id:"swepub:oai:DiVA.org:kth-116884"
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- Hofström, Camilla,1979-KTH,Molekylär Bioteknologi,Affinity-protein Based Blocking of Cellular Proteins and their Delivery (författare)
Engineering of Affibody molecules for Radionuclide Molecular Imaging and Intracellular Targeting
- BokEngelska2013
Förlag, utgivningsår, omfång ...
- Stockholm :KTH Royal Institute of Technology,2013
- xi, 65 s.
- electronicrdacarrier
Nummerbeteckningar
- LIBRIS-ID:oai:DiVA.org:kth-116884
- ISBN:9789175016139
- https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-116884URI
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- Språk:engelska
- Sammanfattning på:engelska
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- SwePubSwePub
Klassifikation
Anmärkningar
- QC 20130129
- Affibody molecules are small (7 kDa) affinity proteins of non-immunoglobulin origin that have been generated to specifically interact with a large number of clinically important molecular targets.In this thesis, Affibody molecules have been employed as tracers for radionuclide molecular imaging of HER2- and IGF-1R-expressing tumors, paper I-IV, and for surface knock-down of EGFR, paper V. In paper I, a tag with the amino acid sequence HEHEHE was fused to the N-terminus of a HER2-specific Affibody molecule, (ZHER2), and was shown to enable facile IMAC purification and efficient tri-carbonyl 99mTc-labeling. In vivo evaluation of radioactivity uptake in different organs showed an improved biodistribution, including a 10-fold lower radioactivity uptake in liver, compared to the same construct with a H6-tag. In paper II, it was further shown that an N-terminally placed HEHEHE-tag on ZHER2 provided lower unspecific uptake of radioactivity in liver compared to its H6-tagged counterpart even when radiolabeling was at the C-terminus using alternative chemistries to attach 99mTc, 111In or 125I. In paper III, the H6-tag’s composition and position was varied with regards to charge, hydrophobicity and its C- or N-terminal placement on ZHER2. Among the ten variants investigated, it was found that an N-terminal HEHEHE-tag provided the most favorable overall biodistribution profile and that introduction of hydrophobic and positively charged amino acids provoked liver uptake of radioactivity. In paper IV, the HEHEHE-tag was shown to enable IMAC purification and tri-carbonyl 99mTc-labeling of an IGF-1R-specific Affibody molecule and improved its overall biodistribution when compared to the same construct with a H6-tag. In paper V, the aim was to develop an intracellular receptor-entrapment system to reduce the surface levels of EGFR. An EGFR-specific Affibody molecule was expressed as a fusion to different mutants of an intracellular transport protein in SKOV-3 cells, resulting in a collection of cell lines with 50%, 60%, 80% and 96% reduced surface level of EGFR. Analysis of the proliferation rate of these cell lines showed that a modest reduction (15%) in proliferation occurs between 60% and 80% reduction of the surface level of EGFR.
Ämnesord och genrebeteckningar
- NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
- NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
- TEKNIK OCH TEKNOLOGIER Industriell bioteknik Medicinsk bioteknik hsv//swe
- ENGINEERING AND TECHNOLOGY Industrial Biotechnology Medical Biotechnology hsv//eng
- Affibody molecules
- affinity proteins
- radionuclide molecular imaging
- intracellular targeting
- EGFR
- HER2
- IGF-1R
- SRA - Molecular Bioscience
- SRA - Molekylär biovetenskap
Biuppslag (personer, institutioner, konferenser, titlar ...)
- Gräslund, Torbjörn,DocentKTH,Molekylär Bioteknologi(Swepub:kth)u1dl39rj (preses)
- Muyldermans, Serge,ProfVrije Universiteit Brussel, Structural Biology (opponent)
- KTHMolekylär Bioteknologi (creator_code:org_t)
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