1 Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin.
2 Cellectar Biosciences, Inc. , Madison, Wisconsin.
Cancer Biother Radiopharm. 2018 Apr;33(3):87-95. doi: 10.1089/cbr.2017.2376.
Auger electrons emitted by radioisotopes such as I have a high linear energy transfer and short mean-free path in tissue (<10 μm), making them suitable for treating micrometastases while sparing normal tissues. The authors developed and subsequently investigated a cancer cell-selective small molecule phospholipid ether analog to deliver I to triple-negative breast cancer (TNBC) cells in vivo.
A Current Good Manufacturing Practice (cGMP) method to radiolabel I-CLR1404 (CLR 125) with >95% radiochemical purity was established. To estimate CLR 125 in vivo dosimetry and identify dose-limiting organs, the biodistribution of the analog compound I-CLR1404 (CLR 124) was investigated using micro-positron emission tomography (PET)/computed tomography (CT) in conjunction with a Monte Carlo dosimetry platform to estimate CLR 125 dosimetry. In vivo antitumor efficacy was tested by injecting nude mice bearing either MDA-MB-231-luc orthotopic xenografts or lung metastases with 74 MBq (3.7 GBq/kg) of CLR 125 or an equivalent mass amount of nonradiolabeled CLR 125. Longitudinal tumor measurements using calipers and bioluminescence imaging were obtained for the xenografts and lung metastases, respectively.
Dosimetry analysis estimated that CLR 125 would impart the largest absorbed dose to the tumor per injected activity (0.261 ± 0.023 Gy/MBq) while the bone marrow, which is generally the dose-limiting organ for CLR1404, appears to have the lowest (0.063 ± 0.005 Gy/MBq). At administered activities of up to 74 MBq (3.7 GBq/kg), mice did not experience signs of toxicity. In addition, a single dose of CLR 125 reduced the volume of orthotopic primary TNBC xenografts by ∼60% compared to control vehicle (p < 0.001) and significantly extended survival. In addition, CLR 125 was efficacious against preclinical metastatic TNBC models by inhibiting the progression of micrometastases (p < 0.01).
Targeted radionuclide therapy with CLR 125 displayed significant antitumor efficacy in vivo, suggesting promise for treatment of TNBC micrometastases.
放射性同位素如 I 发射的俄歇电子在组织中的线性能量转移高，平均自由程短（<10 μm），使其适合治疗微转移灶，同时保护正常组织。作者开发了一种癌症细胞选择性小分子磷脂醚类似物，并随后研究了将其递送至体内三阴性乳腺癌（TNBC）细胞的方法。
建立了一种符合现行良好生产规范（cGMP）的方法，以放射性标记 I-CLR1404（CLR 125），放射化学纯度>95%。为了估计 CLR 125 的体内剂量学并确定限制剂量的器官，使用微正电子发射断层扫描（PET）/计算机断层扫描（CT）与蒙特卡罗剂量学平台相结合，研究了类似物化合物 I-CLR1404（CLR 124）的生物分布，以估计 CLR 125 的剂量学。通过向 MDA-MB-231-luc 原位异种移植或肺转移瘤的裸鼠注射 74 MBq（3.7 GBq/kg）的 CLR 125 或等量的非放射性标记 CLR 125，测试了体内抗肿瘤功效。分别通过卡尺和生物发光成像获得异种移植瘤和肺转移瘤的纵向肿瘤测量值。
剂量学分析估计，CLR 125 每注入单位活性（0.261 ± 0.023 Gy/MBq）将赋予肿瘤最大的吸收剂量，而骨髓通常是 CLR1404 的限制剂量器官，其吸收剂量似乎最低（0.063 ± 0.005 Gy/MBq）。在高达 74 MBq（3.7 GBq/kg）的给药活性下，小鼠没有出现毒性迹象。此外，与对照载体相比，CLR 125 的单次剂量使原位 TNBC 异种移植瘤的体积减少了约 60%（p < 0.001），并显著延长了生存时间。此外，CLR 125 通过抑制微转移灶的进展对临床前转移性 TNBC 模型有效（p < 0.01）。
CLR 125 的靶向放射性核素治疗在体内显示出显著的抗肿瘤功效，这表明其有希望治疗 TNBC 微转移灶。
