Wang Guanyun, Pan Yue, Zheng Lingling, Zhang Xiaojun, Liu Huanhuan, Xu Yanfeng, Zhang Wenwen, Luan Xiaohui, Liu Xiaojie, Xu Xiaodan, Wu Shina, Ma Guangyu, Kan Ying, Zhang Jinming, Wang Ruimin, Yang Jigang
Nuclear Medicine Department, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing 100050, China.
Department of Nuclear Medicine, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853, China.
Mol Pharm. 2025 Apr 7;22(4):2088-2097. doi: 10.1021/acs.molpharmaceut.4c01218. Epub 2025 Feb 23.
Integrin αvβ3 expression is associated with sorafenib resistance in hepatocellular carcinoma (HCC). Therefore, monitoring its expression in HCC may serve as a valuable indicator of the efficacy of sorafenib treatment. In this study, longitudinal positron emission tomography (PET) was performed to assess [F]Alfatide II and [F]fluorodeoxyglucose ([F]FDG) as suitable probes for evaluating the treatment efficacy of sorafenib in a Huh-7 human (HCC) xenograft model. Huh-7 tumor cells were used to establish both normal and sorafenib-resistant cell lines, and xenograft models were developed. The mice were categorized into four groups based on the cell type and treatment: normal nontreatment, normal treatment, sorafenib-resistant nontreatment, and sorafenib-resistant treatment. Huh-7 tumor mice received intragastric injections of sorafenib (30 mg/kg/day) or vehicle for 15 consecutive days. Tumor size and weight were assessed throughout the study. Longitudinal microPET/computed tomography (CT) scans with [F]Alfatide II and [F]FDG were acquired to quantitatively measure angiogenesis on days -2, 3, 7, and 14 and metabolism on days -1, 4, 8, and 15 following therapy initiation. The tumor uptake (ID%/g) of each probe was calculated. No significant difference in [F]FDG uptake was observed between the normal and sorafenib-resistant groups ( = 0.452); however, [F]Alfatide II uptake differed significantly between the two groups ( < 0.001). Sorafenib successfully inhibited normal Huh-7 tumor growth, inducing significant differences in tumor size 9 days after sorafenib treatment ( < 0.05). The uptake of [F]Alfatide II in the tumor lesions changed significantly on day 14 ( = 0.001). However, no change was observed in the uptake of [F]FDG ( > 0.05). The PET imaging data of [F]Alfatide II and [F]FDG were validated through immunohistochemistry analysis targeting integrin αvβ3, VEGF, and GULT-1. [F]Alfatide II PET was more effective in monitoring sorafenib resistance and therapeutic efficacy in the Huh-7 human HCC xenograft model than [F]FDG.
整合素αvβ3的表达与肝细胞癌（HCC）对索拉非尼的耐药性相关。因此，监测其在HCC中的表达可作为索拉非尼治疗疗效的重要指标。在本研究中，进行了纵向正电子发射断层扫描（PET），以评估[F]阿法肽II和[F]氟脱氧葡萄糖（[F]FDG）作为评估索拉非尼在Huh-7人（HCC）异种移植模型中治疗效果的合适探针。使用Huh-7肿瘤细胞建立正常和耐索拉非尼的细胞系，并建立异种移植模型。根据细胞类型和治疗方法将小鼠分为四组：正常未治疗组、正常治疗组、耐索拉非尼未治疗组和耐索拉非尼治疗组。Huh-7肿瘤小鼠连续15天接受索拉非尼（30mg/kg/天）或赋形剂的胃内注射。在整个研究过程中评估肿瘤大小和重量。在治疗开始后的第-2、3、7和14天，用[F]阿法肽II和[F]FDG进行纵向微型PET/计算机断层扫描（CT）扫描，以定量测量血管生成，在第-1、4、8和15天测量代谢。计算每个探针的肿瘤摄取量（ID%/g）。在正常组和耐索拉非尼组之间未观察到[F]FDG摄取的显著差异（=0.452）；然而，两组之间[F]阿法肽II的摄取有显著差异（<0.001）。索拉非尼成功抑制了正常Huh-7肿瘤的生长，在索拉非尼治疗9天后肿瘤大小出现显著差异（<0.05）。肿瘤病变中[F]阿法肽II的摄取在第14天有显著变化（=0.001）。然而，[F]FDG的摄取没有变化（>0.05）。通过针对整合素αvβ3、VEGF和GULT-1的免疫组织化学分析验证了[F]阿法肽II和[F]FDG的PET成像数据。在Huh-7人HCC异种移植模型中，[F]阿法肽II PET在监测索拉非尼耐药性和治疗效果方面比[F]FDG更有效。
