背景:靶向α治疗是核医学中最有效的治疗方式之一。它的治疗效力是基于发射一个或几个α粒子提供强大的和高度局部化的治疗效果的核素。然而,其中一些放射性核素,比如级联中的223Ra或225Ac衰变,其中来自连续α衰变的放射性后代可能离开原始载体并导致非目标器官的不必要辐射。这个后代,即使通过内化过程部分保留在靶组织中,通常不遵循最初靶向的放射性药物的命运,并可能在其自身的生物分布后扩散到体内。在这项研究中,我们旨在估计223Ra表面标记的TiO2纳米粒子在体外的211Pb/211Bi后代的命运,以及在小鼠模型中体内211Pb的命运。
结果:体外稳定性研究表明,母体223Ra及其后代的释放之间存在显着差异(211Pb,211Bi)在所有已测试的生物基质中。最低的释放活性是在盐水中测量的,导致所有核素的释放活性不到5%。与此相反,在5%的白蛋白溶液中观察到在48小时内高达10%的223Ra的最高释放活性。其后代的释放活性;在该测试培养基中,211Pb和211Bi在20-40%的范围内。在每种生物培养基中观察到,与223Ra相比,211Pb和211Bi的释放活性显着提高了至少10%,除了生理盐水,其中没有观察到显著差异。体内生物分布研究导致小鼠模型,显示类似的模式,研究发现,即使纳米粒子在靶组织中积累,大约10%的211Pb在24小时内连续释放到血流中,其次是它在肾脏的自然积累。
结论:这项研究证实了我们的假设,即在某种核素的α链衰变中形成的后代,在这种情况下,223Ra,可以从其原始向量中释放,离开目标组织,重新定位,可以存放在非靶器官中。在我们的模型中,我们没有观察到从其原始目标组织中完全的后代洗出。这表明子代热原子从原始放射性药物制剂中释放后的命运强烈依赖于多种因素,比如它们在细胞中的内在化和保留,细胞膜,细胞外基质,蛋白质结合,等。我们假设,原发肿瘤或转移瘤的大小,它们的代谢活动可能会显著影响体内后代的命运,直接影响递送到非靶组织和器官的剂量。因此,应当遵循自下而上的方法,并且应当优选地进行关于源自链α发射体的放射性后代的释放和生物分布的详细的前/临床研究。
Targeted alpha therapy is one of the most powerful therapeutical modalities available in nuclear medicine. It\'s therapeutic potency is based on the nuclides that emit one or several alpha particles providing strong and highly localized therapeutic effects. However, some of these radionuclides, like e.g.223Ra or 225Ac decay in cascades, where the radioactive progeny originating from the consecutive alpha-decays may leave the original vector and cause unwanted irradiation of non-target organs. This progeny, even if partially retained in target tissues by internalization processes, typically do not follow the fate of originally targeted radiopharmaceutical and potentially spread over body following their own biodistribution. In this
study we aimed to estimate 211Pb/211Bi progeny fate from the 223Ra surface-labelled TiO2 nanoparticles in vitro and the fate of 211Pb in vivo in a mice model.
In vitro stability studies have shown significant differences between the release of the mother 223Ra and its progeny (211Pb, 211Bi) in all the biological matrices that have been tested. The lowest released activities were measured in saline, resulting in less than 5 % of released activity for all nuclides. Contrary to that, the highest released activity of 223Ra of up to 10 % within 48 h was observed in 5 % solution of albumin. The released activity of its progeny; the 211Pb and 211Bi was in the range of 20-40 % in this test medium. Significantly higher released activities of 211Pb and 211Bi compared to 223Ra by at least 10 % was observed in each biological medium, except saline, where no significant differences were observed. The in vivo biodistribution studies results in a mice model, show similar pattern, where it was found that even after accumulation of nanoparticles in target tissues, approximately 10 % of 211Pb is continuously released into the blood stream within 24 h, followed by its natural accumulation in kidneys.
This
study confirms our assumption that the progeny formed in a chain alpha decay of a certain nuclide, in this case the 223Ra, can be released from its original vector, leave the target tissue, relocate and could be deposited in non-target organs. We did not observe complete progeny wash-out from its original target tissues in our model. This indicates strong dependence of the progeny hot atom fate after its release from the original radiopharmaceutical preparation on multiple factors, like their internalization and retention in cells, cell membranes, extracellular matrices, protein binding, etc. We hypothesize, that also the primary tumour or metastasis size, their metabolic activity may significantly influence progeny fate in vivo, directly impacting the dose delivered to non-target tissues and organs. Therefore a bottom-up approach should be followed and detailed pre-/clinical studies on the release and biodistribution of radioactive progeny originating from the chain alpha emitters should be preferably performed.