Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker
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Kiran Kumar Solingapuram Sai1,*, Anirudh Sattiraju1,*, Frankis G. Almaguel1, Ang Xuan1, Stephanie Rideout1, Rahul S. Krishnaswamy1, JoAnn Zhang2, Denise M. Herpai3, Waldemar Debinski3 and Akiva Mintz1
1Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
2MicroPET/CT Imaging Section, TriFoil Imaging, Chatsworth, CA, USA
3Department of Cancer Biology, Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston Salem, NC, USA
*These authors have contributed equally to this work
Kiran Kumar Solingapuram Sai, email: firstname.lastname@example.org
Akiva Mintz, email: email@example.com
Keywords: positron emission tomography (PET), high-grade glioma, doxycycline, biodistribution, IL13RA2
Received: January 25, 2017 Accepted: February 27, 2017 Published: March 24, 2017
Peptides that target cancer cell surface receptors are promising platforms to deliver diagnostic and therapeutic payloads specifically to cancer but not normal tissue. IL13RA2 is a tumor-restricted receptor found to be present in several aggressive malignancies, including in the vast majority of high-grade gliomas and malignant melanoma. This receptor has been successfully targeted for diagnostic and therapeutic purposes using modified IL-13 ligand and more recently using a specific peptide, Pep-1L. In the current work, we establish the in vitro and in vivo tumor binding properties of radiolabeled Pep-1L, designed for tumor imaging. We radiolabeled Pep-1L with Copper-64 and demonstrated specific cell uptake in the IL13RA2-over expressing G48 glioblastoma cell line having abundant IL13RA2 expression. [64Cu]Pep-1L binding was blocked by unlabeled ligand, demonstrating specificity. To demonstrate in vivo tumor uptake, we intravenously injected into tumor-bearing mice and demonstrated that [64Cu]Pep-1L specifically bound tumors at 24 hours, which was significantly blocked (3-fold) by pre-injecting unlabeled peptide. To further demonstrate specificity of Pep-1L towards IL13RA2 in vivo, we exploited an IL13RA2-inducible melanoma tumor model that does not express receptor at baseline but expresses abundant receptor after treatment with doxycycline. We injected [64Cu]Pep-1L into mice bearing IL13RA2-inducible melanoma tumors and performed in vivo PET/CT and post-necropsy biodistribution studies and found that tumors that were induced to express IL13RA2 receptor by doxycycline pretreatment bound radiolabeled Pep-1L 3-4 fold greater than uninduced tumors, demonstrating receptor specificity. This work demonstrates that [64Cu]Pep-1L selectively binds hIL13RA2-expressing tumors and validates Pep-1L as an effective platform to deliver diagnostics and therapeutics to IL13RA2-expressing cancers.
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