The objective of this study was to determine the safety, kinetics, and dosimetry of the ¹⁷⁷Lu-labeled prostate-specific membrane antigen (PSMA) small molecules ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). Methods: In total, 138 patients (mean age, 70 ± 9 y; age range, 46–90 y) with progressive mCRPC and PSMA expression verified by ⁶⁸Ga-PSMA-11 PET/CT underwent PRLT. Fifty-one patients received 6.1 ± 1.0 GBq (range, 3.4–7.6 GBq) of ¹⁷⁷Lu-PSMA I&T, and 87 patients received 6.5 ± 1.1 GBq (range, 3.5–9.0 GBq) of ¹⁷⁷Lu-PSMA-617. Dosimetry was performed on all patients using an identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 5.0, of the National Cancer Institute. Results: The whole-body half-lives were shorter for ¹⁷⁷Lu-PSMA I&T (35 h) than for ¹⁷⁷Lu-PSMA-617 (42 h). The mean whole-body dose of ¹⁷⁷Lu-PSMA-617 was higher than that of ¹⁷⁷Lu-PSMA I&T (0.04 vs. 0.03 Gy/GBq, P < 0.00001). Despite the longer half-life of ¹⁷⁷Lu-PSMA-617, the renal dose was lower for ¹⁷⁷Lu-PSMA-617 than for ¹⁷⁷Lu-PSMA I&T (0.77 vs. 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to the parotid glands (0.5 Gy/GBq, P = 0.27). Among all normal organs, the lacrimal glands exhibited the highest mean absorbed doses, 5.1 and 3.7 Gy/GBq, for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T, respectively. All tumor metastases exhibited a higher initial uptake when using ¹⁷⁷Lu-PSMA I&T than when using ¹⁷⁷Lu-PSMA-617, as well as a shorter tumor half-life (P < 0.00001). The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 (5.8 vs. 5.9 Gy/GBq, P = 0.96). All patients tolerated the therapy without any acute adverse effects. After ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T, there was a small, statistically significant reduction in hemoglobin, leukocyte counts, and platelet counts that did not need any clinical intervention. No nephrotoxicity was observed after either ¹⁷⁷Lu-PSMA I&T or ¹⁷⁷Lu-PSMA-617 PRLT. Conclusion: Both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands—not, however, resulting in any significant clinical sequel. ¹⁷⁷Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did ¹⁷⁷Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.

本研究的目的是确定¹⁷⁷ Lu 标记的前列腺特异性膜抗原 (PSMA) 小分子¹⁷⁷ Lu-PSMA I&T 和¹⁷⁷ Lu-PSMA-617 在一大群患有前列腺癌的患者中的安全性、动力学和剂量学。接受 PSMA 放射性配体治疗 (PRLT) 的转移性去势抵抗性前列腺癌 (mCRPC)。方法：共有 138 名患者（平均年龄，70 ± 9 岁；年龄范围，46-90 岁）经⁶⁸ Ga-PSMA-11 PET/CT 证实具有进行性 mCRPC 和 PSMA 表达，接受了 PRLT。51 名患者接受 6.1 ± 1.0 GBq（范围，3.4-7.6 GBq）的¹⁷⁷ Lu-PSMA I&T，87 名患者接受 6.5 ± 1.1 GBq（范围，3.5-9.0 GBq）的¹⁷⁷卢-PSMA-617。使用相同的方案对所有患者进行剂量测定。平均吸收剂量用 OLINDA 软件 (MIRD Scheme) 估算。治疗相关的不良事件根据美国国家癌症研究所的不良事件通用术语标准 5.0 版进行分级。结果：¹⁷⁷ Lu-PSMA I&T（35 小时）的全身半衰期短于¹⁷⁷ Lu-PSMA-617（42 小时）。¹⁷⁷ Lu-PSMA-617的平均全身剂量高于¹⁷⁷ Lu-PSMA I&T (0.04 vs. 0.03 Gy/GBq, P < 0.00001)。^尽管177 Lu-PSMA-617的半衰期较长，但¹⁷⁷的肾脏剂量较低Lu-PSMA-617 比¹⁷⁷ Lu-PSMA I&T（0.77 对 0.92 Gy/GBq，P = 0.0015）。两种 PSMA 小分子均表现出与腮腺相当的剂量 (0.5 Gy/GBq, P = 0.27)。^{在所有正常器官中，对于177} Lu-PSMA-617 和¹⁷⁷ Lu-PSMA I&T，泪腺的平均吸收剂量最高，分别为 5.1 和 3.7 Gy/GBq 。^{与使用177 Lu-PSMA-617 相比，使用177} Lu-PSMA I&T 时所有肿瘤转移灶的初始摄取量均较高，且肿瘤半衰期较短（P < 0.00001）。¹⁷⁷ Lu-PSMA I&T 和¹⁷⁷的平均吸收肿瘤剂量相当Lu-PSMA-617（5.8 对 5.9 Gy/GBq，P = 0.96）。所有患者均耐受治疗，没有任何急性副作用。在¹⁷⁷ Lu-PSMA-617 和¹⁷⁷ Lu-PSMA I&T 之后，不需要任何临床干预的血红蛋白、白细胞计数和血小板计数都有小幅且具有统计学意义的降低。¹⁷⁷ Lu-PSMA I&T 或¹⁷⁷ Lu-PSMA-617 PRLT后未观察到肾毒性。结论： 177 Lu-PSMA I&T^和177Lu-PSMA-617 PRLT 在 mCRPC 患者中表现出良好的安全性。健康器官中吸收剂量最高的是泪腺和腮腺——然而，这并没有导致任何显着的临床后果。^与177 Lu-PSMA I&T相比， ¹⁷⁷ Lu-PSMA-617 对全身和泪腺的吸收剂量更高，但肾脏剂量更低。¹⁷⁷ Lu-PSMA I&T 和¹⁷⁷ Lu-PSMA-617的平均吸收肿瘤剂量相当。剂量学参数存在很大的患者间变异性。因此，基于个体患者的剂量测定似乎有利于个性化 PRLT。