Theranostics 2016; 6(12):2278-2291. doi:10.7150/thno.15898

Research Paper

Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery

Helge Thisgaard1,2,# ✉, Bo Halle2,3,4,#, Charlotte Aaberg-Jessen1,3, Birgitte Brinkmann Olsen1, Anne Sofie Nautrup Therkelsen1, Johan Hygum Dam1, Niels Langkjær1, Sune Munthe2,3,4, Kjell Någren1, Poul Flemming Høilund-Carlsen1,2*, Bjarne Winther Kristensen2,3*

1. PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark;
2. Department of Clinical Research, University of Southern Denmark, Odense, Denmark;
3. Department of Pathology, Odense University Hospital, Odense, Denmark;
4. Department of Neurosurgery, Odense University Hospital, Odense, Denmark.
# These authors contributed equally to the work.
* Shared last authorship.

Abstract

Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [125I]5-Iodo-2'-deoxyuridine (125I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining 125I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. 125I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and 125I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and 125I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy.

Keywords: Glioblastoma, Auger-electron therapy, convection-enhanced delivery, [125I]5-Iodo-2'-deoxyuridine, temozolomide.

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How to cite this article:
Thisgaard H, Halle B, Aaberg-Jessen C, Olsen BB, Therkelsen ASN, Dam JH, Langkjær N, Munthe S, Någren K, Høilund-Carlsen PF, Kristensen BW. Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery. Theranostics 2016; 6(12):2278-2291. doi:10.7150/thno.15898. Available from http://www.thno.org/v06p2278.htm