Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using 90Y or 177Lu
Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using 90Y or 177Lu
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DOI：
10.1016/j.nucmedbio.2014.10.004
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发表时间：
2015-03-01
影响因子：
3.1
通讯作者：
Chong, Hyun-Soon
中科院分区：
文献类型：
--
作者：
Kang, Chi Soo;Chen, Yunwei;Chong, Hyun-Soon
简介：β-发射细胞毒性放射性核素Y-90和Lu-177的治疗潜力已在许多临床前和临床试验中得到证实。一种能与放射性同位素有效络合的双功能螯合物是分子靶向放射治疗Y-90和Lu-177的关键组分。合成了一种新的双功能螯合物5 p-C-NETA，其在螯合骨架和功能单元之间具有相对长的烷基间隔基，用于与肿瘤靶向部分缀合。将5 p-C-NETA缀合至模型靶向部分，一种环状Arg-Gly-Asp-D-Tyr-Lys（RGDyK）肽结合在各种癌症上过表达的整合素α（v）β（3）蛋白。方法：将5 p-C-NETA与c（RGDyK）肽偶联，体外研究5 p-C-NETA与c（RGDyK）肽的放射性标记、血清稳定性、结合亲和力，并与3 p-C-NETA-c（RGDyK）进行比较。结果：新的螯合物与用于癌症治疗的细胞毒性放射性同位素Y-90或Lu-177快速且紧密地结合，在温和条件下（> 99%，RT，
Introduction: Therapeutic potential of beta-emitting cytotoxic radionuclides Y-90 and Lu-177 has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy Y-90 and Lu-177. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin alpha(v)beta(3) protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of Y-90 and Lu-177.Methods: 5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-C-NETA-c (RGDyK). Lu-177-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice.Result: The new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, Y-90 or Lu-177 with excellent radiolabeling efficiency and maximum specific activity under mild condition (>99%, RT,