On Target Laboratories, West Lafayette, Indiana.
Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, Indiana.
Clin Cancer Res. 2019 Jan 1;25(1):177-187. doi: 10.1158/1078-0432.CCR-18-0803. Epub 2018 Sep 10.
The ability to locate and remove all malignant lesions during radical prostatectomy leads not only to prevent biochemical recurrence (BCR) and possible side effects but also to improve the life expectancy of patients with prostate cancer. Fluorescence-guided surgery (FGS) has emerged as a technique that uses fluorescence to highlight cancerous cells and guide surgeons to resect tumors in real time. Thus, development of tumor-specific near-infrared (NIR) agents that target biomarkers solely expressed on prostate cancer cells will enable to assess negative tumor margins and affected lymph nodes.
Because PSMA is overexpressed in prostate cancer cells in >90% of the prostate cancer patient population, a prostate-specific membrane antigen (PSMA)-targeted NIR agent (OTL78) was designed and synthesized. Optical properties, and specificity, tumor-to-background ratio (TBR), accomplishment of negative surgical tumor margins using FGS, pharmacokinetics (PKs) properties, and preclinical toxicology of OTL78 were then evaluated in requisite models.
OTL78 binds to PSMA-expressing cells with high affinity, concentrates selectively to PSMA-positive cancer tissues, and clears rapidly from healthy tissues with a half-time of 17 minutes. It also exhibits an excellent TBR (5:1) as well as safety profile in animals.
OTL78 is an excellent tumor-specific NIR agent for use in fluorescence-guided radical prostatectomy and FGS of other cancers.
在根治性前列腺切除术期间能够定位和切除所有恶性病变，不仅可以预防生化复发（BCR）和可能的副作用，还可以提高前列腺癌患者的预期寿命。荧光引导手术（FGS）已成为一种使用荧光突出显示癌细胞并指导外科医生实时切除肿瘤的技术。因此，开发仅针对前列腺癌细胞表达的肿瘤特异性近红外（NIR）试剂将能够评估肿瘤阴性切缘和受影响的淋巴结。
由于 PSMA 在 >90%的前列腺癌患者人群中的前列腺癌细胞中过度表达，因此设计并合成了一种前列腺特异性膜抗原（PSMA）靶向 NIR 试剂（OTL78）。然后在必要的模型中评估了 OTL78 的光学特性、特异性、肿瘤与背景比（TBR）、使用 FGS 实现阴性手术肿瘤切缘、药代动力学（PKs）特性和临床前毒理学。
OTL78 与表达 PSMA 的细胞具有高亲和力结合，选择性地集中在 PSMA 阳性的癌症组织中，并在 17 分钟内从健康组织中快速清除，半衰期为 17 分钟。它还表现出优异的 TBR（5:1）和动物安全性。
OTL78 是一种出色的肿瘤特异性 NIR 试剂，可用于荧光引导根治性前列腺切除术和其他癌症的 FGS。
