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- Altai, MohamedUppsala universitet,Enheten för biomedicinsk strålningsvetenskap (author)
Tumour Targeting using Radiolabelled Affibody Molecules : Influence of Labelling Chemistry
- BookEnglish2014
Publisher, publication year, extent ...
- Uppsala :Acta Universitatis Upsaliensis,2014
- 77 s.
- electronicrdacarrier
Numbers
- LIBRIS-ID:oai:DiVA.org:uu-229090
- ISBN:9789155489830
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-229090URI
Supplementary language notes
- Language:English
- Summary in:English
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- SwePubSwePub
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Series
- Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;1013
Notes
- Affibody molecules are promising candidates for targeted radionuclide-based imaging and therapy applications. Optimisation of targeting properties would permit the in vivo visualization of cancer-specific surface receptors with high contrast. In therapy, this may increase the ratio of radioactivity uptake between tumour and normal tissues. This thesis work is based on 5 original research articles (papers I-V) and focuses on optimisation of targeting properties of anti-HER2 affibody molecules by optimising the labelling chemistry.Paper I and II report the comparative evaluation of the anti-HER2 ZHER2:2395 affibody molecule site specifically labelled with 111In (suitable for SPECT imaging) and 68Ga (suitable for PET imaging) using the thiol reactive derivatives of DOTA and NODAGA as chelators. The incorporation of different macrocyclic chelators and labelling with different radionuclides modified the biodistribution properties of affibody molecules. This indicates that the labelling strategy may have a profound effect on the targeting properties of radiotracers and must be carefully optimized.Paper III reports the study of the mechanism of renal reabsorption of anti-HER2 ZHER2:2395 affibody molecule. An unknown receptor (not HER2) is suspected to be responsible for the high reabsorption of ZHER2:2395 molecules in the kidneys.Paper IV reports the optimization and development of in vivo targeting properties of 188Re-labelled anti-HER2 affibody molecules. By using an array of peptide based chelators, it was found that substitution of one amino acid by another or changing its position can have a dramatic effect on the biodistribution properties of 188Re-labelled affibody molecules. This permitted the selection of –GGGC chelator whichdemonstrated the lowest retention of radioactivity in kidneys compared to other variants and showed excellent tumour targeting properties.Paper V reports the preclinical evaluation of 188Re-ZHER2:V2 as a potential candidate for targeted radionuclide therapy of HER2-expressing tumours. In vivo experiments in mice along with dosimetry assessment in both murine and human models revealed that future human radiotherapy studies using 188Re-ZHER2:V2 may be feasible.It would be reasonable to believe that the results of optimisation of anti-HER2 affibody molecules summarized in this thesis can be of importance for the development of other scaffold protein-based targeting agents.
Subject headings and genre
- HER2
- Affibody molecule
- Radionuclide molecular maging
- Targeted radionuclide therapy
- Labeling chemistry
Added entries (persons, corporate bodies, meetings, titles ...)
- Tolmachev, Vladimir,ProfessorUppsala universitet,Enheten för biomedicinsk strålningsvetenskap (thesis advisor)
- Barbet, Jacques,ProfessorHead of GIP ARRONAX, National Accelerator Research Centrum in Nantes, France (opponent)
- Uppsala universitetEnheten för biomedicinsk strålningsvetenskap (creator_code:org_t)
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