title: PET imaging drug distribution after intratumoral injection: the case for (124)I-iododeoxyuridine in malignant gliomas.
abstract: 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 (124)I-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 (124)I-IUdR instillation. (124)I-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 (124)I-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 (124)I-IUdR in the reservoir was (124)I-iodouracil. (124)I-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 (124)I-IUdR retention (K(local)) ranged from 0.006 to 0.017 micro L/g/min, which is substantially lower compared with the IUdR-DNA incorporation reported recently after intravenous injection of (124)I-IUdR (K(i), 3.9 +/- 2.3 micro L/g/min, where K(i) is the DNA incorporation rate of (124)I-IUdR after intravenous tracer injection).
  
  
  CONCLUSIONS
  Although a single injection of (124)I-IUdR resulted in radioactivity distribution over the tumor, retention at 24 h was substantially lower compared with intravenous injection of (124)I-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.
authors.affiliation: PET Program, Paul Scherrer Institute, Villigen, Switzerland. roelcke@ksa.ch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Roelcke
authors.forename: Oliver
authors.initials: O
authors.lastname: Hausmann
authors.forename: Adrian
authors.initials: A
authors.lastname: Merlo
authors.forename: John
authors.initials: J
authors.lastname: Missimer
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Maguire
authors.forename: Peter
authors.initials: P
authors.lastname: Freitag
authors.forename: Ernst W
authors.initials: EW
authors.lastname: Radü
authors.forename: Regin
authors.initials: R
authors.lastname: Weinreich
authors.forename: Otmar
authors.initials: O
authors.lastname: Gratzl
authors.forename: Klaus L
authors.initials: KL
authors.lastname: Leenders
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy; D005260:Female; D006801:Humans; D007065:Idoxuridine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016499:Radioimmunotherapy; D014055:Tomography, Emission-Computed
chemical_list: D007457:Iodine Radioisotopes; D011838:Radiation-Sensitizing Agents; D007065:Idoxuridine