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90Y labeled Phosphorodiamidate Morpholino Oligomer for Pretargeting Radiotherapy

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Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, United States
Guozheng Liu, Ph. D. Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0243. Phone: 508-856-1958; Fax: 508-856-6363. E-mail: [email protected]
Cite this: Bioconjugate Chem. 2011, 22, 12, 2539–2545
Publication Date (Web):October 11, 2011
https://doi.org/10.1021/bc200366t
Copyright © 2011 American Chemical Society
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    Abstract

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    While 188Re has been used successfully in mice for tumor radiotherapy by MORF/cMORF pretargeting, previous radiolabeling of the amine-derivatized cMORF with 90Y, a longer physical half-life nuclide, was not very successful. After developing a method involving a prepurification heating step during conjugation that increases labeling efficiency and label stability, the biodistribution of 90Y-DOTA-Bn-SCN-cMORF (90Y-DOTA-cMORF) was measured in normal mice and in MORF-CC49 pretargeted mice that bear LS174T tumors. Absorbed radiation doses were then estimated and compared to those estimated for 188Re. The pharmacokinetics of the 90Y-DOTA-cMORF in normal mice and in the pretargeted nude mice was similar to that observed previously with 99mTc- and 188Re-MAG3-cMORFs. While the 90Y-DOTA-cMORF cleared rapidly from normal tissues, tumor clearance was very slow and tumor radioactivity accumulation was constant for at least 7 days such that the tumor/blood (T/B) ratio increased linearly from 6 to 25 over this period. Therefore, by extrapolation, normal tissue toxicities following administration of therapeutic doses of 90Y may be comparable to that observed for 188Re in which the T/B increased from 5 to 20. In conclusion, radiolabeling of DOTA-cMORF with 90Y was improved by introducing a prepurification heating step during conjugation. The 90Y-DOTA-cMORF provided a similar T/B ratio and biodistribution to that of 188Re-MAG3-cMORF and was retained well in the tumor pretargeted with MORF-CC49. Because of the longer physical half-life, the T/NT absorbed radiation dose ratios were improved in most organs and especially in blood.

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