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PET Imaging Drug Distribution After Intratumoral Injection: The Case for ¹²⁴I-Iododeoxyuridine in Malignant Gliomas

¹ PET Program, Paul Scherrer Institute, Villigen, Switzerland
² Department of Neurosurgery, University Hospital, Basel, Switzerland
³ Department of Neuroradiology, University Hospital, Basel, Switzerland
⁴ Institute of Medical Radiobiology, Paul Scherrer Institute, Villigen, Switzerland

Locoregional administration may yield higher tumor drug concentrations compared with intravenous injection and may reduce the risk of systemic adverse effect. Furthermore, in the case of brain tumors, it may circumvent limited drug delivery imposed by the blood–brain barrier. We used PET to study the retention and spatial distribution of iododeoxyuridine (IUdR), which has been used as a DNA-targeting radiosensitizing drug and which can be charged with therapeutic nuclides. Methods: Locoregional (resection cavity, tumor) instillation of 5–19 MBq ¹²⁴I-IUdR was achieved in 7 postoperative patients with malignant gliomas through a reservoir implanted in the skull. Patients were scanned with PET during the first hour and at 2, 24, and 48 h after ¹²⁴I-IUdR instillation. ¹²⁴I-IUdR metabolism was measured in the reservoir fluid in the presence or absence of a degradation inhibitor (5'-butyryl-IUdR [butyryl-IUdR]). Region-of-interest analysis was applied to calculate intratumoral retention (K_local) of ¹²⁴I-IUdR from the PET images after a 24-h washout phase using an autoradiographic method. Results: At 24 h, radioactivity concentration in the reservoir was approximately 1% of the concentration 5 min after tracer instillation. The major metabolite of ¹²⁴I-IUdR in the reservoir was ¹²⁴I-iodouracil. ¹²⁴I-IUdR degradation could be partially inhibited by butyryl-IUdR. In the plasma, radioactivity peaked between 2 and 6 h. The area of tissue radioactivity increased with time up to 3-fold compared with the initial distribution. Tumor ¹²⁴I-IUdR retention (K_local) ranged from 0.006 to 0.017 µL/g/min, which is substantially lower compared with the IUdR-DNA incorporation reported recently after intravenous injection of ¹²⁴I-IUdR (K_i, 3.9 ± 2.3 µL/g/min, where K_i is the DNA incorporation rate of ¹²⁴I-IUdR after intravenous tracer injection). Conclusion: Although a single injection of ¹²⁴I-IUdR resulted in radioactivity distribution over the tumor, retention at 24 h was substantially lower compared with intravenous injection of ¹²⁴I-IUdR. Slow diffusion after locoregional administration, in contrast to fast delivery via tumor capillaries after intravenous injection, may account for our findings, resulting in a low amount of drug incorporation into DNA before degradation and washout from tissue.

Key Words: malignant brain tumor • locoregional treatment • iododeoxyuridine • PET

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