Abstract
Abstract Interleukin-13 Pseudomonas exotoxin (IL-13PE), a powerful targeted agent for IL-13 receptor α2 (IL-13Rα2) - positive tumors is being tested for safety and effectiveness in glioblastoma multiforme (GBM) clinical trials. However, distribution of IL-13PE after intra-cranial convection-enhanced delivery (CED) has not been determined. To study this, we radiolabeled IL-13PE with 125I and determined its binding and biological activity in vitro and distribution in a murine model of GBM. 125IL-13PE maintained its specific binding activity to IL-13Rα2 positive U251 glioblastoma tumor cells but not to T98G cells, as these cells did not express IL-13Rα2. 125IL-13PE was as cytotoxic to glioblastoma cells as non-radiolabeled IL-13PE, which killed U251 tumor cells in a concentration dependent manner but not T98G cells. Both binding and cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated that IL-13PE binding was specific. Athymic nude mice with intracranially implanted U251 tumors were given stereotactic intratumoral injections of 125I-IL-13PE by either a bolus injection or a 3-day-CED. Animals were imaged by micro-SPECT/CT at various time points. SPECT/CT imaging revealed retention of 125I-IL-13PE in U251 tumors. CED showed significantly higher volumes of distribution and maintained detectable drug levels for longer periods of time compared to bolus injection. SPECT/CT images of whole brains corroborated with the autoradiography results performed on sectioned brain. These results indicate that IL-13PE can be successfully radiolabled with 125I without the loss of binding and cytotoxic activity and that 125I-IL-13PE administered by CED showed higher volumes of distribution than the bolus route. Thus, future clinical studies with 125I-IL-13PE or other agents should consider the CED mode of delivery for better distribution in intracranial environments. Volume of distribution of 125I-IL-13PE after bolus or CED administration into mouse brain Injection parameters SPECT Time Vi (μl)* Vd (mm3)** Vd:Vi ratio Bolus - day 1 10 minutes 5 10.2 ± 0.4 204.7 ± 7.0 Bolus - day 7 10 minutes 5 0.1 ± 0.02 2.0 ± 0.4 CED - day 1 3 days 100 120.4 ± 21.8 120.4 ± 21.6 CED - day 7 3 days 100 81.7 ± 6.9 81.7 ± 6.7 *Vi: Volume of injection **Vd: Volume of distribution Citation Format: Akiko Suzuki, Pamela Leland, Peter L. Choyke, Tomio Inoue, Bharat H. Joshi, Raj K. Puri. SPECT/CT analysis of distribution of intracranially infused interleukin-13 Pseudomonas exotoxin, a targeted agent for interleukin-13 receptor expressing brain tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2013-2663
Published Version
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