Journal article
IL13RA2 targeted alpha particle therapy against glioblastomas
Oncotarget, Vol.8(26), pp.42997-43007
06/27/2017
DOI: 10.18632/oncotarget.17792
PMCID: PMC5522122
PMID: 28562337
Abstract
Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM-specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [Cu-64] Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [Ac-225] Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups (p < 0.05). GBM tissue extracted from mice treated with [Ac-225] Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [Ac-225] Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents.
Details
- Title: Subtitle
- IL13RA2 targeted alpha particle therapy against glioblastomas
- Creators
- Anirudh Sattiraju - Wake Forest UniversityKiran Kumar Solingapuram Sai - Wake Forest UniversityAng Xuan - Zhengzhou UniversityDarpan N. Pandya - Wake Forest UniversityFrankis G. Almaguel - Wake Forest UniversityThaddeus J. Wadas - Wake Forest UniversityDenise M. Herpai - Wake Forest UniversityWaldemar Debinski - Wake Forest UniversityAkiva Mintz - Wake Forest University
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.8(26), pp.42997-43007
- DOI
- 10.18632/oncotarget.17792
- PMID
- 28562337
- PMCID
- PMC5522122
- NLM abbreviation
- Oncotarget
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Publisher
- Impact Journals LLC
- Number of pages
- 11
- Grant note
- UL1TR001420 / Translational Imaging Program of the Wake Forest CTSA 124443-MRSG-13-121-01-CDD / American Cancer Society Mentored Research Scholar grant; American Cancer Society UL1TR001420 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) P50CA108961 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 1R01CA179072-01A1; R01 CA74145; P30 CA012197 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 06/27/2017
- Academic Unit
- Radiology; Radiation Oncology
- Record Identifier
- 9984312978302771
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