Targeted radioiodine therapy of neuroblastoma tumors following systemic nonviral delivery of the sodium iodide symporter gene.
OBJECTIVE
We recently reported the significant therapeutic efficacy of radioiodine therapy in various tumor mouse models following transcriptionally targeted sodium iodide symporter (NIS) gene transfer. These studies showed the high potential of NIS as a novel diagnostic and therapeutic gene for the treatment of extrathyroidal tumors. As a next crucial step towards clinical application of NIS-mediated radionuclide therapy we aim at systemic delivery of the NIS gene to target extrathyroidal tumors even in the metastatic stage.


METHODS
In the current study, we used synthetic polymeric vectors based on pseudodendritic oligoamines with high intrinsic tumor affinity (G2-HD-OEI) to target a NIS-expressing plasmid (CMV-NIS-pcDNA3) to neuroblastoma (Neuro2A) cells.


RESULTS
Incubation with NIS-containing polyplexes (G2-HD-OEI/NIS) resulted in a 51-fold increase in perchlorate-sensitive iodide uptake activity in Neuro2A cells in vitro. Through (123)I-scintigraphy and ex vivo gamma counting Neuro2A tumors in syngeneic A/J mice were shown to accumulate 8% to 13% ID/g (123)I with a biological half-life of 13 hours, resulting in a tumor-absorbed dose of 247 mGy/MBq (131)I after i.v. application of G2-HD-OEI/NIS. Nontarget organs, including liver, lung, kidneys, and spleen revealed no significant iodide uptake. Moreover, two cycles of systemic NIS gene transfer followed by (131)I application (55.5 MBq) resulted in a significant delay in tumor growth associated with markedly improved survival.


CONCLUSIONS
In conclusion, our data clearly show the high potential of novel pseudodendritic polymers for tumor-specific NIS gene delivery after systemic application, opening the prospect of targeted NIS-mediated radionuclide therapy of nonthyroidal tumors even in metastatic disease.
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Kathrin
K
Klutz
Verena
V
Russ
Michael J
MJ
Willhauck
Nathalie
N
Wunderlich
Christian
C
Zach
Franz Josef
FJ
Gildehaus
Burkhard
B
Göke
Ernst
E
Wagner
Manfred
M
Ogris
Christine
C
Spitzweg
D000818:Animals; D001682:Biological Availability; D003131:Combined Modality Therapy; D050091:Dendrimers / Q000008:administration & dosage / Q000493:pharmacokinetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011878:Radiotherapy / Q000379:methods; D018714:Radiotherapy, Adjuvant; D027981:Symporters / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
D050091:Dendrimers; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters