90Y labeled Phosphorodiamidate Morpholino Oligomer for Pretargeting Radiotherapy

While Re-188 has been used successfully in mice for tumor radiotherapy by MORF/cMORF pretargeting, previous radio-labeling of the amine-derivatized cMORF with Y-90, 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 Y-90-DOTA-Bn-SCN-cMORF (Y-90-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 Re-188. The pharmacokinetics of the Y-90-DOTA-cMORF in normal mice and in the pretargeted nude mice was similar to that observed previously with Tc-99m- and Re-188-MAG(3)-cMORFs. While the Y-90-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 Y-90 may be comparable to that observed for Re-188 in which the T/B increased from 5 to 20. In conclusion, radiolabeling of DOTA-cMORF with Y-90 was improved by introducing a prepurification heating step during conjugation. The Y-90-DOTA-cMORF provided a similar T/B ratio and biodistribution to that of Re-188-MAG(3)-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.