Lewis Michael R, Schaedler Alexander W, Ho Khanh-Van, Golzy Mojgan, Mathur Anupam, Pun Michael, Gallazzi Fabio, Watkinson Lisa D, Carmack Terry L, Sikligar Kanishka, Anderson Carolyn J, Smith Charles J
Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States of America; Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO, United States of America; Ellis Fischel Cancer Center, University of Missouri, Columbia, MO, United States of America.
Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, United States of America; Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO, United States of America.
Nucl Med Biol. 2024 Sep-Oct;136-137:108938. doi: 10.1016/j.nucmedbio.2024.108938. Epub 2024 Jul 14.
Prostate cancer affects 1 in 6 men, and it is the second‑leading cause of cancer-related death in American men. Surgery is one of the main treatment modalities for prostate cancer, but it often results in incomplete resection margins or complete resection that leads to nerve damage and undesirable side effects. In the present work, we have developed a new bimodal tracer, NODAGA-sCy7.5 PSMAi (prostate-specific membrane antigen inhibitor), labeled with the true matched theranostic pair Cu/Cu and a near-infrared fluorescent dye. This agent could potentially be used for concomitant PET imaging, optical surgical navigation, and targeted radiopharmaceutical therapy.
A prostate-specific membrane antigen (PSMA)-targeting urea derivative was conjugated to NODAGA for copper radiolabeling and to the near-infrared fluorophore sulfo-Cy7.5 (sCy7.5). Binding studies were performed in PSMA-positive PC-3 PIP cells, as well as uptake and internalization assays in PC-3 PIP cells and PSMA-negative PC-3 wild type cells. Biodistribution studies of the Cu-labeled compound were performed in PC-3 PIP- and PC-3 tumor-bearing mice, and Cu biodistributions of the agent were obtained in PC-3 PIP tumor-carrying mice. PET imaging and fluorescence imaging were also performed, using the same molar doses, in the two mouse models.
The PSMA conjugate bound with high affinity to PSMA-positive prostate cancer cells, as opposed to cells that were PSMA-negative. Uptake and internalization were rapid and PSMA-mediated in PC-3 PIP cells, while only minimal non-specific uptake was observed in PC-3 cells. Biodistribution studies showed specific uptake in PC-3 PIP tumors, while accumulation in PC-3 tumor-bearing mice was low. Furthermore, tumor uptake of the Cu-labeled agent in the PC-3 PIP model was statistically equivalent to that of Cu. PET and fluorescence imaging at 0.5 nmol per mouse also demonstrated that PC-3 PIP tumors could be clearly detected, while PC-3 tumors showed no tumor accumulation.
NODAGA-sCy7.5-PSMAi was specific and selective in detecting PSMA-positive, as opposed to PSMA-negative, tumors in mouse models of prostate cancer. This bioconjugate could potentially be used for PET staging with Cu, targeted radiopharmaceutical therapy with Cu, and/or image-guided surgery with sCy7.5.
前列腺癌影响着六分之一的男性，是美国男性癌症相关死亡的第二大原因。手术是前列腺癌的主要治疗方式之一，但它常常导致手术切缘不完整或完全切除，进而导致神经损伤和不良副作用。在本研究中，我们开发了一种新的双模态示踪剂，NODAGA-sCy7.5 PSMAi（前列腺特异性膜抗原抑制剂），用真正匹配的诊疗对Cu/Cu和一种近红外荧光染料进行标记。这种试剂可能可用于同步正电子发射断层显像（PET）成像、光学手术导航和靶向放射性药物治疗。
将一种靶向前列腺特异性膜抗原（PSMA）的尿素衍生物与NODAGA偶联，用于铜放射性标记，并与近红外荧光团磺基-Cy7.5（sCy7.5）偶联。在PSMA阳性的PC-3 PIP细胞中进行结合研究，并在PC-3 PIP细胞和PSMA阴性的PC-3野生型细胞中进行摄取和内化试验。在PC-3 PIP荷瘤小鼠和PC-3荷瘤小鼠中进行铜标记化合物的生物分布研究，并在PC-3 PIP荷瘤小鼠中获得该试剂的铜生物分布。在两种小鼠模型中，也使用相同的摩尔剂量进行PET成像和荧光成像。
与PSMA阴性细胞相反，PSMA偶联物与PSMA阳性前列腺癌细胞具有高亲和力结合。在PC-3 PIP细胞中摄取和内化迅速且由PSMA介导，而在PC-3细胞中仅观察到极少的非特异性摄取。生物分布研究显示在PC-3 PIP肿瘤中有特异性摄取，而在PC-3荷瘤小鼠中的蓄积较低。此外，在PC-3 PIP模型中铜标记试剂的肿瘤摄取在统计学上与铜的摄取相当。每只小鼠0.5 nmol时的PET和荧光成像也表明可以清晰检测到PC-3 PIP肿瘤，而PC-3肿瘤未显示肿瘤蓄积。
在前列腺癌小鼠模型中，NODAGA-sCy7.5-PSMAi在检测PSMA阳性而非PSMA阴性肿瘤方面具有特异性和选择性。这种生物偶联物可能可用于用Cu进行PET分期、用Cu进行靶向放射性药物治疗和/或用sCy7.5进行图像引导手术。
