64Cu-Labeled Stapled Peptide-Based RadiopharmaceuticalsTargeting MDM2/MDMX for Pan-p53 Tumors

作者：Hao Tian, Quan Zuo, Siqi Zhang, Hongyi Huang, Wu Dong, Zihan Huang, Xiangding Liu, Lin Xie, Yiding Zhang, Hailong Zhang, Yekuan Shi, Suping Li, Ming‐Rong Zhang, Rui Wang, Kuan Hu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c02183 · 被引用次数：12 · 研究领域：Radiopharmaceutical Chemistry and Applications、Cancer-related Molecular Pathways、Lung Cancer Research Studies

Abstract The development of ideal peptide-based radiopharmaceuticals faces critical bottlenecks, primarily due to limited cellular internalization and insufficient deep tissue penetration of peptide carriers. To address this, we developed an intracellular targeting and DNA-adjacent radiotherapeutic strategy using stapled peptides. The MDM2/MDMX-targeting stapled peptide-based radiopharmaceuticals, denoted as [64Cu]Cu-DOTA-STP, exhibited prolonged circulation in the bloodstream and slow systemic clearance. Furthermore, in vitro studies demonstrated that nearly 50% of administered [64Cu]Cu-DOTA-STP was internalized, achieving efficient intracellular accumulation. In addition, [64Cu]Cu-DOTA-STP demonstrated high tumor accumulation, with a standard uptake value of up to 9.39 ± 1.52%ID/g. Finally, targeted radionuclide therapy confirmed that [64Cu]Cu-DOTA-STP effectively inhibited tumor growth, irrespective of p53 phenotypes. Taken together, this study leveraged PET imaging as a noninvasive and longitudinal tool to elucidate the in vivo fate of stapled peptides and demonstrated that stapled peptides can serve as ideal vehicles for developing intracellular protein-targeting radiopharmaceuticals, achieving efficient 64Cu-based targeted radionuclide therapy.