[36] Dosimetry and optimization of in vivo targeting with radiolabeled antisense oligodeoxynucleotides: Oligonucleotide radiotherapy

Antisense oligomers may serve as a vehicle for carrying cytotoxic or radioactive compounds into a particular location. Radiolabeled oligodeoxynucleotides (ODNs) have the potential of having both direct antisense inhibition and radiation effects. This chapter extends the conventional use of radioactive ODNs from limited biokinetic studies to therapeutic use. It presents calculations from macroscopic biodistribution data to cell nuclear doses. Oligonucleotide therapy may be effective with internally labeled ( 32 P, 33 P, and 35 S) oligodeoxynucleotide phosphorothioates. In addition, the chapter evaluates auger- and γ -emitting radionuclides 51 Cr, 67 Ga, 111 In, 114m In, 123 I, 125 I, 131 I, and 201 TI. In an experiment described in the chapter, subcellular biodistribution was used in the evaluation of the best targeting inside the cell with one oligomer: 35 S gives the lowest variation of nuclear dose in the different cell dimensions (nuclear diameter, 6–16 μ m; cellular diameter, 12–20 μ m). Therefore, cell nuclear targets should be treated with short-range β emitters, such as 35 S or 33 P, suitable for internal labeling of oligonucleotides in optimal oligonucleotide radiotherapy. In addition, dual labeling with 32 P and 35 S may provide therapeutic benefits when treating small and large tumors simultaneously. In vivo development of labeled anticancer ODNs, optimally with 33 P and 35 S, is highly indicated.