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US Molecular Imaging of Glypican-3 Expression in Hepatocellular Carcinoma Using Targeted Biosynthetic Gas Vesicles
Xiaoxin Liang1,2, Lingling Li1,2, Yuanyuan Wang2
1Department of Ultrasound, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, PR China.
Abstract:
Purpose To develop L5 peptide-modified gas vesicles (L5-GVs) for US molecular imaging (USMI) of glypican-3 (GPC3) expression in hepatocellular carcinoma (HCC). Materials and Methods This study was conducted from October 2022 to December 2024. L5-GVs were synthesized by conjugating L5 peptides to gas vesicles derived from Halobacterium NRC-1. In vitro binding was evaluated by incubating fluorescein isothiocyanate-labeled L5-GVs or control GVs (con-GVs) with GPC3-positive HepG2 and GPC3-negative A549 cells. In vivo USMI was performed in subcutaneous HepG2 and A549 tumor-bearing BALB/c nude mice (4-6 weeks old; female; 18-22 g) after injection of con-GVs or L5-GVs. The correlation between USMI signal intensity at 10 minutes and tumor GPC3 immunofluorescence staining was calculated. Single-cell suspensions from 10 resected human HCC specimens were incubated with fluorescein isothiocyanate-labeled L5-GVs, and the correlation between L5-GVs adhesion-positive cell rate and immunohistochemical GPC3 expression was calculated. Results L5-GVs (approximately 252.23 nm ± 1.87) produced stronger fluorescence intensity than con-GVs in HepG2 cells (P < .001), whereas no difference was observed in A549 cells (P = .96). L5-GVs generated stronger contrast signal than con-GVs in HepG2 tumor-bearing mice (P = .004), with no difference observed in A549 tumors (P = .82); the signal intensity at 10 minutes after injection correlated with GPC3 expression (R2 = 0.89). In patient-derived HCC samples, L5-GVs adhesion-positive cell rate strongly correlated with immunohistochemical GPC3 expression (R2 = 0.94). Conclusion GPC3-targeted L5-GVs enabled specific USMI of HCC in preclinical models, with strong correlation to clinical pathology supporting potential translation for early HCC diagnostic imaging. Keywords: Molecular Imaging, Animal Studies, Ultrasound-Contrast, Contrast Agents-Other Supplemental material is available for this article. © RSNA, 2026 See also commentary by Xu in this issue See also editorial by Zhou in this issue.
