Prostate-Specific Membrane Antigen Targeted Imaging and Therapy of Prostate Cancer Using a PSMA Inhibitor as a Homing Ligand
Prostate-Specific Membrane Antigen Targeted Imaging and Therapy of Prostate Cancer Using a PSMA Inhibitor as a Homing Ligand
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DOI：
10.1021/mp900069d
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发表时间：
2009-05-01
影响因子：
4.9
通讯作者：
Low, Philip S.
中科院分区：
文献类型：
--
作者：
Kularatne, Sumith A.;Wang, Kevin;Low, Philip S.
前列腺癌（PCa）是当今西方社会死亡率和发病率的主要原因。目前用于检测前列腺癌的方法是有限的，留下大多数早期恶性肿瘤未诊断和晚期疾病的转移部位未被检测到。在PCa，特别是转移性疾病的治疗中也存在重大缺陷。为了改善PCa的检测和治疗，我们开发了一种PSMA靶向配体，其选择性地将附着的成像和治疗剂递送至PCa细胞而不靶向正常细胞。发现PSMA靶向放射性成像剂（DUPA-Tc-99 m）以纳摩尔亲和力（K-D = 14 nM）结合PSMA阳性人PCa细胞（LNCaP细胞系）。成像和生物分布研究表明，DUPA-Tc-99 m主要定位于nu/nu小鼠中的LNCaP细胞肿瘤异种移植物（注射后4小时，%注射剂量/克= 11.3;肿瘤-肌肉比= 75：1）。两种PSMA靶向的光学成像剂（DUPA-FITC和DUPA-罗丹明B）也显示出有效地标记PCa细胞并内化和运输至细胞内内体。PSMA靶向化疗剂（DUPA-TubH）被证明可以杀死培养物中的PSMA阳性LNCaP细胞（IC 50 = 3 nM），并消除nu/nu小鼠中已建立的肿瘤异种移植物，而没有可检测到的体重减轻。在施用过量PSMA抑制剂（PMPA）后肿瘤靶向的阻断和对PSMA阴性肿瘤的靶向的缺乏证实了上述每种靶向试剂对PSMA的特异性。靶向相同受体的成像剂和治疗剂的串联使用可以允许PCa的检测、分期、监测和治疗，其具有提高的准确性和有效性。
Prostate cancer (PCa) is a major cause of mortality and morbidity in Western society today. Current methods for detecting PCa are limited, leaving most early malignancies undiagnosed and sites of metastasis in advanced disease undetected. Major deficiencies also exist in the treatment of PCa, especially metastatic disease. In an effort to improve both detection and therapy of PCa, we have developed a PSMA-targeted ligand that delivers attached imaging and therapeutic agents selectively to PCa cells without targeting normal cells. The PSMA-targeted radioimaging agent (DUPA-Tc-99m) was found to bind PSMA-positive human PCa cells (LNCaP cell line) with nanomolar affinity (K-D = 14 nM). Imaging and biodistribution studies revealed that DUPA-Tc-99m localizes primarily to LNCaP cell tumor xenografts in nu/nu mice (% injected dose/gram = 11.3 at 4 h postinjection; tumor-to-muscle ratio = 75:1). Two PSMA-targeted optical imaging agents (DUPA-FITC and DUPA-rhodamine B) were also shown to efficiently label PCa cells and to internalize and traffic to intracellular endosomes. A PSMA-targeted chemotherapeutic agent (DUPA-TubH) was demonstrated to kill PSMA-positive LNCaP cells in culture (IC50 = 3 nM) and to eliminate established tumor xenografts in nu/nu mice with no detectable weight loss. Blockade of tumor targeting upon administration of excess PSMA inhibitor (PMPA) and the absence of targeting to PSMA-negative tumors confirmed the specificity of each of the above targeted reagents for PSMA. Tandem use of the imaging and therapeutic agents targeted to the same receptor could allow detection, staging, monitoring, and treatment of PCa with improved accuracy and efficacy.