title: Analysis of biodistribution of intracranially infused radiolabeled interleukin-13 receptor-targeted immunotoxin IL-13PE by SPECT/CT in an orthotopic mouse model of human glioma.
abstract: Interleukin-13 Pseudomonas exotoxin (IL-13PE), a targeted agent for interleukin-13 receptor α2 (IL-13Rα2)-expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme.
  
  
  METHODS
  IL-13PE was radiolabeled with Na(125)I and evaluated for its activity in vitro in receptor-positive U251 or -negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and (125)I-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantitatively and compared with histology and autoradiography results.
  
  
  RESULTS
  The radioiodination technique resulted in a specific and biologically active (125)I-IL-13PE, which bound and was cytotoxic to IL-13Rα2-positive but not to IL-13Rα2-negative tumor cells. Both the binding and the cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated the specificity of binding and cytotoxicity. SPECT/CT imaging revealed retention of (125)I-IL-13PE administered by CED in U251 tumors and showed significantly higher volumes of distribution and maintained detectable drug levels for a longer period of time than the bolus route. These results were confirmed by autoradiography.
  
  
  CONCLUSIONS
  IL-13PE can be radioiodinated without the loss of specificity, binding, or cytotoxic activity. Intracranial CED administration produces a higher volume of distribution for a longer period of time than the bolus route. Thus, CED of IL-13PE is superior to bolus injection in delivering the drug to the entire tumor.
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Leland
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Jagoda
authors.affiliation: Department of Radiology, Yokohama City University, Yokohama, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland.
authors.forename: Bharat H
authors.initials: BH
authors.lastname: Joshi
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland raj.puri@fda.hhs.gov.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005910:Glioma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism*; D007267:Injections; D007553:Isotope Labeling; D051379:Mice; D011549:Pseudomonas; D053660:Receptors, Interleukin-13 / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D000922:Immunotoxins; D053660:Receptors, Interleukin-13
keywords: IL-13PE; SPECT; biodistribution; brain tumor; convection-enhanced delivery; radioiodination