Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3931-4. doi: 10.1016/j.bmcl.2012.04.110. Epub 2012 Apr 30.
Prostate-specific membrane antigen (PSMA), a type II membrane glycoprotein, its high expression is associated with prostate cancer progression, and has been becoming an active target for imaging or therapeutic applications for prostate cancer. On the other hand, streptavidin-biotin system has been successfully employed in pretargeting therapy towards multiple cancers. Herein, we describe the synthesis of bifunctional ligands (biotin-CTT54, biotin-PEG(4)-CTT54, and biotin-PEG(12)-CTT54) possessing two functional motifs separated by a length-varied polyethylene glycol (PEG) spacer: one (CTT54) binds tumor-marker PSMA and the other (biotin) binds streptavidin or avidin. All three compounds exhibited high potencies (IC(50) values: 1.21, 2.53, and 10nM, respectively) and irreversibility; but only biotin-PEG(12)-CTT54 demonstrated specifically labeling PSMA-positive prostate cancer cells in a two-step pretargeting procedure. Additionally, the pre-formulated complex between biotin-PEG(12)-CTT54 and Cy5-streptavidin displayed the improved inhibitory potency (IC(50)=1.86 nM) and irreversibility against PSMA and rapid uptake of streptavidin conjugate into PSMA-positive prostate cancer cells through PSMA-associated internalization. Together, all these results supported a proof-concept that combination of streptavidin and PSMA's biotinylated inhibitor may lead to development of a novel strategy of tumor-targeting imaging or drug delivery towards prostate cancer.
前列腺特异膜抗原（PSMA）是一种 II 型膜糖蛋白，其高表达与前列腺癌的进展有关，已成为前列腺癌成像或治疗应用的活跃靶点。另一方面，链霉亲和素-生物素系统已成功应用于多种癌症的靶向治疗。本文描述了双功能配体（生物素-CTT54、生物素-PEG（4）-CTT54 和生物素-PEG（12）-CTT54）的合成，这些配体具有两个通过长度变化的聚乙二醇（PEG）间隔物分开的功能基序：一个（CTT54）与肿瘤标志物 PSMA 结合，另一个（生物素）与链霉亲和素或亲和素结合。这三种化合物均表现出高活性（IC（50）值分别为 1.21、2.53 和 10nM）和不可逆性；但只有生物素-PEG（12）-CTT54在两步靶向预处理程序中特异性标记 PSMA 阳性前列腺癌细胞。此外，生物素-PEG（12）-CTT54 与 Cy5-链霉亲和素的预形成复合物表现出改善的抑制活性（IC（50）=1.86nM）和不可逆性，以及对 PSMA 的快速摄取，通过 PSMA 相关内化将链霉亲和素缀合物进入 PSMA 阳性前列腺癌细胞。总之，所有这些结果都支持了一个概念验证，即链霉亲和素和 PSMA 的生物素化抑制剂的结合可能导致开发针对前列腺癌的新型肿瘤靶向成像或药物输送策略。
