Synthesis and preclinical evaluation of bifunctional ligands for improved chelation chemistry of 90Y and 177Lu for targeted radioimmunotherapy.
Synthesis and preclinical evaluation of bifunctional ligands for improved chelation chemistry of 90Y and 177Lu for targeted radioimmunotherapy.
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DOI：
10.1021/bc200696b
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发表时间：
2012-09-19
影响因子：
4.7
通讯作者：
Chong, Hyun-Soon
中科院分区：
文献类型：
--
作者：
Kang, Chi Soo;Sun, Xiang;Jia, Fang;Song, Hyun A.;Chen, Yunwei;Lewis, Michael;Chong, Hyun-Soon
我们报道了一个实用的和高产率的合成双峰双功能配体3 p-C-NETA-NCS含有异硫氰酸酯基团的缀合到肿瘤靶向抗体。将3 p-C-NETA-NCS缀合至肿瘤靶向抗体曲妥珠单抗，并评价相应的3 p-C-NETA-曲妥珠单抗缀合物，并与已知的双功能配体C-DOTA、C-DTPA、C-NOTA和3 p-C-DEPA的曲妥珠单抗缀合物比较90 Y和177 Lu的放射性标记动力学。3 p-C-NETA-曲妥珠单抗偶联物与90 Y和177 Lu表现出极快的络合动力学。90 Y-3 p-C-NETA-曲妥珠单抗和177 Lu-3 p-C-NETA-曲妥珠单抗缀合物在人血清中稳定2周。使用携带ZR-75-1人乳腺癌的裸鼠进行初步生物分布研究以评价177 Lu-放射性标记的曲妥珠单抗缀合物的体内稳定性和肿瘤靶向。177 Lu-3 p-C-NETA-曲妥珠单抗偶联物在120 h时显示出低的血液放射性水平（1.6%）、低的器官摄取（<2.2%）和高的肿瘤-血液比（6.4）。3 p-C-NETA具有良好的体外和体内特性，是一种优异的双功能螯合剂，可用于使用90 Y和177 Lu的靶向RIT应用，并有潜力在当前临床应用中取代DOTA和DTPA类似物。
We report a practical and high yield synthesis of a bimodal bifunctional ligand 3p-C-NETA-NCS containing the isothiocyanate group for conjugation to a tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a tumor-targeting antibody, trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to trastuzumab conjugates of the known bifunctional ligands C-DOTA, C-DTPA, C-NOTA, and 3p-C-DEPA for radiolabeling kinetics with 90Y and 177Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with 90Y and 177Lu. 90Y-3p-C-NETA-trastuzumab and 177Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and tumor targeting of 177Lu-radiolabeled trastuzumab conjugate using nude mice bearing ZR-75-1 human breast cancer. 177Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional chelator that can be used for targeted RIT applications using 90Y and 177Lu and has potential to replace DOTA and DTPA analogues in current clinical use.
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影响因子：
50.5
作者：
Baselga, J
通讯作者：
Baselga, J
影响因子：
2.7
作者：
Chong, Hyun-Soon;Lim, Sooyoun;Lewis, Michael R.
通讯作者：
Lewis, Michael R.
影响因子：
4.7
作者：
BRECHBIEL, MW;GANSOW, OA
通讯作者：
GANSOW, OA
影响因子：
4.6
作者：
HINZ, FP;MARGERUM, DW
通讯作者：
MARGERUM, DW
影响因子：
5.8
作者：
Vose, JM
通讯作者：
Vose, JM