PDF(Pubmed)
Abstract：
Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising option for metastatic castration-resistant prostate cancer. Clinical experience using 177Lu or 225Ac has demonstrated encouraging treatment responses; however, responses are not durable. Dual-isotope combinations, or \"tandem\" approaches, may improve tolerability while retaining a high tumor dose. In this study, we directly compared α- versus β-particle treatment, as well as a combination thereof, at different stages of disease in a murine model of disseminated prostate cancer. Methods: First, to determine comparable injected activities from 177Lu- and 225Ac-PSMA-617, ex vivo biodistribution studies were performed at 5 time points after treatment of C4-2 subcutaneous tumor-bearing NSG mice. To establish a more representative model of metastatic prostate cancer, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle, leading to disseminated visceral and bone lesions. At either 3 or 5 wk after inoculation, the mice were treated with equivalent tumor dose-depositing activities of 177Lu- or 225Ac-PSMA-617 alone or in combination (35 MBq of 177Lu, 40 kBq of 225Ac, or 17 MBq of 177Lu + 20 kBq 225Ac; 10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole-body tumor burden and overall survival. Results: The ex vivo biodistribution studies revealed that 35 MBq of 177Lu and 40 kBq of 225Ac yield equivalent absorbed tumor doses in a subcutaneous C4-2 model. The disease burden of mice treated at 3 wk after inoculation (microscopic disease) with 177Lu was not significantly different from that of untreated mice. However, 225Ac-PSMA-617 both as a single agent and in combination with 177Lu (17 MBq of 177Lu + 20 kBq of 225Ac) were associated with significant whole-body tumor growth retardation and survival benefit (overall survival, 8.3 wk for nontreatment, 9.4 wk for 177Lu, 15.3 wk for 225Ac alone, and 14.1 wk for tandem therapy). When treated at 5 wk after inoculation (macroscopic disease), all treatment groups showed retarded tumor growth and improved survival, with no significant differences between 225Ac alone and administration of half the 225Ac activity in tandem with 177Lu (overall survival, 7.9 wk for nontreatment, 10.3 wk for 177Lu, 14.6 wk for 225Ac alone, and 13.2 wk for tandem therapy). Conclusion: Treatment of a disseminated model of prostate cancer with simultaneous 225Ac- and 177Lu-PSMA-617 results in significantly decreased tumor growth compared with 177Lu, which was ineffective as a single agent against microscopic lesions. Mice treated later in the disease progression and bearing macroscopic, millimeter-sized lesions experienced significant tumor growth retardation and survival benefit in both monoisotopic and tandem regimens of 177Lu and 225Ac. Although the greatest benefits were observed with the single agent 225Ac, the tandem arm experienced no significant difference in disease burden or survival benefit, suggesting that the reduced activity of 225Ac was adequately compensated in the tandem arm. The superior therapeutic efficacy of 225Ac in this model suggests a preference for α-emitters alone, or possibly in combination, in the microscopic disease setting.
摘要：
针对前列腺特异性膜抗原（PSMA）的放射性核素治疗是转移性去势抵抗性前列腺癌的有希望的选择。使用177Lu或225Ac的临床经验显示出令人鼓舞的治疗反应；然而，回答是不持久的。双同位素组合,或“串联”方法，可以提高耐受性，同时保留高肿瘤剂量。在这项研究中,我们直接比较了α-和β-颗粒处理，以及它们的组合，在播散性前列腺癌小鼠模型的不同疾病阶段。方法：首先，为了确定来自177Lu-和225Ac-PSMA-617的可比较的注射活性,在处理C4-2皮下荷瘤NSG小鼠后的5个时间点进行离体生物分布研究。树立更具代表性的转移性前列腺癌模子，NSG小鼠在左心室接种表达荧光素酶的C4-2细胞，导致弥漫性内脏和骨骼病变。接种后3或5周，小鼠单独或联合使用等效的肿瘤剂量沉积活性177Lu-或225Ac-PSMA-617（177Lu的35MBq，40kBq的225Ac，或177Lu+20kBq225Ac的17MBq；10/组）。通过每周生物发光成像评估疾病负担。使用全身肿瘤负荷和总生存期评估治疗效果。结果：离体生物分布研究表明，在皮下C4-2模型中，177Lu的35MBq和225Ac的40kBq产生等效的吸收肿瘤剂量。接种177Lu（微观疾病）后3周处理的小鼠的疾病负担与未处理的小鼠没有显着差异。然而,225Ac-PSMA-617作为单一药物和与177Lu（177Lu的17MBq+225Ac的20kBq）联合使用与显着的全身肿瘤生长迟缓和生存益处（总体生存率，不治疗8.3周，177Lu为9.4周，仅225Ac就需要15.3周，和14.1wk串联治疗)。接种后5周治疗（宏观疾病），所有治疗组显示肿瘤生长迟缓，生存率提高，单独使用225Ac和一半的225Ac活性与177Lu(总生存期，非治疗7.9周，10.3周，177Lu，仅225Ac为14.6周，和13.2wk串联治疗)。结论：与177Lu相比，同时使用225Ac-和177Lu-PSMA-617治疗播散性前列腺癌模型可显著降低肿瘤生长，作为单一药物对微观病变无效。小鼠在疾病进展和携带宏观治疗的后期，在177Lu和225Ac的单同位素和串联方案中，毫米大小的病变经历了显着的肿瘤生长迟缓和生存益处。尽管使用单一药剂225Ac观察到最大的益处，串联臂在疾病负担或生存获益方面没有显着差异，表明串联臂中225Ac活性的降低得到了充分补偿。在该模型中，225Ac的优异治疗效果表明，单独使用α-发射体，或者可能是组合，在微观疾病环境中。
