Kronberger Julia, Balber Theresa, Schueffl Hemma, Wahrmann Raphaela, Federa Anja, Gradl Mathias, Brandt Marie R, Wanek Thomas, Mitterhauser Markus, Kowol Christian R, Mindt Thomas L, Heffeter Petra
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria.
Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria.
J Med Chem. 2025 Jun 26;68(12):12925-12939. doi: 10.1021/acs.jmedchem.5c00803. Epub 2025 Jun 17.
Human serum albumin (HSA) is a clinically validated drug carrier that improves drug delivery to tumor tissues. However, clinical imaging strategies are lacking to stratify patients who will benefit from HSA-bound drugs. In this study, we site-selectively radiolabeled HSA with zirconium-89 (Zr), using the octadentate chelator DFO*, to provide an imaging probe with enhanced stability and sufficient half-life to elucidate the long-term (tumoral) albumin homeostasis. [Zr]Zr-DFOmalHSA demonstrated excellent metabolic stability and high tumor uptake in a longitudinal PET study (72 h p.i.) using a subcutaneous colorectal cancer allograft model (CT26). Preliminary results also showed enhanced enrichment of the PET probe in an intraperitoneally injected CT26 model indicating the role of the EPR effect not only in subcutaneous models. Consequently, [Zr]Zr-DFOmalHSA is a promising tool to image albumin accumulation in malignant tissues and should be further (pre)clinically developed as a companion diagnostic agent for patient stratification in trials with albumin-binding drugs.
人血清白蛋白（HSA）是一种经过临床验证的药物载体，可改善药物向肿瘤组织的递送。然而，目前缺乏临床成像策略来对将从与HSA结合的药物中获益的患者进行分层。在本研究中，我们使用八齿螯合剂DFO*，用锆-89（Zr）对HSA进行位点选择性放射性标记，以提供一种具有增强稳定性和足够半衰期的成像探针，以阐明长期（肿瘤）白蛋白稳态。在使用皮下结直肠癌同种异体移植模型（CT26）的纵向PET研究（注射后72小时）中，[Zr]Zr-DFOmalHSA表现出优异的代谢稳定性和高肿瘤摄取。初步结果还显示，在腹腔注射的CT26模型中，PET探针的富集增强，这表明EPR效应不仅在皮下模型中起作用。因此，[Zr]Zr-DFOmalHSA是一种很有前景的工具，可用于对恶性组织中的白蛋白积累进行成像，并且应该在临床前进一步开发，作为白蛋白结合药物试验中患者分层的伴随诊断剂。
