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In vivo and in vitro uptake of In-111, delivered with the affibody molecule(Z(EGFR:955))(2), in EGFR expressing tumour cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.ORCID iD: 0000-0001-6120-2683
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2008 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 19, no 4, 853-857 p.Article in journal (Refereed) Published
Abstract [en]

The epidermal growth factor receptor, EGFR, is overexpressed in many carcinomas. Targeting this receptor with radionuclides is important for imaging and therapy applications in nuclear medicine. We investigated the in vitro and in vivo properties of a new high affinity EGFR binding affibody molecule, (Z(EGFR:955))(2), when conjugated with CHXA"-DTPA and labelled with In-111. The binding time patterns and retention studies were performed using cultured squamous carcinoma A431 cells that overexpress EGFR. In the in vivo studies, female BALB/c nu/nu mice carrying tumours from xenografted A431 cells were used. The in vitro studies showed EGFR specific binding, high uptake and good retention of In-111 when delivered as [In-111](Z(EGFR:955))(2). The retention after 72 h of incubation was 38.0 +/- 1.15% of the initial level. The biodistribution study showed a tumour specific In-111 uptake of 3.8 +/- 1.4% of injected dose per gram turnout tissue 4 h post-injection. The tumour to blood ratio was 9.1 and the tumours could easily be visualized with a gamma camera at this time-point. In-111 delivered with [In-111](Z(EGFR:955))(2) gave an EGFR specific uptake and the results indicated that the (Z(EGFR:955))(2) affibody molecule is a candidate for radionuclide-based tumour imaging. Potential therapy applications are discussed.

Place, publisher, year, edition, pages
2008. Vol. 19, no 4, 853-857 p.
Keyword [en]
a431, affibody molecule, EGFR, mouse, radionuclide
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-152588ISI: 000254496100003PubMedID: 18357367OAI: oai:DiVA.org:uu-152588DiVA: diva2:413503
Available from: 2011-04-28 Created: 2011-04-28 Last updated: 2017-12-11Bibliographically approved
In thesis
1. EGFR and HER2 Targeting for Radionuclide-Based Imaging and Therapy: Preclinical Studies
Open this publication in new window or tab >>EGFR and HER2 Targeting for Radionuclide-Based Imaging and Therapy: Preclinical Studies
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The optimal way to detect and treat cancer is to target cancer cells exclusively without affecting the surrounding tissue. One promising approach is to use radiolabelled molecules to target receptors that are overexpressed in cancer cells. Since the epidermal growth factor receptor (EGFR) family is overexpressed in many types of cancer, it is an attractive target for both diagnostic and therapeutic applications.

This thesis can be divided into two parts. In part one (paper I), studies were conducted to modulate radionuclide uptake in tumour cells. The results showed that it was possible to modulate the cellular uptake of 125I delivered by trastuzumab (targeting HER2) by adding EGF (targeting EGFR).

In part two (papers II-V) a high affinity EGFR-targeting affibody molecule (ZEGFR:955)2 was selected and analysed both in vitro and in vivo. In papers II, III and V, the results obtained when using (ZEGFR:955)2 were compared with those obtained with the two EGFR-binding molecules, EGF and cetuximab. These studies demonstrated that the affibody molecule bound specifically to EGFR (probably to subdomain III) with high affinity (~50 nM in biosensor analysis and ~1 nM in cellular studies) and produced intracellular signalling changes similar to those with cetuximab. In paper IV, in vivo studies were made, demonstrating that [111In](ZEGFR:955)2 gave a tumour-specific 111In uptake of 3.8±1.4% of injected dose per gram tumour tissue, 4 h post-injection. The tumours could be easily visualized with a gamma camera at this time-point.

The results of these studies indicated that the affibody molecule (ZEGFR:955)2 is a possible candidate for radionuclide-based imaging of EGFR-expressing tumours. The biological effects of (ZEGFR:955)2 might be of interest for therapy applications.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 50 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 350
Keyword
Biomedicine, EGFR, HER2, affibody molecule, tumour targeting, 125I, 111In, Biomedicin
Identifiers
urn:nbn:se:uu:diva-8721 (URN)978-91-554-7197-2 (ISBN)
Public defence
2008-05-24, Fåhraeussalen, Rudbecklaboratoriet, Daghammarskjöldsväg 20, Uppsala Science Park, Uppsala, 09:15
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Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2011-07-08Bibliographically approved

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Orlova, AnnaTolmachev, Vladimir

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