Division of Radiopharmaceutical Science, Department of Radiology, Weill Cornell Medicine, New York, New York.
Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, New York.
J Nucl Med. 2019 May;60(5):649-655. doi: 10.2967/jnumed.118.219592. Epub 2018 Nov 9.
Promising biochemical responses to Ac-prostate-specific membrane antigen (PSMA) 617, even in patients who are refractory to β-particle radiation, illustrate the potential of targeted α-therapy for the treatment of metastatic castration-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. To fully harness the potential of targeted α-therapy, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37, 74, and 148 kBq of Ac-RPS-074 and compared with positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1,500 mmAc-RPS-074 was labeled in greater than 98% radiochemical yield and showed high (>10% injected dose/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h after injection and cleared by 7 d. The tumor-to-kidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6 of 7 tumors, with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7 of 7 tumors, but from 42 d, 6 of 7 experienced significant regrowth. The 37-kBq group experienced a survival benefit relative to the negative control but not compared with the positive control group. A single dose of 148 kBq of Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal-tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted α-therapeutic.
针对前列腺特异性膜抗原（PSMA）617 的有前途的生化反应，即使在对β粒子辐射有抗性的患者中也是如此，这表明针对转移性去势抵抗性前列腺癌的靶向α治疗具有潜力。然而，口干等副作用是严重且不可逆转的。为了充分发挥靶向α治疗的潜力，有必要提高靶向放射性配体的治疗指数。一种新兴策略是通过增强与血清白蛋白的结合来延长清除半衰期。我们已经在 LNCaP 异种移植模型中评估了结合白蛋白的 PSMA 靶向配体 RPS-074，以确定其在前列腺癌治疗中的潜在价值。在携带 LNCaP 异种移植肿瘤的雄性 BALB/c 小鼠中评估了 Ac-RPS-074。进行了 21 天的生物分布研究，以确定肿瘤和正常组织中的剂量学。使用 37、74 和 148 kBq 的 Ac-RPS-074 在 7 只小鼠的组中测量剂量反应，并与阳性和阴性对照组进行比较。当肿瘤体积超过 1500mm3 时，将小鼠处死。RPS-074 的放射性标记率大于 98%，从 24 小时到超过 14 天，在 LNCaP 肿瘤中表现出高（>10%注入剂量/g）和持续的积累。在注射后 24 小时内可以明显观察到血液和高度血管化组织中的信号，并在 7 天内清除。24 小时时肿瘤与肾脏的比值为 4.3±0.7，14 天时为 62.2±9.5。单次注射 148 kBq 可使 7 个肿瘤中的 6 个完全反应，无明显毒性作用。7 个肿瘤中的 7 个接受了 74 kBq 的治疗，但是从第 42 天开始，有 6 个肿瘤出现了明显的复发。与阴性对照组相比，37 kBq 组具有生存优势，但与阳性对照组相比则没有。单次给予 148 kBq 的 Ac-RPS-074 可使 86%的肿瘤完全反应，肿瘤与正常组织的比值预示着治疗指数的提高。使用大环螯合剂可实现定量放射性标记，并可能促进这种有前途的靶向α治疗的临床转化。
