International Journal of Nanomedicine (Jul 2021)
Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model
Abstract
Vijaya Sarangthem,1,2,* Aena Yi,1,* Yunjae Kim,1 Alnawaz Rehemtulla,3 Byung-Heon Lee,1 Young Hyun Jeon,4 Thoudam Debraj Singh,5 Rang-Woon Park1 1Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea; 2Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India; 3Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; 4Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea; 5Department of Medical Oncology Laboratory, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India*These authors contributed equally to this workCorrespondence: Rang-Woon ParkDepartment of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of KoreaTel +82 53 420 4822Fax +82 53 422 1466Email [email protected] Debraj SinghDepartment of Medical Oncology Laboratory, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, IndiaEmail [email protected]: Thermal-responsive self-assembled elastin-like polypeptide (ELP)-based nanoparticles are an emerging platform for controlled delivery of therapeutic peptides, proteins and small molecular drugs. The antitumor effect of bioengineered chimeric polypeptide AP1-ELP-KLAK containing an interleukin-4 receptor (IL-4R) targeting peptide and pro-apoptotic peptide (KLAKLAK) was evaluated in glioblastoma (GBM) in vitro and in vivo.Methods and Results: Herein, the therapeutic effect of AP1-ELP-KLAK was tested in advanced, and less curable glioblastoma cells with higher expression of IL-4R. Glioblastoma cell lines stably expressing different reporter systems i.e., caspase-3 sensor (surrogate marker for cellular apoptosis) or effluc/enhanced firefly luciferase (cellular viability) were established to measure cell death non-invasively. Bioluminescence imaging (BLI) of D54/effluc and U97MG/effluc treated with AP1-ELP-KLAK exhibited higher cell death up to 2∼ 3-fold than the control. Treatment with AP1-ELP-KLAK resulted in time-dependent increase of caspase-3 sensor BLI activity in D54/C cells and D54/C tumor-bearing mice. Intravenous injection of AP1-ELP-KLAK dramatically reduced tumor growth by inducing cellular apoptosis in D54/effluc tumor-bearing mice. Further, the immuno-histological examination of the excised tumor tissue confirmed the presence of apoptotic cells as well as caspase-3 activation.Conclusion: Collectively, AP1-ELP-KLAK effectively induced cellular apoptosis of glioblastoma cells and non-invasive imaging provides a window for real-time monitoring of anti-tumor effect with the provision of improving therapeutic efficacy in a glioblastoma mice model.Keywords: tumor targeting, ELP, caspase-sensor, apoptosis, IL-4 receptor, glioblastoma
