A novel interleukin‐13 receptor alpha 2‐targeted hybrid peptide for effective glioblastoma therapy

Abstract

We previously designed and reported a novel class of drugs, namely hybrid peptides, which are chemically synthesized and composed of a targeted binding peptide and a lytic‐type peptide containing cationic amino acid residues that cause cancer cell death. In the present study, we screened for peptides that bind to interleukin‐13 receptor alpha 2 (IL‐13Rα2) by using a T7 random peptide phage display library system and isolated several positive phage clones. The A2b11 peptide, which was one of the positive clones, was shown to bind to IL‐13Rα2 protein by Biacore analysis and a binding assay using glioblastoma (GB) cell lines. This peptide was linked with a lytic peptide containing a linker sequence to form the IL‐13Rα2–lytic hybrid peptide. The IL‐13Rα2–lytic hybrid peptide showed cytotoxic activity against GB cell lines in vitro. The IL‐13Rα2–lytic hybrid peptide also affected Akt and Erk1/2 activation following treatment with interleukin‐13 and induced rapid ATP dynamics in GB cells. Anti‐tumor activity of the IL‐13Rα2–lytic hybrid peptide was observed in vivo after intratumoral injection in a mouse xenograft model of human GB cells. These results suggest that the IL‐13Rα2–lytic hybrid peptide might be a potent therapeutic option for patients with GB.

From oncolytic peptides to oncolytic polymers: A new paradigm for oncotherapy

“…Fourthly, in order to broaden its application scope, the feasibility and effectiveness of oncolytic polymers in the treatment of some complex tumor models (e.g., glioma/glioblastoma brain tumors) should also be carefully studied. Although there has been some researches showing that oncolytic peptides were able to induce glioma/glioblastoma tumor cells lysis and inhibit growth of subcutaneous glioblastoma tumor [ 118 , [213] , [214] , [215] , [216] , [217] ], the blood-brain barrier (BBB) remains a major obstacle in the treatment of brain tumors in vivo . So far, there has been a controversy about whether the oncolytic peptides/polymers could cross the BBB.…”

Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges

“…The ability to cause lysis can be put to good use, at least in principle, not only against noxious microorganisms but also against cancer, since cancer cells appear to be more sensitive to them than normal ones, probably due to differences in lipid composition. , For example, breast and prostate cancers and their metastases have been attacked with lytic peptides conjugated to ligands of hormone receptors. − Kawakami’s group has coupled, via a glycine triplet, a lytic peptide (KLLLKLLK­KLLKLLKKK or KLlLKlLk­kLLKlLKKK) with peptides targeting the epidermal growth factor receptor (EGFR), the transferrin receptor (TfR), the receptor for IL-4 (IL-4R), the epidermal growth factor receptor 2 (HER2/Erb2), and interleukin-13 receptor alpha 2 (IL-13Rα2) to obtain selective cancer cell-killing tools.…”

“…442 , 443 For example, breast and prostate cancers and their metastases have been attacked with lytic peptides conjugated to ligands of hormone receptors. 444 − 446 Kawakami’s group has coupled, via a glycine triplet, a lytic peptide (KLLLKLLKKLLKLLKKK or KLlLKlLkkLLKlLKKK) with peptides targeting the epidermal growth factor receptor (EGFR), 447 the transferrin receptor (TfR), 448 the receptor for IL-4 (IL-4R), 449 the epidermal growth factor receptor 2 (HER2/Erb2), 450 and interleukin-13 receptor alpha 2 (IL-13Rα2) 451 to obtain selective cancer cell-killing tools.…”

Use of Pep-1-guided PDA-loaded temozolomide nanoparticles a dual combination therapy against glioblastoma

“…Il-13Rα2, a monomer of IL-13, is encoded by the X chromosome as a receptor with high a nity comprising 380 amino acids, a 17-amino acid structural domain, and a 26-amino acid signal sequence. 41,42 IL-13Rα2 is highly expressed in GBMs but is lowly expressed in normal brain cells. Hence, it can be an ideal target in GBM treatment.…”