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Improved Tumor-to-Organ Ratios of a Novel 67Ga-Human Epidermal Growth Factor Radionuclide Conjugate with Preadministered Antiepidermal Growth Factor Receptor Affibody Molecules
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
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2011 (Engelska)Ingår i: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 26, nr 5, s. 593-601Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The over-expression of the epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis. Targeted nuclear imaging of the EGFR expression could improve the diagnostics in patients with HNSCC. However, the high expression of EGFR in normal organs may conceal the tumor uptake and therefore limit the use.

In this study, we have assessed the biodistribution of a novel hEGF radionuclide conjugate after pre-injection with anti-EGFR Affibody molecules. hEGF was conjugated with p-SCN-Bn-NOTA and labeled with 67Ga. The biodistribution of [67Ga]Ga-NOTA-Bn-NCS-hEGF in nude mice with EGFR-expressing xenografts was evaluated either alone or 45 minutes after pre-injection with one of the anti-EGFR Affibody molecules ZEGFR:1907, (ZEGFR:1907)2 or (ZEGFR:955)2.

The novel radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF demonstrated high stability in vitro and specific binding to hEGF in vitro and in vivo. Pre-injection with anti-EGFR Affibody molecules improved the tumor-to-organ ratio in the liver, salivary glands and colon. Overall, the dimeric high affinity Affibody molecule (ZEGFR:1907)2 exhibited the best results.

These findings show that pre-blocking with an anti-EGFR Affibody molecule is a promising tool that could improve the outcome of radionuclide-based imaging of EGFR-expressing tumors.

Ort, förlag, år, upplaga, sidor
2011. Vol. 26, nr 5, s. 593-601
Nyckelord [en]
EGFR, Gallium, Affibody molecule, Head and neck cancer, Molecular imaging, Tumor-to-organ ratio
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-156521DOI: 10.1089/cbr.2011.0981ISI: 000296087300009PubMedID: 21834651OAI: oai:DiVA.org:uu-156521DiVA, id: diva2:432052
Tillgänglig från: 2011-07-28 Skapad: 2011-07-28 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. Radioimmunodiagnosis of Head and Neck Squamous Cell Carcinomas: Preclinical Studies
Öppna denna publikation i ny flik eller fönster >>Radioimmunodiagnosis of Head and Neck Squamous Cell Carcinomas: Preclinical Studies
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Despite improvements in treatment, the prognosis for patients with advanced head and neck squamous cell carcinomas (HNSCC) has only improved to a minor degree. To raise the success rate and minimize morbidity further developments in diagnostics are highly desired. Radioimmunodiagnosis could offer a more specific and sensitive diagnostic method. Herein, we have evaluated different radioimmunoconjugates directed against CD44v6 and epidermal growth factor receptor (EGFR) for imaging of HNSCC. The studies were performed in a murine HNSCC xenograft model.

Initially, the 111In-labeled anti CD44v6 chimeric monoclonal antibody U36 (cMAb U36) was evaluated. The novel radioimmunoconjugate showed high and accumulating tumor uptake. Since small molecules might be advantageous for imaging, due mainly to their shorter circulation half-life in the bloodstream, we then investigated antibody fragments F(ab’)2 and Fab’ derived from cMAb U36. The highest tumor-to-blood ratio was achieved with the dimeric antibody fragment F(ab’)2, compared with both the intact anti-body and monomeric Fab’.

Furthermore, the possibility of improving EGFR-targeted imaging was explored by pre-blocking EGFR. The liver uptake of injected labeled human epidermal growth factor (hEGF) was significantly reduced when an excess of unlabeled hEGF was injected 30 minutes in advance. However, as hEGF stimulates cell proliferation it may be inadvisable to treat cancer patients with large amounts. Alternatively, pre-blocking with an anti-EGFR Affibody molecule (ZEGFR:955)2 demonstrated similar decrease in liver uptake as unlabeled hEGF. Finally, (ZEGFR:955)2 was compared with other Affibody molecules with higher affinity to EGFR, ZEGFR:1907 and (ZEGFR:1907)2, as pre-blocking agents. In addition, a novel hEGF radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF was used for EGFR targeting. The dimeric (ZEGFR:1907)2 showed greatest reduction in non-tumor uptake, and highest tumor-to-organ ratio in EGFR expressing organs, when injected in advance of the radioimmunoconjugate.

To summarize, the results presented here demonstrate how different radioimmunoconjugates as well as pre-blocking EGFR can improve the radioimmunodiagnosis of head and neck squamous cell carcinomas.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2011. s. 54
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 682
Nyckelord
Head and neck squamos cell carcinoma, radioimmunotargeting, radioimmunodiagnosis
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-156523 (URN)978-91-554-8111-7 (ISBN)
Disputation
2011-09-16, Skoogsalen, Ing 78-79, Akademiska sjukhuset, Uppsala, 13:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2011-08-25 Skapad: 2011-07-28 Senast uppdaterad: 2011-09-08Bibliografiskt granskad

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