-binding moiety). Comparative analyses revealed that <sup>68</sup>Ga-ALB-GBP, which includes the albumin-binding moiety, exhibited\nsuperior in vivo stability, enhanced tumor uptake, and an improved\ntumor-to-liver ratio relative to <sup>68</sup>Ga-PEG<sub>2</sub>-GBP\nin subcutaneous HCC mouse models. Micro-PET/computed tomography imaging\nof orthotopic liver cancer with <sup>68</sup>Ga-ALB-GBP demonstrated\na tumor-to-liver ratio of 2.29 ± 0.13 and a tumor-to-muscle ratio\nof 13.03 ± 1.63 at 3 h postinjection, outperforming the performance\nof the clinically used <sup>18</sup>F-fluorodeoxyglucose PET imaging.\nThese findings suggest that <sup>68</sup>Ga-ALB-GBP is a promising\ndiagnostic tool for HCC and a strong candidate for clinical translation\nwith potential utility in both diagnostic and therapeutic settings.\nMoreover, the incorporation of an albumin-binding moiety into PET\ntracers significantly extends blood circulation time, thereby enhancing\nbioavailability and facilitating high-contrast PET imaging.