Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand.
Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand.
复制标题
朝着具有18元大环配体的生物医学应用的稳定螯合。
DOI：
10.1039/d0sc06867e
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发表时间：
2021-01-29
期刊：
影响因子：
8.4
通讯作者：
Thorek DLJ
中科院分区：
文献类型：
--
作者：
Abou DS;Thiele NA;Gutsche NT;Villmer A;Zhang H;Woods JJ;Baidoo KE;Escorcia FE;Wilson JJ;Thorek DLJ
靶向阿尔法治疗是治疗播散性癌症的一种新兴策略。[223Ra]RaCl2是临床批准的唯一一种α粒子发射药物，用于治疗去势抵抗的前列腺癌骨转移，[223Ra]Ra2+定位于该骨转移。为了将[223Ra]Ra~(2+)特异性地定向到非骨性疾病部位，需要对肿瘤靶向部分进行螯合和结合。虽然以前为此目的稳定地螯合[223Ra]Ra2+的努力只取得了有限的成功，但在这里我们报告了一种生物稳定的与18元大环络合剂MANPA的放射性络合物。[223Ra]Ra~(2+)定量标记在室温下5分钟内完成，放射性标记效率为~gt；95%，比传统的络合剂如DOTA和EDTA有了很大的进步，后者在这种条件下不能完全络合[223Ra]Ra~(2+)。[223Ra][Ra(Manpa)]在人血清中高度稳定，与骨靶向[223Ra]RaCl2相比，小鼠的骨骼和脾摄取显著减少，这意味着[223Ra][Ra(Manpa)]在体内保持完好。当MANPA与单一氨基酸β-丙氨酸以及前列腺膜抗原靶向多肽DUPA偶联后，两种构建物都保持了对溶液中95%的Ra~(2+)的高亲和力。此外，[223Ra][Ra(manpa-β-Alanine)]从小鼠体内迅速被清除，并显示出较低的223Ra骨吸收，表明该结合物在生物学条件下是稳定的。意想不到的是，这种稳定性在MANPA与DUPA结合后丢失，这表明靶向载体在该系统的体内复杂稳定性中发挥了作用。尽管如此，我们成功地用223Ra标记了β-丙氨酸结合物及其随后的体内稳定性，首次确立了使用功能化螯合剂将[223Ra]Ra~(2+)输送到骨外转移瘤的可能性，标志着这种放射性金属在临床上的治疗作用的显著扩展。治疗性阿尔法发射体223Ra可以在体内稳定地络合，为开发具有这种放射性核素的靶向放射性药物创造了机会。
Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [223Ra]RaCl2 is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [223Ra]Ra2+ localizes. To specifically direct [223Ra]Ra2+ to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate [223Ra]Ra2+ for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with [223Ra]Ra2+ was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex [223Ra]Ra2+ under these conditions. [223Ra][Ra(macropa)] was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted [223Ra]RaCl2, signifying that [223Ra][Ra(macropa)] remains intact in vivo. Upon conjugation of macropa to a single amino acid β-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for 223Ra, complexing >95% of Ra2+ in solution. Furthermore, [223Ra][Ra(macropa-β-alanine)] was rapidly cleared from mice and showed low 223Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stability in vivo for this system. Nonetheless, our successful demonstration of efficient radiolabeling of the β-alanine conjugate with 223Ra and its subsequent stability in vivo establishes for the first time the possibility of delivering [223Ra]Ra2+ to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic. The therapeutic alpha-emitter 223Ra can be stably complexed in vivo, creating opportunities for the development of targeted radiopharmaceutical agents with this radionuclide.
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影响因子：
4.6
作者：
Ferreiros-Martinez, Raquel;Esteban-Gomez, David;Rodriguez-Blas, Teresa
通讯作者：
Rodriguez-Blas, Teresa
影响因子：
4.9
作者：
GUNN, KB;MISTRY, KB
通讯作者：
MISTRY, KB
影响因子：
3.4
作者：
Jadvar, Hossein;Challa, Sudha;Conti, Peter S.
通讯作者：
Conti, Peter S.
影响因子：
9.3
作者：
Maguire, William F.;McDevitt, Michael R.;Scheinberg, David A.
通讯作者：
Scheinberg, David A.
影响因子：
2.3
作者：
Gott, Matthew;Steinbach, Joerg;Mamat, Constantin
通讯作者：
Mamat, Constantin