Dansylated Amino Acid–Modified Long-Acting PSMA Derivatives 68Ga/177Lu-LNC1011 as Prostate Cancer Theranostics

Hongzhang Yang, Jiarou Wang, Xuejun Wen, Huifeng Guo, Vivianne Jakobsson, Tianzhi Zhao, Fantian Zeng, Huaxiang Shen, Heng Zhang, Xiaomin Liu, Yatong Qin, Xinyi Li, Hehe Xiong, Zijian Zhou, Jingjing Zhang, Xiaoyuan Chen
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Abstract

Prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy has demonstrated promising potential for treating metastatic castration-resistant prostate cancer. Recently, albumin-binding motif-modified PSMA radioligands with prolonged blood circulation were developed to improve tumor uptake and therapeutic effectiveness, properties which, however, were associated with an increased risk of bone marrow toxicity. This study presents new PSMA-targeted radioligands incorporating dansylated amino acids as relatively weak and preferable albumin binders to achieve a fine balance between increased tumor accumulation, safety, and diagnostic efficacy, facilitating a unified approach to theranostics within a single molecular framework. Methods: Three novel PSMA ligands ([68Ga]Ga-Dan-Gly-PSMA, [68Ga]Ga-Dan-Nva-PSMA, and [68Ga]Ga-Dan-Phe-PSMA, denoted as [68Ga]Ga-LNC1011) were synthesized with dansylated amino acids and measured the albumin-binding properties with human serum albumin through ultrafiltration experiments. Binding affinity and PSMA-targeting specificity were investigated using a saturation binding assay and cell uptake in the PSMA-induced prostate cancer 3 cell line (PC3-PIP). PET imaging in PC3-PIP tumor–bearing mice was performed to evaluate the preclinical pharmacokinetics and diagnostic efficiency of 68Ga-labeled PSMA ligands. Tumor uptake of [177Lu]Lu-LNC1011 was evaluated through SPECT/CT imaging and biodistribution studies. Radiopharmaceutical therapy studies were conducted to systematically assess the therapeutic effect of the radioligand. Results: Three novel PSMA radioligands ([68Ga]Ga-Dan-Gly-PSMA, [68Ga]Ga-Dan-Nva-PSMA, and [68Ga]Ga-LNC1011) with various dansylated amino acids were successfully synthesized with a radiochemical yield greater than 97%. In the PC3-PIP xenograft tumor model, the tumor/heart, tumor/liver, tumor/kidney, and tumor/muscle ratios were 9.82 ± 2.35, 12.42 ± 3.71, 4.36 ± 0.29, and 52.88 ± 12.08 at 4 h after injection, respectively. Biodistribution studies confirmed the significantly higher tumor uptake of [177Lu]Lu-LNC1011 (127.36 ± 16.95 %ID/g) over [177Lu]Lu-PSMA-617 (17.44 ± 6.29 %ID/g) at 4 h after injection, and no decrease was measured for the [177Lu]Lu-LNC1011 at up to 72 h after injection, which was corroborated with SPECT imaging. A single injection of 9.3 MBq of [177Lu]Lu-LNC1011 achieved 89.43% inhibition of tumor growth, equivalent to 18.5 MBq of [177Lu]Lu-PSMA-617 (90.87%). [68Ga]Ga-LNC1011 PET/CT scans of patients with metastatic castration-resistant prostate cancer identified as many lesions as [68Ga]Ga-PSMA-11 did, confirming its diagnostic efficacy. Conclusion: 68Ga/177Lu-LNC1011, characterized by high tumor uptake and retention along with timely clearance from normal organs and tissues, thus emerges as a promising single-molecule theranostic radioligand.

丹化氨基酸修饰的长效PSMA衍生物68Ga/177Lu-LNC1011在前列腺癌治疗中的应用
前列腺特异性膜抗原(PSMA)靶向放射药物治疗已经显示出治疗转移性去势抵抗性前列腺癌的良好潜力。最近,白蛋白结合基序修饰的具有延长血液循环的PSMA放射配体被开发出来,以改善肿瘤摄取和治疗效果,然而,这些特性与骨髓毒性风险增加有关。本研究提出了一种新的psma靶向放射配体,将丹化氨基酸作为相对较弱和较好的白蛋白结合物,在增加肿瘤积累、安全性和诊断疗效之间实现了良好的平衡,促进了单一分子框架内治疗的统一方法。方法:以丹酰化氨基酸为原料合成三种新型PSMA配体([68Ga] ga - dan - gli -PSMA、[68Ga]Ga-Dan-Nva-PSMA、[68Ga] ga - dan - ph -PSMA,标记为[68Ga]Ga-LNC1011),并通过超滤实验测定其与人血清白蛋白的结合性能。通过饱和结合实验和psma诱导的前列腺癌3细胞系(PC3-PIP)的细胞摄取,研究了psma的结合亲和力和psma靶向特异性。对PC3-PIP小鼠进行PET显像,评价68ga标记的PSMA配体的临床前药代动力学和诊断效率。通过SPECT/CT成像和生物分布研究评估[177Lu]Lu-LNC1011的肿瘤摄取情况。进行了放射性药物治疗研究,以系统地评估放射性配体的治疗效果。结果:成功合成了3个具有不同丹化氨基酸的新型PSMA放射配体([68Ga] ga - dan - gli -PSMA、[68Ga]Ga-Dan-Nva-PSMA和[68Ga]Ga-LNC1011),放射化学产率大于97%。在PC3-PIP异种移植肿瘤模型中,注射后4 h,肿瘤/心脏、肿瘤/肝脏、肿瘤/肾脏、肿瘤/肌肉的比值分别为9.82±2.35、12.42±3.71、4.36±0.29、52.88±12.08。生物分布研究证实,注射后4 h, [177Lu]Lu-LNC1011的肿瘤摄取(127.36±16.95% ID/g)明显高于[177Lu] lu - pma -617(17.44±6.29% ID/g),注射后72 h, [177Lu]Lu-LNC1011的肿瘤摄取未见减少,SPECT成像证实了这一点。单次注射9.3 MBq的[177Lu]Lu-LNC1011对肿瘤生长的抑制作用达到89.43%,相当于18.5 MBq的[177Lu]Lu-PSMA-617的抑制作用(90.87%)。[68Ga]Ga-LNC1011在转移性去势抵抗性前列腺癌患者的PET/CT扫描中发现的病变数量与[68Ga]Ga-PSMA-11相当,证实了其诊断效能。结论:68Ga/177Lu-LNC1011具有较高的肿瘤摄取和滞留性,并能及时从正常器官和组织中清除,是一种有前景的单分子放射治疗配体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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