Division of Radiopharmaceutical Sciences and MI3, Department of Radiology, Weill Cornell Medicine, New York, NY, USA.
Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, USA.
Eur J Nucl Med Mol Imaging. 2018 Oct;45(11):1841-1851. doi: 10.1007/s00259-018-4004-5. Epub 2018 Apr 6.
Treatment of late-stage prostate cancer by targeted radiotherapeutics such as I-MIP-1095 and Lu-PSMA-617 has shown encouraging early results. Lu-177 is preferred to I-131 in clinical settings, but targeted radioligand therapy (RLT) with Lu-PSMA-617 has not reached its full potential due to insufficient dose delivery to the tumor. We recently developed a dual-targeting radioiodinated ligand, RPS-027, that targets PSMA and uses albumin binding to enable good tumor uptake and significantly reduced kidney uptake in a preclinical model. Further development of this ligand is limited by the inability to independently modify PSMA and albumin binding and the requirement of I-131 for therapeutic application. We therefore sought to devise a new class of trifunctional ligands for RLT with (1) a high-affinity PSMA-binding domain, (2) an albumin-binding group (ABG), and (3) a chelator for radiometals such as Ga, Lu and Ac.
Ligands incorporating a triazolylphenylurea-containing PSMA-targeting group, an N-(2-(4-iodophenyl)acetyl)lysine ABG and the bifunctional chelator p-SCN-Bn-DOTA linked by a PEG-containing polymer containing 0,3,4,6,8 or 12 repeats were prepared. PSMA affinity was determined in LNCaP cells and uptake and tissue distribution was studied in mice bearing LNCaP tumor xenografts and compared to Lu-PSMA-617. Imaging studies were performed up to 24 h post-injection (p.i.) using Ga and biodistribution studies at 4 h, 24 h and 96 h p.i. with Lu.
PSMA affinity was high (IC = 1-10 nM) and inversely proportional to the linker length. Tumor uptake correlated with binding affinity and was significantly greater than for Lu-PSMA-617 over 96 h. The highest uptake was achieved with Lu-RPS-063 (30.0 ± 6.9 %ID/g; 4 h p.i.). Kidney uptake was generally high, with the exception of the lowest affinity ligand Lu-RPS-067. Each of the compounds showed slower blood clearance than Lu-PSMA-617, with clearance proportional to linker length.
The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4×) doses delivered to the tumor than can be achieved with Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT.
针对晚期前列腺癌的靶向放射治疗药物，如 I-MIP-1095 和 Lu-PSMA-617，已显示出令人鼓舞的早期结果。与 I-131 相比，Lu-177 在临床环境中更受欢迎，但由于未能将足够的剂量递送至肿瘤，Lu-PSMA-617 的靶向放射性配体治疗（RLT）尚未充分发挥潜力。我们最近开发了一种双靶向放射性碘标记配体，RPS-027，该配体靶向 PSMA，并利用白蛋白结合来实现良好的肿瘤摄取，并在临床前模型中显著减少肾脏摄取。由于无法独立修饰 PSMA 和白蛋白结合，以及治疗应用需要 I-131，因此该配体的进一步开发受到限制。因此，我们试图设计一类新的用于 RLT 的三功能配体，（1）具有高亲和力的 PSMA 结合结构域，（2）白蛋白结合基团（ABG），和（3）用于镓、镥和锕等放射性金属的螯合剂。
我们制备了含有三唑基苯脲基 PSMA 靶向基团、N-（2-（4-碘乙酰基）赖氨酸）ABG 和双功能螯合剂 p-SCN-Bn-DOTA 的配体，它们通过含有 0、3、4、6、8 或 12 个重复的聚乙二醇连接。在 LNCaP 细胞中测定 PSMA 亲和力，并在携带 LNCaP 肿瘤异种移植的小鼠中研究摄取和组织分布，并与 Lu-PSMA-617 进行比较。使用 Ga 进行了高达 24 小时注射后（p.i.）的成像研究，并在 4、24 和 96 小时 p.i.时使用 Lu 进行了生物分布研究。
PSMA 亲和力高（IC=1-10 nM），且与连接子长度成反比。肿瘤摄取与结合亲和力相关，在 96 小时内明显大于 Lu-PSMA-617。Lu-RPS-063 实现了最高的摄取（30.0±6.9%ID/g；4 小时 p.i.）。除了亲和力最低的配体 Lu-RPS-067 外，肾脏摄取通常较高。每种化合物的血液清除率均比 Lu-PSMA-617 慢，且清除率与连接子长度成正比。
这些三功能配体实现的高肿瘤摄取预测可以比 Lu-PSMA-617 实现更高的肿瘤剂量（高达 4 倍）。尽管也观察到了 PSMA 介导的肾脏摄取，但肿瘤的曲线下面积（AUC）特别高，这使得这些新型配体作为 RLT 的候选物值得进一步研究。
