[131I]Iodoazomycin arabinoside for low-dose-rate isotope radiotherapy: radiolabeling, stability, long-term whole-body clearance and radiation dosimetry estimates in mice.
BACKGROUND
The preliminary characterization of [(131)I]iodoazomycin arabinoside ([(131)I]IAZA) as a potential radiotherapeutic radiopharmaceutical is described.


METHODS
High-specific-activity [(131)I]IAZA was prepared in therapeutic doses (up to 3 GBq per batch) by isotope exchange in pivalic acid melt and was purified on Sep-Pak cartridges. Stability in 15% ethanol in saline at 4 degrees C was determined by high-performance liquid chromatography. IAZA cytotoxicity (IC(50), approximately 0.1 mM) against both murine (EMT-6) and human (143B, 143B-LTK) tumor cells determined by MTT test was in the range previously reported for EMT-6 cells using a clonogenic assay. Tissue radioactivity levels were measured in a murine tumor model for the 24- to 168-h postinjection period. Radiation dose estimates obtained from the tissue activity levels for this period were calculated from pharmacokinetic (WinNonlin) and dosimetry (MIRD and RAdiation Dose Assessment Resource) parameters.


RESULTS
The radioiodination efficiency was >90%, but with systematic losses during Sep-Pak purification, the recovered yields of [(131)I]IAZA were approximately 75%. The product (specific activity, 4.6-6.4 GBq/micromol) was stable for at least 2 weeks, with only approximately 6% degradation over this storage period. Extended biodistribution studies in Balb/c mice bearing implanted EMT-6 tumors showed that the highest tumor/blood radioactivity ratio (T/B; 4.8) occurred 24 h after dosing; the T/B ratio was approximately 1.5 at the end of the 7-day study. The 24- to 168-h tissue radioactivity data fit a one-compartment model except for liver data, which best fit a two-compartment model. Dosimetry estimates showed a tumor self-dose of 7.4 mGy/MBq, which is several-fold higher than for the liver or the kidney.


CONCLUSIONS
[(131)I]IAZA can be efficiently radiolabeled at high specific activity, purified by a simple Sep-Pak technique and stored with little radiolysis or chemical decomposition at these specific activities. Based on measured radioactivity burdens during the week following injection and on published animal ([(125)I]IAZA) and clinical ([(123)I]IAZA) dosimetry data, the current dose estimates point to selective tumor irradiation at low dose rates.
Kumar
Piyush
P
Department of Oncologic Imaging, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
McQuarrie
Steven A
SA
Zhou
Aihya
A
McEwan
Alexander J B
AJ
Wiebe
Leonard I
LI
D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000532:radiotherapy*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016499:Radioimmunotherapy; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D013778:Tetrazolium Salts; D013844:Thiazoles; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D007457:Iodine Radioisotopes; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D013778:Tetrazolium Salts; D013844:Thiazoles; C070588:iodoazomycin arabinoside; C022616:thiazolyl blue