Price Eric W, Edwards Kimberly J, Carnazza Kathryn E, Carlin Sean D, Zeglis Brian M, Adam Michael J, Orvig Chris, Lewis Jason S
Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Department of Chemistry, Hunter College and the Ph.D. Program in Chemistry, the Graduate Center of the City University of New York, 413 East 69th Street, New York, NY 10021, United States.
Nucl Med Biol. 2016 Sep;43(9):566-576. doi: 10.1016/j.nucmedbio.2016.06.004. Epub 2016 Jun 28.
To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H4octapa with the therapeutic radiometal (90)Y.
The bifunctional chelators p-SCN-Bn-H4octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with (90)Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer.
High radiochemical yields (>95%) were obtained with (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab after 15min at room temperature. Both (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3±4.0%ID/g for (90)Y-CHX-A″-DTPA-trastuzumab and 30.1±7.4%ID/g for (90)Y-octapa-trastuzumab at 72h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, (90)Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls.
Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H4octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring (90)Y.
比较螯合剂CHX-A″-DTPA和H4octapa与治疗性放射性金属钇（90）Y的放射性标记性能、稳定性及实际疗效。
将双功能螯合剂对-异硫氰酸苄基-H4octapa和对-异硫氰酸苄基-CHX-A″-DTPA与靶向HER2的抗体曲妥珠单抗偶联。将所得免疫偶联物用（90）Y进行放射性标记，以比较放射性标记效率、体外和体内稳定性以及在卵巢癌小鼠模型中的体内性能。
室温下15分钟后，（90）Y-CHX-A″-DTPA-曲妥珠单抗和（90）Y-octapa-曲妥珠单抗获得了高放射化学产率（>95%）。（90）Y-CHX-A″-DTPA-曲妥珠单抗和（90）Y-octapa-曲妥珠单抗均表现出优异的体外和体内稳定性。此外，放射性免疫偶联物在表达HER2的SKOV3卵巢癌异种移植小鼠中显示出高肿瘤摄取值（注射后72小时，（90）Y-CHX-A″-DTPA-曲妥珠单抗为42.3±4.0%ID/g，（90）Y-octapa-曲妥珠单抗为30.1±7.4%ID/g）。最后，在荷瘤小鼠中进行的（90）Y放射免疫治疗研究表明，（90）Y-CHX-A″-DTPA-曲妥珠单抗和（90）Y-octapa-曲妥珠单抗是同样有效的治疗剂，因为与对照组相比，两种放射性免疫偶联物治疗均使肿瘤生长显著降低。
最终，这项工作表明，无环螯合剂CHX-A″-DTPA和H4octapa具有可比的放射性标记、稳定性和体内性能，使其成为需要（90）Y的应用的合适选择。
