Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, P. R. China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnosis & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, P. R. China.
ACS Biomater Sci Eng. 2020 Oct 12;6(10):5874-5885. doi: 10.1021/acsbiomaterials.0c00921. Epub 2020 Sep 8.
Irregular hepatectomy plays a prominent role in the treatment of small hepatocellular carcinoma (HCC) patients with severe cirrhosis and localized liver metastasis. In clinical practices, intraoperative tumor boundaries delineation facilitates to accomplish tumor resection with negative margin, remarkably decreasing the recurrence rates. Currently, ultrasound (US) and ICG fluorescence-guided surgery has been used for intraoperative navigation in irregular hepatectomy, but insufficient specificity results in a limited prevalence. Inspired by the high resolution of photoacoustic (PA) imaging and established clinical efficacy of F-Alfatide that is specific for integrin αβ-overexpressed tumors, we herein developed a fluorescent analogue IR820-E[c(RGDfK)], and a proof-of-concept intraoperative multispectral PA imaging navigation for precise irregular hepatectomy using hand-held PA/US imaging system. An integrin αβ-targeted fluorescent contrast agent IR820-E[c(RGDfK)] was designed, synthesized, and characterized. In vitro studies were performed to determine optical and PA properties, affinity and specificity and biocompatibility. Multispectral PA imaging, the optimal imaging time point and contrast, multispectral PA imaging-guided irregular hepatectomy, pharmacokinetics, and safety profile were evaluated in subcutaneous and orthotopic HCC tumor models. Ex vivo macroscopic three-dimensions (3D) PA imaging with IR820-E[c(RGDfK)] staining was also performed in surgical biospecimens from patients with HCC. IR820-E[c(RGDfK)] has a simple synthetic method at gram scale, high affinity, and specificity for integrin αβ, excellent pharmacokinetic and safety profile can effectively differentiate tumor from normal liver tissues in animal models and surgical biospecimens from HCC patients. Preoperative tumor localization, intraoperative tumor boundaries delineation, and tumor excision, and postoperative negative margin assessment were successfully achieved during irregular hepatectomy. This initial attempt allows one to preoperatively detect tumor lesions, intraoperatively delineate tumor boundaries and guide tumor resection, and postoperatively evaluate tumor margin status during irregular hepatectomy. IR820-E[c(RGDfK)] has the potential to be an investigational new drug for clinical use in multispectral photoacoustic imaging-guided irregular hepatectomy.
不规则肝切除术在治疗伴有严重肝硬化和局限性肝转移的小肝细胞癌（HCC）患者中发挥着重要作用。在临床实践中，术中肿瘤边界的描绘有助于实现无肿瘤边缘的肿瘤切除，显著降低复发率。目前，超声（US）和 ICG 荧光引导手术已用于不规则肝切除术的术中导航，但由于特异性不足，其应用范围有限。受光声（PA）成像高分辨率和特异性针对整合素αβ过表达肿瘤的 F-Alfatide 临床疗效的启发，我们在此设计并合成了一种荧光类似物 IR820-E[c（RGDfK）]，并使用手持式 PA/US 成像系统开发了一种用于精确不规则肝切除术的术中多光谱 PA 成像导航的概念验证。设计、合成并表征了一种整合素αβ靶向荧光对比剂 IR820-E[c（RGDfK）]。进行了体外研究以确定光学和 PA 特性、亲和力和特异性以及生物相容性。在皮下和原位 HCC 肿瘤模型中评估了多光谱 PA 成像、最佳成像时间点和对比、多光谱 PA 成像引导的不规则肝切除术、药代动力学和安全性。还在 HCC 患者的手术生物标本中进行了基于 IR820-E[c（RGDfK）]染色的宏观三维（3D）PA 成像的离体研究。IR820-E[c（RGDfK）]具有简单的克级合成方法、对整合素αβ的高亲和力和特异性、优异的药代动力学和安全性，可有效区分动物模型和 HCC 患者手术生物标本中的肿瘤与正常肝组织。在不规则肝切除术中成功实现了术前肿瘤定位、术中肿瘤边界描绘、肿瘤切除以及术后阴性切缘评估。这一初步尝试使得人们能够在不规则肝切除术前检测肿瘤病变，术中描绘肿瘤边界并指导肿瘤切除，术后评估不规则肝切除术后肿瘤边缘状态。IR820-E[c（RGDfK）]有潜力成为一种用于多光谱光声成像引导不规则肝切除术的研究性新药。
