دورية أكاديمية
أعرض في EDS

A novel ligand delivery system to non-invasively visualize and therapeutically exploit the IL13Rα2 tumor-restricted biomarker.

التفاصيل البيبلوغرافية
العنوان: A novel ligand delivery system to non-invasively visualize and therapeutically exploit the IL13Rα2 tumor-restricted biomarker.
المؤلفون: Nguyen V; The Brain Tumor Center of Excellence, Department of Neurosurgery, USA., Conyers JM, Zhu D, Gibo DM, Hantgan RR, Larson SM, Debinski W, Mintz A
المصدر: Neuro-oncology [Neuro Oncol] 2012 Oct; Vol. 14 (10), pp. 1239-53. Date of Electronic Publication: 2012 Sep 05.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 100887420 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-5866 (Electronic) Linking ISSN: 15228517 NLM ISO Abbreviation: Neuro Oncol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2010- : Oxford : Oxford University Press
Original Publication: 1999-<2002> : Charlottesville, VA : Carden Jennings Pub.,
مواضيع طبية MeSH: Cell Proliferation*, Brain Neoplasms/*metabolism , Glioblastoma/*metabolism , Interleukin-13/*genetics , Interleukin-13 Receptor alpha1 Subunit/*metabolism , Interleukin-13 Receptor alpha2 Subunit/*metabolism, Animals ; Binding Sites ; Blotting, Western ; Brain Neoplasms/pathology ; Cell Line, Tumor ; Chromatography, Thin Layer ; Circular Dichroism ; Electrophoretic Mobility Shift Assay ; Glioblastoma/pathology ; Humans ; Image Processing, Computer-Assisted ; Immunoenzyme Techniques ; Interleukin-13/metabolism ; Ligands ; Male ; Mice ; Mice, Nude ; Mutagenesis, Site-Directed ; Mutation/genetics ; Positron-Emission Tomography ; Protein Binding ; Recombinant Proteins ; Xenograft Model Antitumor Assays
مستخلص: Our objective was to exploit a novel ligand-based delivery system for targeting diagnostic and therapeutic agents to cancers that express interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-restricted plasma membrane receptor overexpressed in glioblastoma multiforme (GBM), meningiomas, peripheral nerve sheath tumors, and other peripheral tumors. On the basis of our prior work, we designed a novel IL13Rα2-targeted quadruple mutant of IL13 (TQM13) to selectively bind the tumor-restricted IL13Rα2 with high affinity but not significantly interact with the physiologically abundant IL13Rα1/IL4Rα heterodimer that is also expressed in normal brain. We then assessed the in vitro binding profile of TQM13 and its potential to deliver diagnostic and therapeutic radioactivity in vivo. Surface plasmon resonance (SPR; Biacore) binding experiments demonstrated that TQM13 bound strongly to recombinant IL13Rα2 (Kd∼5 nM). In addition, radiolabeled TQM13 specifically bound IL13Rα2-expressing GBM cells and specimens but not normal brain. Of importance, TQM13 did not functionally activate IL13Rα1/IL4Rα in cells or bind to it in SPR binding assays, in contrast to wtIL13. Furthermore, in vivo targeting of systemically delivered radiolabeled TQM13 to IL13Rα2-expressing subcutaneous tumors was demonstrated and confirmed non-invasively for the first time with 124I-TQM13 positron emission tomography imaging. In addition, 131I-TQM13 demonstrated in vivo efficacy against subcutaneous IL13Rα2-expressing GBM tumors and in an orthotopic synergeic IL13Rα2-positive murine glioma model, as evidenced by statistically significant survival advantage. Our results demonstrate that we have successfully generated an optimized biomarker-targeted scaffolding that exhibited specific binding activity toward the tumor-associated IL13Rα2 in vitro and potential to deliver diagnostic and therapeutic payloads in vivo.
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معلومات مُعتمدة: R21NS067471-0110 United States NS NINDS NIH HHS
المشرفين على المادة: 0 (Interleukin-13)
0 (Interleukin-13 Receptor alpha1 Subunit)
0 (Interleukin-13 Receptor alpha2 Subunit)
0 (Ligands)
0 (Recombinant Proteins)
تواريخ الأحداث: Date Created: 20120907 Date Completed: 20130314 Latest Revision: 20211021
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC3452345
DOI: 10.1093/neuonc/nos211
PMID: 22952195
قاعدة البيانات: MEDLINE
الوصف
تدمد:1523-5866
DOI:10.1093/neuonc/nos211