白蛋白结合PSMA配体：组织分布图的优化。,Molecular Pharmaceutics

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白蛋白结合PSMA配体：组织分布图的优化。
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-02-05 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00877
Martina Benešová _{1,

2} , Christoph A. Umbricht ₁ , Roger Schibli _{1,

2} , Cristina Müller _{1,

2}

Affiliation

前列腺特异性膜抗原（PSMA）已成为使用PSMA特异性放射性配体进行放射治疗的有吸引力的前列腺癌相关靶标。这项研究的目的是设计用白蛋白结合部分修饰的新的PSMA配体，以优化其组织分布特征。通过使用多步固相合成将基于尿素的PSMA结合实体，DOTA螯合剂和4-（对碘苯基）丁酸偶联来制备化合物。设计了三个配体（PSMA-ALB-02，PSMA-ALB-05和PSMA-ALB-07），并带有不同的连接体。用^177进行放射性标记以高达50 MBq / nmol的比活进行Lu，导致放射性配体的化学纯度大于98％，稳定性高。体外研究表明，所有三种PSMA放射性配体均与小鼠（> 64％）和人血浆蛋白（> 94％）具有高结合力。对于所有放射性配体，PSMA阳性PC-3 PIP肿瘤细胞的摄取和内在化都同样高。在PSMA阴性的PC-3流感细胞中发现的积聚微不足道，表明所有放射性配体的PSMA特异性结合。在PC-3 PIP / flu荷瘤小鼠中进行的生物分布和成像研究表明，与临床使用的相比，新放射性配体的血液循环增强了¹⁷⁷Lu-PSMA-617。注射后24 h（pi），所有三种放射性配体的PC-3 PIP肿瘤摄取非常高（分别为76.4±2.5％IA / g，79.4±11.1％IA / g和84.6±14.2％IA / g）。导致肿瘤与血液的比例分别为176、48和107，而对PC-3流感肿瘤的吸收微不足道。在pi 24 h肾脏摄取最低，为¹⁷⁷ Lu-PSMA-ALB-02（10.7±0.92％IA / g），而¹⁷⁷ Lu-PSMA-ALB-05和¹⁷⁷ Lu-PSMA-ALB-07显示较高的肾脏retention留（分别为23.9±4.02％IA / g和51.9±6.34％IA / g。由时间依赖性生物分布数据的曲线下面积（AUC）值计算得出的肿瘤与背景之比有利于¹⁷⁷ Lu-PSMA-ALB-02（肿瘤与血液，46；肿瘤与肾脏，5.9）与¹⁷⁷ Lu-PSMA-ALB-05（分别为17和3.7）和¹⁷⁷ Lu-PSMA-ALB-07（分别为39和2.1）。在SPECT / CT图像上可以看到PC-3 PIP肿瘤中放射性配体的高度积累，表明随着时间的推移，肾脏与肾脏的比率不断增加。考虑到所有特征，¹⁷⁷ Lu-PSMA-ALB-02成为最有前途的候选者。所应用的概念对于将来的临床翻译可能具有吸引力，从而有可能实现更有效，更方便的前列腺癌放射性核素治疗。

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Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile

The prostate-specific membrane antigen (PSMA) has emerged as an attractive prostate cancer associated target for radiotheragnostic application using PSMA-specific radioligands. The aim of this study was to design new PSMA ligands modified with an albumin-binding moiety in order to optimize their tissue distribution profile. The compounds were prepared by conjugation of a urea-based PSMA-binding entity, a DOTA chelator, and 4-(p-iodophenyl)butyric acid using multistep solid phase synthesis. The three ligands (PSMA-ALB-02, PSMA-ALB-05, and PSMA-ALB-07) were designed with varying linker entities. Radiolabeling with ¹⁷⁷Lu was performed at a specific activity of up to 50 MBq/nmol resulting in radioligands of >98% radiochemical purity and high stability. In vitro investigations revealed high binding of all three PSMA radioligands to mouse (>64%) and human plasma proteins (>94%). Uptake and internalization into PSMA-positive PC-3 PIP tumor cells was equally high for all radioligands. Negligible accumulation was found in PSMA-negative PC-3 flu cells, indicating PSMA-specific binding of all radioligands. Biodistribution and imaging studies performed in PC-3 PIP/flu tumor-bearing mice showed enhanced blood circulation of the new radioligands when compared to the clinically employed ¹⁷⁷Lu-PSMA-617. The PC-3 PIP tumor uptake of all three radioligands was very high (76.4 ± 2.5% IA/g, 79.4 ± 11.1% IA/g, and 84.6 ± 14.2% IA/g, respectively) at 24 h post injection (p.i.) resulting in tumor-to-blood ratios of ∼176, ∼48, and ∼107, respectively, whereas uptake into PC-3 flu tumors was negligible. Kidney uptake at 24 h p.i. was lowest for ¹⁷⁷Lu-PSMA-ALB-02 (10.7 ± 0.92% IA/g), while ¹⁷⁷Lu-PSMA-ALB-05 and ¹⁷⁷Lu-PSMA-ALB-07 showed higher renal retention (23.9 ± 4.02% IA/g and 51.9 ± 6.34% IA/g, respectively). Tumor-to-background ratios calculated from values of the area under the curve (AUC) of time-dependent biodistribution data were in favor of ¹⁷⁷Lu-PSMA-ALB-02 (tumor-to-blood, 46; tumor-to-kidney, 5.9) when compared to ¹⁷⁷Lu-PSMA-ALB-05 (17 and 3.7, respectively) and ¹⁷⁷Lu-PSMA-ALB-07 (39 and 2.1, respectively). The high accumulation of the radioligands in PC-3 PIP tumors was visualized on SPECT/CT images demonstrating increasing tumor-to-kidney ratios over time. Taking all of the characteristics into account, ¹⁷⁷Lu-PSMA-ALB-02 emerged as the most promising candidate. The applied concept may be attractive for future clinical translation potentially enabling more potent and convenient prostate cancer radionuclide therapy.

更新日期：2018-02-05

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