Sham Jonathan G, Kievit Forrest M, Grierson John R, Miyaoka Robert S, Yeh Matthew M, Zhang Miqin, Yeung Raymond S, Minoshima Satoshi, Park James O
Department of Surgery, University of Washington, Seattle, Washington.
J Nucl Med. 2014 May;55(5):799-804. doi: 10.2967/jnumed.113.132118. Epub 2014 Mar 13.
Hepatocellular carcinoma (HCC) is a devastating malignancy in which imperfect imaging plays a primary role in diagnosis. Glypican-3 (GPC3) is an HCC-specific cell surface proteoglycan overexpressed in most HCCs. This paper presents the use of (89)Zr-conjugated monoclonal antibody against GPC3 ((89)Zr-αGPC3) for intrahepatic tumor localization using PET.
Polymerase chain reaction confirmed relative GPC3 expression in cell lines. In vitro binding, in vivo biodistribution, and small-animal PET studies were performed on GPC3-expressing HepG2 and non-GPC3-expressing HLF and RH7777 cells and orthotopic xenografts.
(89)Zr-αGPC3 demonstrated antibody-dependent, antigen-specific tumor binding. HepG2 liver tumors exhibited high peak uptake (836.6 ± 86.6 percentage injected dose [%ID]/g) compared with background liver (27.5 ± 1.6 %ID/g). Tumor-to-liver contrast ratio was high and peaked at 32.5. The smallest HepG2 tumor (<1 mm) showed lower peak uptake (42.5 ± 6.4 %ID/g) and tumor-to-liver contrast (1.57) but was still clearly visible on PET. Day 7 tissue activity was still substantial in HepG2 tumors (466.4 ± 87.6 %ID/g) compared with control RH7777 tumors (3.9 ± 1.3 %ID/g, P < 0.01), indicating antigen specificity by (89)Zr-αGPC3. HepG2 tumor treated with unlabeled αGPC3 or heat-denatured (89)Zr-αGPC3 demonstrated tumor activity (2.1 %ID/g) comparable to that of control xenografts, confirming antibody dependency.
This study demonstrated the feasibility of using (89)Zr-αGPC3 to image HCC in the liver, as well as the qualitative determination of GPC3 expression via small-animal PET. The ability to clarify the identity of small liver lesions with an HCC-specific PET probe would provide clinicians with vital information that could significantly alter patient management, warranting further investigation for clinical translation.
肝细胞癌（HCC）是一种极具破坏性的恶性肿瘤，不完善的影像学检查在其诊断中起主要作用。磷脂酰肌醇蛋白聚糖-3（GPC3）是一种在大多数HCC中过表达的HCC特异性细胞表面蛋白聚糖。本文介绍了使用（89）Zr标记的抗GPC3单克隆抗体（（89）Zr-αGPC3）通过PET进行肝内肿瘤定位。
聚合酶链反应证实了细胞系中GPC3的相对表达。对表达GPC3的HepG2细胞、不表达GPC3的HLF和RH7777细胞以及原位异种移植瘤进行了体外结合、体内生物分布和小动物PET研究。
（89）Zr-αGPC3表现出抗体依赖性、抗原特异性肿瘤结合。与肝脏背景（27.5±1.6%ID/g）相比，HepG2肝肿瘤表现出较高的峰值摄取（836.6±86.6注射剂量百分比[％ID]/g）。肿瘤与肝脏的对比度很高，在32.5时达到峰值。最小的HepG2肿瘤（<1mm）显示出较低的峰值摄取（42.5±6.4%ID/g）和肿瘤与肝脏的对比度（1.57），但在PET上仍清晰可见。与对照RH7777肿瘤（3.9±1.3%ID/g，P<0.01）相比，HepG2肿瘤在第7天的组织活性仍然很高（466.4±87.6%ID/g），表明（89）Zr-αGPC3具有抗原特异性。用未标记的αGPC3或热变性的（89）Zr-αGPC3处理的HepG2肿瘤显示出与对照异种移植瘤相当的肿瘤活性（2.1%ID/g），证实了抗体依赖性。
本研究证明了使用（89）Zr-αGPC3对肝脏中的HCC进行成像以及通过小动物PET定性测定GPC3表达的可行性。用HCC特异性PET探针明确小肝病变的性质的能力将为临床医生提供重要信息，可能会显著改变患者的治疗管理，值得进一步研究以进行临床转化。
