title: An interleukin 13 receptor α 2-specific peptide homes to human Glioblastoma multiforme xenografts.
abstract: Interleukin 13 receptor α 2 (IL-13Rα2) is a glioblastoma multiforme (GBM)-associated plasma membrane receptor, a brain tumor of dismal prognosis. Here, we isolated peptide ligands for IL-13Rα2 with use of a cyclic disulphide-constrained heptapeptide phages display library and 2 in vitro biopanning schemes with GBM cells that do (G26-H2 and SnB19-pcDNA cells) or do not (G26-V2 and SnB19-asIL-13Rα2 cells) over-express IL-13Rα2. We identified 3 peptide phages that bind to IL-13Rα2 in cellular and protein assays. One of the 3 peptide phages, termed Pep-1, bound to IL-13Rα2 with the highest specificity, surprisingly, also in a reducing environment. Pep-1 was thus synthesized and further analyzed in both linear and disulphide-constrained forms. The linear peptide bound to IL-13Rα2 more avidly than did the disulphide-constrained form and was efficiently internalized by IL-13Rα2-expressing GBM cells. The native ligand, IL-13, did not compete for the Pep-1 binding to the receptor and vice versa in any of the assays, indicating that the peptide might be binding to a site on the receptor different from the native ligand. Furthermore, we demonstrated by noninvasive near infrared fluorescence imaging in nude mice that Pep-1 binds and homes to both subcutaneous and orthotopic human GBM xenografts expressing IL-13Rα2 when injected by an intravenous route. Thus, we identified a linear heptapeptide specific for the IL-13Rα2 that is capable of crossing the blood-brain tumor barrier and homing to tumors. Pep-1 can be further developed for various applications in cancer and/or inflammatory diseases.
authors.affiliation: Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. debinski@wfubmc.edu
authors.forename: Hetal
authors.initials: H
authors.lastname: Pandya
authors.forename: Denise M
authors.initials: DM
authors.lastname: Gibo
authors.forename: Shivank
authors.initials: S
authors.lastname: Garg
authors.forename: Steven
authors.initials: S
authors.lastname: Kridel
authors.forename: Waldemar
authors.initials: W
authors.lastname: Debinski
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019151:Peptide Library; D010455:Peptides / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D053663:Interleukin-13 Receptor alpha2 Subunit; D019151:Peptide Library; D010455:Peptides