Kiess Ana P, Minn Il, Vaidyanathan Ganesan, Hobbs Robert F, Josefsson Anders, Shen Colette, Brummet Mary, Chen Ying, Choi Jaeyeon, Koumarianou Eftychia, Baidoo Kwamena, Brechbiel Martin W, Mease Ronnie C, Sgouros George, Zalutsky Michael R, Pomper Martin G
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
J Nucl Med. 2016 Oct;57(10):1569-1575. doi: 10.2967/jnumed.116.174300. Epub 2016 May 26.
Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC).
PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-At-astatobenzamido)pentyl)ureido)-pentanedioic acid (At- 6: ) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after At- 6: treatment. The antitumor efficacy of At- 6: was evaluated in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo.
At- 6: treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells and caused significant tumor growth delay in PSMA+ PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of At- 6: in PSMA+ PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy.
PSMA-targeted At- 6: α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. At- 6: also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry.
α粒子发射体具有高线性能量传递和短射程，为治疗微转移灶同时保护正常组织提供了潜力。我们开发了一种基于尿素的、用砹标记的小分子，靶向前列腺特异性膜抗原（PSMA），用于治疗前列腺癌（PC）引起的微转移灶。
合成了靶向PSMA的（2S）-2-（3-（1-羧基-5-（4-砹代苯甲酰胺基）戊基）脲基）-戊二酸（砹-6：）。在用砹-6：处理后，在PSMA阳性（PSMA+）的PC3 PIP和PSMA阴性（PSMA-）的PC3 flu人前列腺癌细胞中测试细胞摄取和克隆形成存活情况。在携带PSMA+ PC3 PIP和PSMA- PC3 flu侧腹异种移植瘤的小鼠中，以740 kBq的剂量评估砹-6：的抗肿瘤疗效，并在携带PSMA+、表达荧光素酶的PC3-ML微转移灶的小鼠中进行评估。在携带PSMA+ PC3 PIP和PSMA- PC3 flu侧腹异种移植瘤的小鼠中测定生物分布。使用α相机图像评估亚器官分布，并建立微观剂量学模型。在小鼠中评估12个月的长期毒性。
砹-6：处理导致PSMA特异性细胞摄取，并降低了PSMA+ PC3 PIP细胞中的克隆形成存活，且使PSMA+ PC3 PIP侧腹肿瘤的肿瘤生长显著延迟。在新开发的PSMA+微转移前列腺癌模型中，存活情况得到显著改善。生物分布显示砹-6：在PSMA+ PC3 PIP肿瘤和肾脏中摄取。基于α相机图像和肾单位模型的微观肾脏剂量学显示近端肾小管中有热点。长期毒性研究证实剂量限制性毒性是晚期放射性肾病。
靶向PSMA的砹-6：α粒子放疗在全身给药后，使携带前列腺癌微转移灶的小鼠存活情况得到显著改善。砹-6：还显示在肾近端小管中摄取，导致晚期肾毒性，突出了长期毒性研究和微观剂量学的重要性。
