Development of [177Lu]Lu-LNC1003 for radioligand therapy of prostate cancer with a moderate level of PSMA expression,European Journal of Nuclear Medicine and Molecular Imaging

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Development of [177Lu]Lu-LNC1003 for radioligand therapy of prostate cancer with a moderate level of PSMA expression
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2023-04-25 , DOI: 10.1007/s00259-023-06229-w
Xuejun Wen ₁ , Pengfei Xu _{2,

3} , Xinying Zeng ₁ , Jia Liu ₁ , Chao Du ₁ , Xueyuan Zeng ₁ , Xingxing Cheng ₁ , Xueqi Wang ₁ , Yuanyuan Liang ₁ , Tianzhi Zhao ₃ , Hongzhang Yang ₁ , Huifeng Li ₁ , Lingxin Meng ₁ , Jianyang Fang ₁ , Hongwu Liu ₁ , Zijian Zhou ₁ , Jingjing Zhang _{3,

4,

5} , Xianzhong Zhang ₁ , Zhide Guo ₁ , Xiaoyuan Chen _{3,

4,

5,

6,

7}

Affiliation

State Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of PublicHealth, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen, 361102, China.
Institute of Clinical Pharmacy & Pharmacology, Jining First People's Hospital, Jining Medical University, Jining, 272000, China.
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119074, Singapore.
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
Departments of Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119074, Singapore.
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.

Purpose

Evans blue as an albumin binder has been widely used to improve pharmacokinetics and enhance tumor uptake of radioligands, including prostate-specific membrane antigen (PSMA) targeting agents. The goal of this study is to develop an optimal Evans blue-modified radiotherapeutic agent that could maximize the absolute tumor uptake and tumor absorbed dose thus the therapeutic efficacy to allow treatment of tumors even with moderate level of PSMA expression.

Methods

[¹⁷⁷Lu]Lu-LNC1003 was synthesized based on PSMA-targeting agent and Evans blue. Binding affinity and PSMA targeting specificity were verified through cell uptake and competition binding assay in 22Rv1 tumor model that has moderate level of PSMA expression. SPECT/CT imaging and biodistribution studies in 22Rv1 tumor-bearing mice were performed to evaluate the preclinical pharmacokinetics. Radioligand therapy studies were conducted to systematically assess the therapeutic effect of [¹⁷⁷Lu]Lu-LNC1003.

Results

LNC1003 showed high binding affinity (IC₅₀ = 10.77 nM) to PSMA in vitro, which was comparable with that of PSMA-617 (IC₅₀ = 27.49 nM) and EB-PSMA-617 (IC₅₀ = 7.91 nM). SPECT imaging of [¹⁷⁷Lu]Lu-LNC1003 demonstrated significantly improved tumor uptake and retention as compared with [¹⁷⁷Lu]Lu-EB-PSMA and [¹⁷⁷Lu]Lu-PSMA-617, making it suitable for prostate cancer therapy. Biodistribution studies further confirmed the remarkably higher tumor uptake of [¹⁷⁷Lu]Lu-LNC1003 (138.87 ± 26.53%ID/g) over [¹⁷⁷Lu]Lu-EB-PSMA-617 (29.89 ± 8.86%ID/g) and [¹⁷⁷Lu]Lu-PSMA-617 (4.28 ± 0.25%ID/g) at 24 h post-injection. Targeted radioligand therapy results showed noteworthy inhibition of 22Rv1 tumor growth after administration of a single dose of 18.5 MBq [¹⁷⁷Lu]Lu-LNC1003. There was no obvious antitumor effect after [¹⁷⁷Lu]Lu-PSMA-617 treatment under the same condition.

Conclusion

In this study, [¹⁷⁷Lu]Lu-LNC1003 was successfully synthesized with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With greatly enhanced tumor uptake and retention, [¹⁷⁷Lu]Lu-LNC1003 has the potential to improve therapeutic efficacy using significantly lower dosages and less cycles of ¹⁷⁷Lu that promises clinical translation to treat prostate cancer with various levels of PSMA expression.

中文翻译：

开发[177Lu]Lu-LNC1003用于中等水平PSMA表达的前列腺癌的放射配体治疗

目的

伊文思蓝作为白蛋白结合剂已广泛用于改善药代动力学并增强肿瘤对放射性配体的摄取，包括前列腺特异性膜抗原 (PSMA) 靶向剂。本研究的目标是开发一种最佳的伊文思蓝修饰放射治疗剂，可以最大限度地提高绝对肿瘤摄取和肿瘤吸收剂量，从而提高治疗效果，即使具有中等水平的 PSMA 表达也能治疗肿瘤。

方法

基于PSMA靶向剂和伊文思蓝合成了[ ^{177 Lu]Lu-LNC1003。}在具有中等水平 PSMA 表达的 22Rv1 肿瘤模型中，通过细胞摄取和竞争结合测定验证了结合亲和力和 PSMA 靶向特异性。在 22Rv1 荷瘤小鼠中进行 SPECT/CT 成像和生物分布研究，以评估临床前药代动力学。进行放射配体治疗研究以系统评估[ ¹⁷⁷ Lu]Lu-LNC1003的治疗效果。

结果

LNC1003 在体外表现出与 PSMA 的高结合亲和力 (IC _{50 = 10.77 nM)，与 PSMA-617 (IC}₅₀ = 27.49 nM) 和 EB-PSMA-617 (IC ₅₀ = 7.91 nM) 相当。^{与[ 177} Lu] Lu-EB-PSMA 和[ 177 Lu ^] Lu-PSMA-617相比，[ 177 Lu]Lu-LNC1003 的 SPECT 成像显示肿瘤摄取和保留显着改善^，使其适合前列腺癌治疗。^{生物分布研究进一步证实，[ 177} Lu]Lu-LNC1003 (138.87 ± 26.53%ID/g)的肿瘤摄取明显高于[ ¹⁷⁷ Lu]Lu-EB-PSMA-617 (29.89 ± 8.86%ID/g) 和 [ ¹⁷⁷ Lu]Lu-PSMA-617 (4.28 ± 0.25%ID/g) 注射后 24 小时。靶向放射性配体治疗结果显示，单剂量 18.5 MBq [ ¹⁷⁷ Lu]Lu-LNC1003 给药后，22Rv1 肿瘤生长受到显着抑制。相同条件下[ ¹⁷⁷ Lu]Lu-PSMA-617治疗后未见明显抗肿瘤作用。

结论

本研究成功合成了具有高放射化学纯度和稳定性的[ ^{177 Lu]Lu-LNC1003。}在体外和体内均鉴定出高结合亲和力和 PSMA 靶向特异性。由于大大增强了肿瘤的摄取和保留，[ ¹⁷⁷ Lu]Lu-LNC1003 有潜力使用显着较低的剂量和更少的¹⁷⁷ Lu 周期来提高治疗效果，这有望临床转化为治疗具有不同水平 PSMA 表达的前列腺癌。

更新日期：2023-04-25

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