Roy Jyoti, Kaake Miranda, Low Philip S
Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Oncotarget. 2019 Jan 4;10(2):152-160. doi: 10.18632/oncotarget.26520.
Overexpression of Luteinizing Hormone Releasing Hormone Receptor (LHRH-R) in various cancers and restricted expression of the receptor in healthy cells qualifies it as a valuable cancer biomarker. Previously, LHRH-R targeted peptides have been utilized to deliver attached payloads to LHRH-R expressing cancers. We report here for the first time the utilization of a small molecule non-peptidic ligand (BOEPL) of LHRH-R to deliver attached payloads to LHRH-R positive tumors. For this purpose, we linked the BOEPL ligand to a near infrared dye via various linkers. , these conjugates demonstrated low nanomolar binding affinity and they exhibited receptor-mediated uptake specifically in tumor tissue. Moreover, tumor uptake could be blocked by administration of excess unlabeled conjugate, and time course experiments showed retention of the dye conjugate in the tumor up to 12 h post injection. Because uptake of BOEPL-targeted NIR dye conjugates by nonmalignant organs/tissues was negligible and since the transient presence of targeted NIR dye in the kidneys was a result of clearance mechanism, we suggest that a BOEPL-targeted NIR dye might constitute a useful agent for fluorescence-guided surgery of LHRH-R positive cancers. Moreover, our results also provide proof of concept that BOEPL can be successfully used to deliver attached payloads to LHRH-R positive tumors .
促黄体生成素释放激素受体（LHRH-R）在多种癌症中过表达，而在健康细胞中表达受限，这使其成为一种有价值的癌症生物标志物。此前，LHRH-R靶向肽已被用于将附着的有效载荷递送至表达LHRH-R的癌症。我们在此首次报告利用LHRH-R的小分子非肽配体（BOEPL）将附着的有效载荷递送至LHRH-R阳性肿瘤。为此，我们通过各种连接子将BOEPL配体与近红外染料相连。这些缀合物表现出低纳摩尔结合亲和力，且它们在肿瘤组织中特异性地表现出受体介导的摄取。此外，给予过量未标记的缀合物可阻断肿瘤摄取，时间进程实验表明，注射后长达12小时，染料缀合物仍保留在肿瘤中。由于非恶性器官/组织对BOEPL靶向的近红外染料缀合物的摄取可忽略不计，且由于靶向近红外染料在肾脏中的短暂存在是清除机制的结果，我们认为BOEPL靶向的近红外染料可能构成一种用于LHRH-R阳性癌症荧光引导手术的有用试剂。此外，我们的结果还提供了概念验证，即BOEPL可成功用于将附着的有效载荷递送至LHRH-R阳性肿瘤。
