Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Laboratory of Nanoradiopharmaceuticals and Synthesis of Novel Radiopharmaceuticals, Rio de Janeiro 21941906, Brazil.
School of Pharmacy, DEFARMED, Rio de Janeiro Federal University, Rio de Janeiro 21941900, Brazil.
Int J Pharm. 2024 Mar 5;652:123765. doi: 10.1016/j.ijpharm.2023.123765. Epub 2024 Jan 7.
Despite the successful use of the radiopharmaceutical radium-223 dichloride ([Ra]RaCl) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [Ra]RaCl and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [Ra]RaCl in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [Ra]RaCl. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1-0.02) from 24 to 96 h after administration. In addition, the micellar [Ra]RaCl exhibited a significantly higher uptake in left (%ID/g = 0.85-0.23) and right (%ID/g = 0.76-0.24) kidneys than in small (%ID/g = 0.43-0.06) and large intestines (%ID/g = 0.24-0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [Ra]RaCl. The micellar [Ra]RaCl also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [Ra]RaCl indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [Ra]RaCl, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose-response outcomes and organ/tissue dosimetry for clinical translation.
尽管放射性药物镭-223 二氯化物（[Ra]RaCl）在有骨转移的去势抵抗性前列腺癌患者的靶向α治疗中取得了成功，但已记录到一些短期副作用，如腹泻和呕吐，导致患者不适。因此，我们制备了[Ra]RaCl 的纳米胶束溶液，并评估了其在健康小鼠中的生物分布、药代动力学和在腹腔给药后 96 小时内引起的生化变化，作为克服先前局限性的替代方法。此外，我们还评估了胶束[Ra]RaCl 在骨肉瘤模型中患者来源异种移植中的骨特异性。生物分布研究表明，胶束[Ra]RaCl 具有很高的骨靶向特性。有趣的是，从给药后 24 至 96 小时，肝脏摄取率（%ID/g=0.1-0.02）仍显著较低。此外，与小（%ID/g=0.43-0.06）和大（%ID/g=0.24-0.09）肠相比，胶束[Ra]RaCl 在左（%ID/g=0.85-0.23）和右（%ID/g=0.76-0.24）肾脏中的摄取率随时间显著增加，这表明其排泄途径主要是通过肾脏进入尿液，与非胶束[Ra]RaCl 不同。胶束[Ra]RaCl 的分布容积也较低（0.055±0.003 L），消除半衰期较长（28±12 天）。该纳米系统未能改变接受治疗的小鼠中丙氨酸氨基转移酶、天冬氨酸氨基转移酶、γ-GT、葡萄糖和液化脂肪酶的酶活性。最后，用胶束[Ra]RaCl 治疗的骨肉瘤肿瘤动物的显微镜检查表明肿瘤消退，有大面积坏死。相比之下，在对照组中，我们观察到肿瘤细胞密度和细胞异形性、有丝分裂和肿瘤细胞外骨基质的形成，这是骨肉瘤的典型特征。因此，我们的研究结果表明，纳米胶束制剂的效率和安全性可最大程度地减少临床放射性药物[Ra]RaCl 的胃肠道排泄途径，此外还可促进骨肉瘤的消退。必须进行进一步的研究来评估剂量反应结果和器官/组织剂量学，以实现临床转化。
