Abouzayed Ayman, Seitova Kamila, Lundmark Fanny, Bodenko Vitalina, Oroujeni Maryam, Tolmachev Vladimir, Rosenström Ulrika, Orlova Anna
Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
Scientific and Research Laboratory of Chemical and Pharmaceutical Research, Siberian State Medical University, Tomsk, Russia.
Front Oncol. 2023 Sep 27;13:1221103. doi: 10.3389/fonc.2023.1221103. eCollection 2023.
Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.
BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution , target specificity and dosimetry. [Lu]Lu-PSMA-617 was simultaneously evaluated for comparison.
BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific and when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K = 3.8 nM and K = 25 nM. The half-maximal inhibitory concentration for Lu-BQ7876 was 59 nM that is equal to 61 nM for Lu-PSMA-617. Cellular processing of [Lu]Lu-BQ7876 was accompanied by slow internalization. [Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.
Biodistribution studies in mice demonstrated that targeting properties of [Lu]Lu-BQ7876 are not inferior to properties of [Lu]Lu-PSMA-617, but do not offer any decisive advantages.
前列腺特异性膜抗原（PSMA）在转移性去势抵抗性前列腺癌（mCRPC）中高度表达，是一个既定的治疗靶点。治疗诊断用的PSMA靶向剂广泛应用于患者管理，并已显示出可改善mCRPC患者的治疗效果。此前，我们利用计算机建模优化了一种基于尿素的探针，用于PSMA表达的放射性核素可视化。为了开发一种同样适用于放射性核素成像和治疗的靶向剂，设计了一种含有DOTA螯合剂的试剂（BQ7876）。本研究的目的是检验以下假设：镥标记的BQ7876具有靶标结合和生物分布特性，有可能用于放射治疗。
合成BQ7876并用镥-177进行标记。评估了[镥-177]镥-BQ7876对表达PSMA的PC3-pip细胞的特异性和亲和力，并研究了其与细胞结合后的处理情况。在小鼠身上进行动物研究，以评估其生物分布、靶标特异性和剂量测定。同时评估[镥-177]镥-PSMA-617以作比较。
BQ7876用镥-177标记，放射化学产率>99%。其与PSMA的结合具有特异性，在抗原饱和条件下以及在PSMA阴性的PC-3肿瘤中进行测试时均如此。[镥-177]镥-BQ7876与活细胞的结合特点是快速结合，而解离包括一个快速阶段和一个缓慢阶段，亲和力K = 3.8 nM和K = 25 nM。镥-BQ7876的半数抑制浓度为59 nM，与镥-PSMA-617的61 nM相当。[镥-177]镥-BQ7876的细胞处理过程伴随着缓慢的内化。[镥-177]镥-BQ7876从血液和正常组织中迅速清除。肾脏最初的摄取量升高后迅速下降，注射后3小时，肾脏摄取量（13±3%ID/g）与肿瘤摄取量（9±3%ID/g）无显著差异。肿瘤摄取量在1至3小时之间保持稳定，随后缓慢下降。吸收剂量最高的是肾脏，其次是腹部的器官和组织。
在小鼠身上进行的生物分布研究表明，[镥-177]镥-BQ7876的靶向特性不低于[镥-177]镥-PSMA-617，但也没有任何决定性优势。
