Gene therapy using antisense oligodeoxynucleotides labeled with Auger-emitting radionuclides.

Antisense oligomers may be used as a vehicle for carrying a radiation source into a specific location inside a tumor cell. The effects of radioactive-labeled oligodeoxynucleotides (ODNs) may have both direct antisense inhibition and radiation. Thus far, the use of radioactive ODNs has been limited mostly to clinical biokinetic studies. Therapeutic possibilities remain unknown if the basic question of the optimal source of radiation is unanswered. We have shown previously that oligonucleotide therapy can be effective theoretically with the internally labeled ODN phosphorothioates 32P, 33P, and 35S. Here, we expand the selection of radionuclides; we calculated in vivo subcellular tissue distribution for ODN phosphorothioates using the decay characteristics of several beta- and Auger-emitting radionuclides: 32P, 35S, 51Cr, 67Ga, 111In, (1114m)In, 123I, 125I, 131I, and 201Tl. The absorbed nuclear doses of these radiolabeled oligonucleotides were estimated in different cellular dimensions using the subcellular biodistribution data for two oligonucleotides (ISIS 2105 and ISIS 2922). Our results indicate that Auger-emitter isotopes do not give higher absorbed cell nuclear doses than the isotopes suitable for internal labeling of ODN phosphorothioates. However, the biological difference is difficult to estimate. The best isotope for subcellular targeting was 35S, which gives the smallest variation of nuclear dose in the different cell dimensions we studied (nuclear diameter, 6-16 microm; cellular diameter, 12-20 microm). Therefore, we conclude that in oligonucleotide radiotherapy, nuclear targets should be treated with short-range beta-emitters (35S or 33P) that are suitable for the internal labeling of oligonucleotides unless the relative biological effectiveness of Auger-emitters could be remarkably improved. Dual labeling with 32P and 35S may provide therapeutic benefits when treating smaller and larger targets simultaneously. Further in vivo development, especially with 33P and 35S labels for ODNs, is strongly indicated.