Department of Biomedical Engineering, University of California, Davis, One Shields Avenue, Davis, California 95616, United States.
Department of Internal Medicine, Division of Hematology/Oncology, University of California, Davis, 4150 V Street, Sacramento, California 95817, United States.
J Med Chem. 2023 Jul 27;66(14):9842-9852. doi: 10.1021/acs.jmedchem.3c00631. Epub 2023 Jul 7.
Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin αβ are emerging as powerful tools to overcome these challenges. The development of an integrin αβ-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the αβ-binding peptide (αβ-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [Cu]PDC- was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin αβ-selective internalization, cell binding, and cytotoxicity. Integrin αβ-selective tumor accumulation of the [Cu]PDC- was visualized with PET-imaging and corroborated by biodistribution, and [Cu]PDC- showed promising in vivo pharmacokinetics. The [Cu]PDC- treatment resulted in prolonged survival of mice bearing αβ (+) tumors (median survival: 77 days, vs αβ (-) tumor group 49 days, and all other control groups 37 days).
许多抗癌药物表现出很高的系统脱靶毒性，导致严重的副作用。靶向肿瘤特异性受体（如整合素αβ）的肽-药物偶联物（PDCs）正成为克服这些挑战的有力工具。通过将细胞毒性药物单甲基奥瑞他汀 E 的治疗功效与αβ 结合肽（αβ-BP）的选择性以及正电子发射断层扫描（PET）成像的铜-64 能力相结合，开发了一种整合素αβ 选择性 PDC。[Cu]PDC- 高效且高纯度地产生。PDC 表现出高的人血清稳定性、整合素αβ 选择性内化、细胞结合和细胞毒性。通过 PET 成像观察到 [Cu]PDC-对整合素αβ 选择性肿瘤的积累，并通过生物分布得到证实，[Cu]PDC-表现出有希望的体内药代动力学。[Cu]PDC-治疗导致携带αβ（+）肿瘤的小鼠的存活时间延长（中位存活时间：77 天，与αβ（-）肿瘤组 49 天和所有其他对照组 37 天相比）。
