Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of 90Y and 177Lu
Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of 90Y and 177Lu
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DOI：
10.1016/j.bmc.2014.12.035
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发表时间：
2015-03-01
影响因子：
3.5
通讯作者：
Song, Hyun A.
中科院分区：
文献类型：
--
作者：
Chong, Hyun-Soon;Sun, Xiang;Song, Hyun A.
Zevalin（R）是一种用细胞毒性放射性同位素（Y-90）放射性标记的抗体-药物偶联物，已被批准用于B细胞非霍奇金淋巴瘤的放射免疫治疗（RIT）。显示有利的络合动力学和体内稳定性的双功能配体是有效的RIT所需的。通过氮丙啶离子与预烷基化的三氮杂或四氮杂大环的区域特异性开环反应，有效地合成了具有RIT潜力的新型双功能配体3 p-C-DE 4 TA和3 p-C-NE 3 TA.新的双功能配体3 p-C-DE 4 TA和3 p-C-NE 3 TA沿着已知的双峰配体3 p-C-NETA和3 p-C-DEPA被比较地评估用于使用β发射放射性核素Y-90和Lu-177的靶向放射治疗的潜在用途。用Y-90和Lu-177评价双功能配体的放射性标记动力学，并研究相应的Y-90或Lu-177-放射性标记的复合物在人血清中的体外稳定性和在小鼠中的体内生物分布。的比较络合动力学和稳定性研究的结果表明，大环腔，配体denticity，和双峰的供体基团的大小有很大的影响与放射性镧系元素的双功能配体的络合。在DE 4 TA和NE 3 TA系列中的新的有前途的双功能螯合物在结合Y-90和Lu-177方面是快速的，并且相应的Y-90-和Lu-177-放射性标记的复合物在人血清中或在小鼠中保持惰性。体外和体内数据表明，3 p-C-DE 4 TA和3 p-C-NE 3 TA是用于Y-90和Lu-177的靶向放射治疗应用的有希望的双功能配体。(C)2014爱思唯尔有限公司版权所有。
Zevalin (R) is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope (Y-90) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin's lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using beta-emitting radionuclides Y-90 and Lu-177. The bifunctional ligands were evaluated for radiolabeling kinetics with Y-90 and Lu-177, and the corresponding Y-90 or Lu-177-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding Y-90 and Lu-177, and the corresponding Y-90- and Lu-177-radiolabeled complexes remained inert in human serumor in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of Y-90 and Lu-177. (C) 2014 Elsevier Ltd. All rights reserved.