Radiolabeling of MAG3-morpholino oligomers with 188Re at high labeling efficiency and specific radioactivity for tumor pretargeting

Abstract

We are investigating a novel pretargeting approach involving an initial IV injection of antitumor antibody conjugated with a phosphorodiamidate morpholino oligomer (MORF, a DNA analog) and the subsequent IV injection of the radiolabeled complement oligomer (cMORF). In this paper, the cMORF was labeled with 188 Re using MAG 3 as chelator for therapeutic applications. Since (c) MORFs are unstable in acidic condition, an optimal labeling pH was first selected and the other labeling factors were then examined. A labeling efficiency of greater than 90% can be achieved even at a concentration of MAG 3 -cMORF as low as 0.8 μM. The labeled cMORF is stable and capable of hybridizing to its complement.

An experimental and theoretical evaluation of the influence of pretargeting antibody on the tumor accumulation of effector

“…The MAG 3 -cMORF was synthesized as described previously (22). To radiolabel, 50 AL 99m Tc-pertechnetate generator eluate was introduced into a combined solution consisting of 30 AL (>0.5 Ag) of MAG 3 -MORF in NH 4 OAc buffer (pH 5.2), 10 AL of 50 Ag/AL Na 2 tartrateÁ2H 2 O in a pH 9.2 buffer, and 3 AL of 4 Ag/AL SnCl 2 Á2H 2 O in ascorbate-HCl solution (1 Ag/AL sodium ascorbate in 10 mmol/L HCl).…”

Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice

“…The MAG 3 -cMORF was prepared and labeled as described earlier [14]. The MORF-MN14 was synthesized using a commercial Hydralink™ method (Solulink Biosciences, San Diego, CA) [15].…”

Successful Radiotherapy of Tumor in Pretargeted Mice by 188Re-Radiolabeled Phosphorodiamidate Morpholino Oligomer, a Synthetic DNA Analogue

“…This similarity permits the use of the same labeling method and, more importantly, results in radiolabeled agents with similar, if not identical, properties. In particular, the stability of the 188 Re radiolabel in the MAG 3 chelator has been extensively investigated and found to be equally stable to that of 99m Tc and, more importantly, suitably stable for radiotherapy trials (17,20). We now report on tumor pretargeting with the therapeutic radionuclide 188 Re and the first therapeutic trial in tumored mice.…”

“…Re labeling of cMORF was scaled up from that previously described (20). Increasing the scale lowered the labeling efficiency somewhat to f85%.…”

“…Increasing the scale lowered the labeling efficiency somewhat to f85%. The radiolabeled cMORF was used without purification because the impurity has been shown to clear from the whole body rapidly as the labeled cMORF (20). Relabeled cMORF.…”