131I)Iodoazomycin arabinoside for low-dose-rate isotope radiotherapy: radiolabeling, stability, long-term whole-body clearance and radiation dosimetry estimates in mice.

摘要

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.