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Gene therapy using antisense oligodeoxynucleotides labeled with Auger-emitting radionuclides
K J Kairemo1, M Tenhunen, A P Jekunen
1Department of Oncology, Helsinki University Central Hospital, Finland.
Cancer Gene Therapy
|January 23, 1999
Summary
Radioactive-labeled antisense oligodeoxynucleotides (ODNs) offer dual therapeutic potential. Sulfur-35 (35S) and Phosphorus-33 (33P) are optimal for targeted radiotherapy, with dual labeling showing promise.
Area of Science:
- Nuclear medicine and molecular radiotherapy
- Oligonucleotide-based drug delivery and therapy
Background:
- Antisense oligodeoxynucleotides (ODNs) can serve as carriers for radionuclides targeting tumor cells.
- Radioactive ODNs offer combined antisense inhibition and radiation therapy, but optimal radionuclide selection remains unclear.
- Previous studies explored 32P, 33P, and 35S for ODN labeling, but therapeutic potential requires further investigation.
Purpose of the Study:
- To evaluate a wider range of beta- and Auger-emitting radionuclides for in vivo subcellular distribution and absorbed nuclear dose in ODN radiotherapy.
- To determine the optimal radionuclide for internal labeling of ODN phosphorothioates for enhanced therapeutic efficacy.
- To assess the potential of dual labeling strategies for simultaneous targeting of different cellular dimensions.
Main Methods:
- Calculated in vivo subcellular tissue distribution for ODN phosphorothioates using decay characteristics of 10 radionuclides (32P, 35S, 51Cr, 67Ga, 111In, (1114m)In, 123I, 125I, 131I, 201Tl).
- Estimated absorbed nuclear doses in different cellular dimensions (nuclear: 6-16 µm, cellular: 12-20 µm) for two ODNs (ISIS 2105, ISIS 2922) using biodistribution data.
- Compared absorbed doses from Auger-emitters versus beta-emitters suitable for ODN phosphorothioate labeling.
Main Results:
- Auger-emitting isotopes did not yield higher absorbed cell nuclear doses compared to isotopes suitable for ODN phosphorothioate labeling.
- Sulfur-35 (35S) demonstrated the smallest variation in nuclear dose across studied cellular dimensions, indicating optimal subcellular targeting.
- Dual labeling with 32P and 35S may offer therapeutic advantages for treating both small and large cellular targets concurrently.
Conclusions:
- For oligonucleotide radiotherapy targeting nuclear components, short-range beta-emitters like 35S or 33P are recommended for internal ODN labeling, unless Auger-emitters' biological effectiveness significantly improves.
- Further in vivo research, particularly focusing on 33P and 35S labeled ODNs, is crucial for therapeutic development.
- The selection of radionuclide significantly impacts absorbed dose distribution and therapeutic potential in ODN-based radiotherapy.