Ganguly Tanushree, Bauer Nadine, Davis Ryan A, Foster Cameron C, Harris Rebecca E, Hausner Sven H, Roncali Emilie, Tang Sarah Y, Sutcliffe Julie L
Department of Biomedical Engineering, University of California Davis, Davis, California.
Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Sacramento, California.
J Nucl Med. 2023 Apr;64(4):639-644. doi: 10.2967/jnumed.122.264749. Epub 2022 Oct 7.
The integrin αβ, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel αβ-targeting peptide, DOTA-5G () radiolabeled with Ga, for PET/CT imaging and Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G (). Peptides and were synthesized on solid phase, and their affinity for αβ was assessed by enzyme-linked immunosorbent assay. The peptides were radiolabeled with Ga and Lu. In vitro cell binding, internalization, and efflux of Ga- and Lu- were evaluated in αβ-positive BxPC-3 human pancreatic cancer cells. PET/CT imaging of Ga- and Ga- was performed on female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for Ga- (1 and 2 h after injection), Ga- (2 and 4 h after injection), and Lu- and Lu- (1, 24, 48, and 72 h after injection). The Lu- biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of Lu- was evaluated in mice bearing BxPC-3 tumors. Peptides and demonstrated high affinity (<55 nM) for αβ by enzyme-linked immunosorbent assay. Ga-, Ga-, Lu-, and Lu- were synthesized in high radiochemical purity. Rapid in vitro binding and internalization of Ga- and Lu- were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the albumin-binding moiety in Lu- resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data, the dose-limiting organ for Lu- is the kidney. Treatment with Lu- prolonged median survival by 1.5- to 2-fold versus controls. Ga- and Lu- demonstrated high affinity for the integrin αβ both in vitro and in vivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in preclinical studies, with predominantly renal excretion and good tumor-to-normal-tissue ratios. Favorable human dosimetry data suggest the potential of Lu- as a treatment for pancreatic ductal adenocarcinoma.
整合素αβ是一种上皮特异性细胞表面受体，在包括高致死性胰腺导管腺癌在内的多种恶性肿瘤中过度表达。在此，我们开发并测试了一种新型的靶向αβ的肽，即经镓放射性标记用于PET/CT成像以及经镥放射性标记用于治疗的DOTA-5G（）。为了开发一种放射诊疗剂，我们进行了进一步修饰以延长循环时间、促进肾脏再循环并提高肿瘤摄取，从而得到了DOTA-白蛋白结合部分-5G（）。肽和在固相上合成，并通过酶联免疫吸附测定法评估它们对αβ的亲和力。这些肽用镓和镥进行放射性标记。在αβ阳性的BxPC-3人胰腺癌细胞中评估了镓-和镥-的体外细胞结合、内化及流出情况。对荷皮下BxPC-3肿瘤的雌性裸鼠进行了镓-和镓- 的PET/CT成像。对镓-（注射后1小时和2小时）、镓-（注射后2小时和4小时）以及镥-和镥-（注射后1小时、24小时、48小时和72小时）进行了生物分布研究。使用OLINDA/EXM 1.1将镥- 的生物分布数据外推以估计人体剂量学数据。在荷BxPC-3肿瘤的小鼠中评估了镥- 的治疗效果。通过酶联免疫吸附测定法，肽和对αβ显示出高亲和力（<55 nM）。镓-、镓-、镥- 和镥- 以高放射化学纯度合成。在BxPC-3细胞中观察到镓-和镥- 的快速体外结合和内化。PET/CT成像和生物分布研究表明在BxPC-3肿瘤中有摄取。在镥- 中引入白蛋白结合部分导致肿瘤摄取随时间增加了5倍并有所保留。基于扩展的剂量学数据，镥- 的剂量限制器官是肾脏。与对照组相比，用镥-治疗使中位生存期延长了1.5至2倍。镓-和镥- 在体外和体内对整合素αβ均显示出高亲和力，能迅速内化到BxPC-3细胞中，并且在小鼠和人血清中稳定。两种放射性示踪剂在临床前研究中均显示出良好的药代动力学，主要经肾脏排泄且肿瘤与正常组织的比率良好。有利的人体剂量学数据表明镥- 作为胰腺导管腺癌治疗方法的潜力。
