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  • 151.
    Sundberg, Åsa Liljegren
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Steffen, Ann-Charlott
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Enhancing the effect of radionuclide tumor targeting, using lysosomotropic weak bases2007Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 67, nr 1, s. 279-287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: The aim of the present study was to investigate if treatment with lysosomotropic weak bases could increase the intracellular retention of radiohalogens and thereby increase the therapeutic effect of radionuclide tumor targeting. METHODS AND MATERIALS: Four different lysosomotropic bases, chloroquine, ammonium chloride, amantadine, and thioridazine, were investigated for their ability to increase radiohalogen retention in vitro. The two most promising substances, chloroquine and ammonium chloride, were studied in several cell lines (A431, U343MGaCl2:6, SKOV-3, and SKBR-3) in combination with radiolabeled epidermal growth factor (EGF) or the HER2 binding affibody (Z(HER2:4))(2). RESULTS: The uptake and retention of radionuclides was found to be substantially increased by simultaneous treatment with the lysosomotropic bases. The effect was, however, more pronounced in the epidermal growth factor:epidermal growth factor receptor (EGF:EGFR) system than in the (Z(HER2:4))(2):HER2 system. The therapeutic effect of ammonium chloride treatment combined with (211)At-EGF was also studied. The effect obtained after combined treatment was found to be much better than after (211)At-EGF treatment alone. CONCLUSIONS: The encouraging results from the present study indicate that the use of lysosomotropic weak bases is a promising approach for increasing the therapeutic effect of radionuclide targeting with radiohalogens.

  • 152.
    Sundín, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Carlsson, L
    Graf, Wilhelm
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Carlsson, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Radioimmunolocalization of hepatic metastases and subcutaneous xenografts from a human colonic cancer in the nude rat: Aspects of tumour implantation site and mode of antibody administration1993Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 32, nr 7-8, s. 877-885Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Antibody localization was analyzed following intraperitoneal (i.p.) or intravenous (i.v.) injection of the 125I-labelled anti-CEA-MAb I-38S1 in 44 nude rats, in order to evaluate the influence of tumour implantation site and the route of MAb administration. The animals were xenografted with a human colonic cancer (LS 174 T), either in the form of hepatic metastases, subcutaneous (s.c.) tumours or both. Tissue measurements, 4 days after MAb injection, showed better uptake for hepatic than for s.c. tumours, irrespective of the route of antibody administration. Antibody accumulation per g liver metastases was not size dependent for noduli weighing between 4 and 1,110 mg. MAb excretion evaluated in 20 animals and blood activity studied in 11 rats were equivalent 24-96 h following i.p. and i.v. injection. Dissimilar autoradiographic patterns were seen in hepatic metastases with predominantly peripherally located clusters following i.p. and more homogeneously distributed grains after i.v. MAb administration. The results indicate that tumour implantation site has a quantitative, and the route of administration at least a qualitative impact on the tumour accretion of anti-CEA MAb I-38S1 in the present xenograft model.

  • 153.
    Thuy, Tran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Engfeldt, Torun
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Widström, Charles
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Bruskin, Alexander
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Eriksson Karlström, Amelie
    In Vivo Evaluation of Cysteine-Based Chelators for Attachment of 99mTc  to Tumor-Targeting Affibody Molecules2007Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 18, nr 2, s. 549-558Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules present a new class of affinity proteins, which utilizes a scaffold based on a 58-amino acid domain derived from protein A. The small (7 kDa) Affibody molecule can be selected to bind to cell-surface targets with high affinity. An Affibody molecule ZHER2:342 with a dissociation constant (Kd) of 22 pM for binding to the HER2 receptor has been reported earlier. Preclinical and pilot clinical studies have demonstrated the utilityof radiolabeled ZHER2:342 in imaging of HER2-expressing tumors. The small size and cysteine-free structure ofAffibody molecules enable complete peptide synthesis and direct incorporation of radionuclide chelators. The goal of this study was to evaluate if incorporation of the natural peptide sequences cysteine-diglycine (CGG) and cysteine-triglycine (CGGG) sequences would enable labeling of Affibody molecules with 99mTc. In a model monomeric form, the chelating sequences were incorporated by peptide synthesis. The HER2-binding affinity was 280 and 250 pM for CGG-ZHER2:342 and CGGG-ZHER2:342, respectively. Conjugates were directly labeled with 99mTc with 90% efficiency and preserved the capacity to bind specifically to HER2-expressing cells. The biodistribution in normal mice showed a rapid clearance from the blood and the majority of organs (except kidneys). In the mice bearing SKOV-3 xenografts, tumor uptake of 99mTc-CGG-ZHER2:342 was HER2-specific and a tumorto- blood ratio of 9.2 was obtained at 6 h postinjection. Gamma-camera imaging with 99mTc-CGG-ZHER2:342 clearly visualized tumors at 6 h postinjection. The results show that the use of a cysteine-based chelator enables 99mTclabeling of Affibody molecules for imaging.

  • 154.
    Tolmachev, V
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Update on Affibody molecules for in vivo imaging of targets for cancer therapy2009Inngår i: Minerva biotecnologica (Testo stampato), ISSN 1120-4826, E-ISSN 1827-160X, Vol. 21, nr 1, s. 21-30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An increasing specificity of the cancer treatment requires an accurate detection of cancer-associated molecular targets to avoid over- and undertreatment. Radionuclide molecular imaging is a pronitising way for visualisation of such targets. Affibody molecules (Affibody (R) molecules), small (7 kDa) robust scaffold proteins constitute a new promising class of high-affinity molecular probes for in vivo molecular imaging. Pre-clinical studies demonstrated a great potential of derivatives of Z(HER2:342) Affibody molecule to visualise expression of HER2 in tumour xenografts. Robustness of the Affibody scaffold enabled labelling in harsh conditions without loosing specificity of the HER2-binding. This paper provides an overview of the recent development of Affibody molecules. During the recent year, an important achievement was the development of site-specific labelling of Affibody molecules providing well-characterised uniform conjugates with defined biodistribution and targeting properties. The site-specific labelling was obtained either by an incorporation of chelators during peptides synthesis of Affibody molecules or by an introduction of a single cysteine in the originally cysteine-free Affibody scaffold and the use of a thiol-directed coupling. A feasibility of modification of the biodistribution of Affibody molecules by different chelators was another interesting fmding. This was demonstrated during development of mercaptoacetyl-containing peptide based chelators for Tc-99m-labelling of Affibody molecules. Several positron-emitting labels enabled the use of advantages of PET for Affibody-mediated radionuclide imaging. it was demonstrated that the rapid targeting of Affibody molecules is compatible with the use of such labels as Ga-68 and F-18.

  • 155.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Imaging of HER-2 overexpression in tumors for guiding therapy2008Inngår i: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 14, nr 28, s. 2999-3019Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Human epidermal growth factor receptor type 2 (HER2) is a transmembrane tyrosine kinase receptor, which is overexpressed in a large fraction of breast, ovarian, urinary bladder and a number of other carcinomas. Overexpression of HER2 is associated with poor prognosis. Treatment of patients with HER2-expressing breast cancer with a humanized anti-HER2 monoclonal antibody trastuzumab has resulted in improved survival. Several kinds of other anti-HER2 therapies are under development. Radionuclide molecular imaging of HER2 expression may influence patient management by selecting patients, who would benefit form anti-HER2 therapy. Other applications, such as therapy response monitoring and follow-up are also possible. In this case, the use of radionuclide imaging may overcome problems associated with biopsies, including sampling errors and discordance of expression between primary tumors and metastases. Important preconditions for development of a successful tracer for radionuclide imaging are high affinity of a targeting agent and suitable chemistry of labeling. The paper reviews information concerning major classes of HER2-targeting agents, including full-length monoclonal antibodies, their enzymatically produced fragments, engineered immunoglobulin based tracers, and alternative high affinity binders. Available information suggests that Affibody molecules or other small non-immunoglobulin based tracers have the best potential for development of high-contrast imaging agents for visualization of HER2 in vivo.

  • 156.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Reply: Molecular Imaging of EGFR: It's Time to Go Beyond Receptor Expression2009Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, nr 7, s. 1196-1196Artikkel i tidsskrift (Fagfellevurdert)
  • 157.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    A limiting factor for the progress of radionuclide-based cancer diagnostics and therapy: availability of suitable radionuclides2004Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, nr 3, s. 264-75Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Advances in diagnostics and targeted radionuclide therapy of haematological and neuroendocrine tumours have raised hope for improved radionuclide therapy of other forms of disseminated tumours. New molecular target structures are characterized and this stimulates the efforts to develop new radiolabelled targeting agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides. The choice is determined by physical, chemical, biological, and economic factors, such as a character of emitted radiation, physical half-life, labelling chemistry, chemical stability of the label, intracellular retention time, and fate of radiocatabolites and availability of the radionuclide. There is actually limited availability of suitable radionuclides and this is a limiting factor for further progress in the field and this is the focus in this article. The probably most promising therapeutic radionuclide, 211At, requires regional production and distribution centres with dedicated cyclotrons. Such centres are, with a few exceptions in the world, lacking today. They can be designed to also produce beta- and Augeremitters of therapeutic interest. Furthermore, emerging satellite PET scanners will in the near future demand long-lived positron emitters for diagnostics with macromolecular radiopharmaceuticals, and these can also be produced at such centres. To secure continued development and to meet the foreseen requirements for radionuclide availability from the medical community it is necessary to establish specialized cyclotron centres for radionuclide production.

  • 158.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Friedman, Mikaela
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Avdelningen för sjukhusfysik.
    Eriksson, Tove L.
    Rosik, Daniel
    Hodik, Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Ståhl, Stefan
    Frejd, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Affibody molecules for epidermal growth factor receptor targeting in vivo: aspects of dimerization and labeling chemistry2009Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, nr 2, s. 274-283Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Noninvasive detection of epidermal growth factor receptor (EGFR) expression in malignant tumors by radionuclide molecular imaging may provide diagnostic information influencing patient management. The aim of this study was to evaluate a novel EGFR-targeting protein, the ZEGFR:1907 Affibody molecule, for radionuclide imaging of EGFR expression, to determine a suitable tracer format (dimer or monomer) and optimal label. METHODS: An EGFR-specific Affibody molecule, ZEGFR:1907, and its dimeric form, (ZEGFR:1907)2, were labeled with 111In using benzyl-diethylenetriaminepentaacetic acid and with 125I using p-iodobenzoate. Affinity and cellular retention of conjugates were evaluated in vitro. Biodistribution of radiolabeled Affibody molecules was compared in mice bearing EGFR-expressing A431 xenografts. Specificity of EGFR targeting was confirmed by comparison with biodistribution of non-EGFR-specific counterparts. RESULTS: Head-to-tail dimerization of the Affibody molecule improved the dissociation rate. In vitro, dimeric forms demonstrated superior cellular retention of radioactivity. For both molecular set-ups, retention was better for the 111In-labeled tracer than for the radioiodinated counterpart. In vivo, all conjugates accumulated specifically in xenografts and in EGFR-expressing tissues. The retention of radioactivity in tumors was better in vivo for dimeric forms; however, the absolute uptake values were higher for monomeric tracers. The best tracer, 111In-labeled ZEGFR:1907, provided a tumor-to-blood ratio of 100 (24 h after injection). CONCLUSION: The radiometal-labeled monomeric Affibody molecule ZEGFR:1907 has a potential for radionuclide molecular imaging of EGFR expression in malignant tumors.

  • 159.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hofström, Camilla
    Malmberg, Jennie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Ahlgren, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hosseinimehr, Seyed Jalal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Abrahmsén, Lars
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Gräslund, Torbjörn
    HEHEHE-Tagged Affibody Molecule May Be Purified by IMAC, Is Conveniently Labeled with [Tc-99m(CO)(3)](+), and Shows Improved Biodistribution with Reduced Hepatic Radioactivity Accumulation2010Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 21, nr 11, s. 2013-2022Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are a class of small (ca. 7 kDa) robust scaffold proteins suitable for radionuclide molecular imaging of therapeutic targets in vivo. A hexahistidine tag at the N-terminus streamlines development of new imaging probes by enabling facile purification using immobilized metal ion affinity chromatography (IMAC), as well as convenient [Tc-99m(CO)(3)](+)-labeling. However, previous studies in mice have demonstrated that Affibody molecules labeled by this method yield higher liver accumulation of radioactivity, compared to the same tracer lacking the hexahistidine tag and labeled by an alternative method. Two variants of the HER2-binding Affibody molecule Z(HER2:342) were made in an attempt to create a tagged tracer that could be purified by immobilized metal affinity chromatography, yet would not result in anomalous hepatic radioactivity accumulation following labeling with [Tc-99m(CO)(3)](+). In one construct, the hexahistidine tag was moved to the C-terminus. In the other construct, every second histidine residue in the hexahistidine tag was replaced by the more hydrophilic glutamate, resulting in a HEHEHE-tag. Both variants, denoted Z(HER2:342)-H-6 and (HE)(3)-Z(HER2:342), respectively, could be efficiently purified using IMAC and stably labeled with [Tc-99m(CO)(3)](+) and were subsequently compared with the parental H-6-Z(HER2:342) having an N-terminal hexahistidine tag. All three variants were demonstrated to specifically bind to HER2-expressing cells in vitro. The hepatic accumulation of radioactivity in a murine model was 2-fold lower with [Tc-99m(CO)(3)](+)-Z(HER2:342)-H-6 compared to [Tc-99m(CO)(3)](+)-H-6-Z(HER2:342), and more than 10-fold lower with [Tc-99m(CO)(3)](+)-(HE)(3)-Z(HER2:342). These differences translated into appreciably superior tumor-to-liver ratio for [Tc-99m(CO)(3)](+)-(HE)(3)-Z(HER2:342) compared to the alternative conjugates. This information might be useful for development of other scaffold-based molecular imaging probes.

  • 160.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Hofström, Camilla
    Malmberg, Jennie
    Ahlgren, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Gräslund, Torbjörn
    HEHEHE: a new chelator for [Tc-99m(CO)(3)](+)-labeling assembling His(6)-tag in protein purification2010Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, nr 6, s. 698-698Artikkel i tidsskrift (Annet vitenskapelig)
  • 161.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Mume, Eskender
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Sjöberg, Stefan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Frejd, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Influence of valency and labelling chemistry on in vivo targeting using radioiodinated HER2-binding2009Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 36, nr 4, s. 692-701Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: HER2 is a transmembrane tyrosine kinase, which is overexpressed in a number of carcinomas. The Affibody molecule Z(HER2:342) is a small (7 kDa) affinity protein binding to HER2 with an affinity of 22 pM. The goal of this study was to evaluate the use of ((4-hydroxyphenyl)ethyl)maleimide (HPEM) for radioiodination of Z(HER2:342) and to compare the targeting properties of monomeric and dimeric forms of Z(HER2:342). METHODS: The biodistribution of different radioiodinated derivatives of Z(HER2:342) was studied in BALB/C nu/nu mice bearing HER2-expressing SKOV-3 xenografts. Biodistributions of (125)I-PIB-Z(HER2:342) and site-specifically labelled (125)I-HPEM-Z(HER2:342)-C were compared. Biodistributions of monomeric (131)I-HPEM-Z(HER2:342)-C and dimeric (125)I-HPEM-(Z(HER2:342))(2)-C were evaluated using a paired-label method. RESULTS: (125)I-HPEM-Z(HER2:342)-C had the same level of tumour accumulation as (125)I-PIB-Z(HER2:342), but fourfold lower renal retention of radioactivity. The monomeric form of Z(HER2:342) provided better tumour targeting than the dimeric form. CONCLUSION: Favourable biodistribution of (131)I-HPEM-Z(HER2:342)-C makes it a promising candidate for radionuclide therapy.

  • 162.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Nilsson, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Widström, Charles
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Rosik, Daniel
    Affibody AB.
    Gedda, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Wennborg, Anders
    Affibody AB.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    111In-benzyl-DTPA-ZHER2:342, an affibody-based conjugate for in vivo imaging of HER2 expression in malignant tumors2006Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 47, nr 5, s. 846-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Data on expression of the HER2 (erbB-2) receptor in breast carcinoma make it possible to select the most efficient treatment. There are strong indications that HER2 expression possesses prognostic and predictive values in ovarian, prostate, and lung carcinomas as well. Visualization of HER2 expression using radionuclide targeting can provide important diagnostic information. The Affibody Z(HER2:342) is a short (approximately 7 kDa) phage-display-selected protein that binds HER2 with an affinity of 22 pmol/L. The goal of this study was to evaluate whether (111)In-labeled HER2:342 can be used for imaging of HER2 overexpression in vivo. METHODS: Z(HER2:342) was labeled with (111)In via isothiocyanate-benzyl-DTPA (DTPA is diethylenetriaminepentaacetic acid) and the conjugate was characterized in vitro and in vivo. RESULTS: (111)In-Benzyl-DTPA-Z(HER2:342) preserved the capacity to bind living HER2-expressing cells specifically. The affinity of In-benzyl-DTPA-Z(HER2:342) to HER2 was 21 pmol/L according to surface plasmon resonance measurements. In nude mice bearing HER2-expressing SKOV-3 xenografts, a tumor uptake of 12% +/- 3% injected activity per gram and a tumor-to-blood ratio of about 100 were obtained 4 h after injection. Tumor uptake in vivo was receptor specific, as it could be blocked with an excess of nonlabeled Z(HER2:342). HER2-expressing xenografts were clearly imaged 4 h after injection using a gamma-camera. CONCLUSION: (111)In-Benzyl-DTPA-Z(HER2:342) is a promising candidate for visualization of HER2 expression in carcinomas, using the single-photon detection technique.

  • 163.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Influence of labelling methods on biodistribution and imaging properties of radiolabelled peptides for visualisation of molecular therapeutic targets2010Inngår i: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 17, nr 24, s. 2636-2655Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Progress in genomics and proteomics provides clinical oncology with new anti-cancer drugs, which target selectively aberrantly expressed membrane proteins and associated signalling pathways in malignant cells. Molecular targeting also enables specific delivery of cytotoxic substances to tumours sparing healthy tissues. Improved selectivity of the treatment reduces side effects and widens the therapeutic window. However, only a part of the patients might benefit from such treatment due to inter- and intrapatient heterogeneity of therapeutic target expression. This makes it necessary to identify patients, who may benefit from targeting therapy. Radiolabelled peptides can provide selective and sensitive detection of molecular therapeutic targets in both primary tumours and metastases in a single non-invasive procedure, making personalised treatment possible. The choice of detection method (single photon emission tomography or positron emission tomography), radionuclide for labelling and labeling chemistry can appreciably influence the imaging property of a tracer. The labelling method might affect the binding affinity, the cellular processing and retention of a radionuclide, the biodistribution of a targeting peptide, and excretion pathways of a non-bound tracer and radiocatabolites. This influences the sensitivity and specificity of the imaging. This influence is exemplified by three classes of tumour-targeting peptides: somatostatin analogues, bombesin analogues and Affibody molecules. The review suggests approaches for selection of an optimal labelling chemistry.

  • 164.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Bruskin, Alexander
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sivaev, Igor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Persson, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sjöberg, S
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    The use of benzyl isothiocyanate derivative of closo-dodecaborate dianion for indirect radioiodination and radiobromination of monoclonal antibodies2002Inngår i: European Journal of Nuclear Medicine, ISSN 0340-6997, E-ISSN 1432-105X, Vol. 29, s. S76-Artikkel, omtale (Annet vitenskapelig)
  • 165.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Lundqvist, Hans
    Optimization of iodination of [125I]-N-succinimidyl-para-iodobenzoate using Chloromine-T for labeling of proteins2000Inngår i: Journal of Radioanalytical and Nuclear Chemistry, ISSN 0236-5731, E-ISSN 1588-2780, Vol. 246, nr 1, s. 207-213Artikkel i tidsskrift (Fagfellevurdert)
  • 166.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Pehrson, Rikard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Galli, Joakim
    Affibody AB.
    Baastrup, Barbro
    Affibody AB.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Rosik, Daniel
    Affibody AB.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Wennborg, Anders
    Affibody AB.
    Nilsson, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific Affibody molecule2007Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, nr 6, s. 2773-2782Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A radiolabeled anti-HER2 Affibody molecule (Z(HER2:342)) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (approximately 7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (Z(HER2:342))(2) was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A''-DTPA and labeled with the low-energy beta-emitter (177)Lu. The obtained conjugate [CHX-A''-DTPA-ABD-(Z(HER2:342))(2)] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z(HER2:342))(2). Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non-HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) as a candidate for treatment of disseminated tumors with a high level of HER2 expression.

  • 167.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Wei, Qichun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Bruskin, Alexander
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Gedda, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Comparative biodistribution of potential anti-glioblastoma conjugates [111In]DTPA-hEGF and [111In]Bz-DTPA-hEGF in normal mice2004Inngår i: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 19, nr 4, s. 491-501Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    EGF-receptors (EGFR) are overexpressed in gliomas, as well as in tumors of breast, lung, and urinary bladder. For this reason, EGFR may be an attractive target for both visualization and therapy of malignant tumors using radioactive nuclides. Natural ligand of EGFR, epidermal growth factor (EGF) is a small 53-amino-acid protein. Low molecular weight of EGF may enable better intratumoral penetration in comparison to antibodies. [111In]DTPA-EGF was proposed for the targeting of glioblastoma and breast cancer, and its tumor-seeking properties were confirmed in animal studies. The aim of this study was to evaluate how the substitution of heptadentate DTPA for octadentate benzyl-DTPA (Bz-DTPA) effects the biodistribution of indium-labeled human EGF (hEGF) in normal NMRI mice. [111In]DTPA-hEGF and [111In]Bz-DTPA-hEGF, obtained by the coupling of ITC-benzyl-DTPA to hEGF, were injected into the tail vein. At 0.5, 1, 4, and 24 hours postinjection, the animals were sacrificed, and radioactivity in different organs was measured. The blood clearance of both conjugates was fast. The uptake of both conjugates in the liver, spleen, stomach, pancreas, intestines, and submaxillary gland was most likely receptor-mediated. The uptake in a majority of organs was similar. However, indium uptake in the case of [111In]DTPA-hEGF was significantly higher in the kidneys and bones. In conclusion, [111In]Bz-DTPA-hEGF seems to have more favourable in vivo distribution in comparison to [111In]DTPA-hEGF.

  • 168.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rosik, Daniel
    Wållberg, Helena
    Sjöberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Hansson, Monika
    Wennborg, Anders
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Imaging of EGFR expression in murine xenografts using site-specifically labelled anti-EGFR In-111-DOTA-Z(EGFR:2377) Affibody molecule: aspect of the injected tracer amount2010Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, nr 3, s. 613-622Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Overexpression of epidermal growth factor receptor (EGFR) is a prognostic and predictive biomarker in a number of malignant tumours. Radionuclide molecular imaging of EGFR expression in cancer could influence patient management. However, EGFR expression in normal tissues might complicate in vivo imaging. The aim of this study was to evaluate if optimization of the injected protein dose might improve imaging of EGFR expression in tumours using a novel EGFR-targeting protein, the DOTA-Z(EGFR:2377) Affibody molecule. METHODS: An anti-EGFR Affibody molecule, Z(EGFR:2377), was labelled with (111)In via the DOTA chelator site-specifically conjugated to a C-terminal cysteine. The affinity of DOTA-Z(EGFR:2377) for murine and human EGFR was measured by surface plasmon resonance. The cellular processing of (111)In-DOTA-Z(EGFR:2377) was evaluated in vitro. The biodistribution of radiolabelled Affibody molecules injected in a broad range of injected Affibody protein doses was evaluated in mice bearing EGFR-expressing A431 xenografts. RESULTS: Site-specific coupling of DOTA provided a uniform conjugate possessing equal affinity for human and murine EGFR. The internalization of (111)In-DOTA-Z(EGFR:2377) by A431 cells was slow. In vivo, the conjugate accumulated specifically in xenografts and in EGFR-expressing tissues. The curve representing the dependence of tumour uptake on the injected Affibody protein dose was bell-shaped. The highest specific radioactivity (lowest injected protein dose) provided a suboptimal tumour-to-blood ratio. The results of the biodistribution study were confirmed by gamma-camera imaging. CONCLUSION: The (111)In-DOTA-Z(EGFR:2377) Affibody molecule is a promising tracer for radionuclide molecular imaging of EGFR expression in malignant tumours. Careful optimization of protein dose is required for high-contrast imaging of EGFR expression in vivo.

  • 169.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Stone-Elander, Sharon
    Radiolabelled proteins for positron emission tomography: pros and cons of labelling methods2010Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1800, nr 5, s. 487-510Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Dynamic biomedical research is currently yielding a wealth of information about disease-associated molecular alterations on cell surfaces and in the extracellular space. The ability to visualize and quantify these alterations in vivo could provide important diagnostic information and be used to guide individually-optimized therapy. Biotechnology can provide proteinaceous molecular probes with highly specific target recognitions. Suitably labelled, these may be used as tracers for radionuclide-based imaging of molecular disease signatures. If the labels are positron-emitting radionuclides, the superior resolution, sensitivity and quantification capability of positron emission tomography (PET) can be exploited.

    SCOPE OF REVIEW: This article discusses different approaches to labelling proteins with positron-emitting nuclides with suggestions made depending on the biological features of the tracers.

    MAJOR CONCLUSIONS: Factors such as matching biological and physical half-lives, availability of the nuclide, labelling yields, and influences of labelling on targeting properties (affinity, charge and lipophilicity, cellular processing and retention of catabolites) should be considered when selecting a labelling strategy for each proteinaceous tracer.

    GENERAL SIGNIFICANCE: The labelling strategy used can make all the difference between success and failure in a tracer application. This review emphasises chemical, biological and pharmacological considerations in labelling proteins with positron-emitting radionuclides.

  • 170.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Stone-Elander, Sharon
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Radiolabelled receptor-tyrosine-kinase targeting drugs for patient stratification and monitoring of therapy response: prospects and pitfalls2010Inngår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 11, nr 10, s. 992-1000Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Transmembrane receptor tyrosine kinases (RTKs) are overexpressed in many malignancies. RTK signalling triggers cell proliferation, suppression of apoptosis, increased motility, and recruitment of neovasculature. Overexpressed RTKs are the molecular targets for an increasing number of anticancer drugs. Monoclonal antibodies block the ligands or their binding sites and prevent receptor dimerisation, thereby hindering RTK signalling. The antibody-dependent cellular cytotoxicity can boost the therapeutic effect. Small-molecule tyrosine kinase inhibitors (TKIs) hamper downstream RTK signalling by targeting the intracellular kinase domain. These drugs have significantly increased survival in several patient groups. Improved patient stratification and therapy monitoring might further enhance the efficacy of anti-RTK therapy. Radionuclide-based molecular imaging can provide methods for localising and estimating the expression of RTKs. It can potentially identify patients who have tumours that overexpress RTK and would, therefore, most likely benefit from a targeted treatment. Monitoring changes in RTK expression during therapy could help avoid overtreatment and undertreatment. Radionuclide-based methods are less invasive and less sensitive to expression heterogeneity than more conventional sampling methods. The biochemical information is also obtained in an anatomical context. The development of radiolabelled anti-RTK drugs and their analogues is the subject of intensive preclinical and translational research. In this review, we present current approaches to developing imaging probes for in-vivo RTK visualisation and discuss their advantages and disadvantages.

  • 171.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Velikyan, Irina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Avdelningen för sjukhusfysik.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    A HER2-binding Affibody molecule labelled with 68Ga for PET imaging: direct in vivo comparison with the 111In-labelled analogue2010Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, nr 7, s. 1356-1367Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Overexpression of HER2 receptors is a prognostic and predictive biomarker in breast cancer and a number of other malignancies. Radionuclide molecular imaging of HER2 overexpression may influence patient management making treatment more personalized. Earlier, (111)In-DOTA-Z(HER2:342-pep2) (ABY-002) Affibody molecule demonstrated excellent imaging of HER2-expressing xenografts in mice shortly after injection. The use of the positron-emitting nuclide (68)Ga instead of (111)In might increase both the sensitivity of HER2 imaging and accuracy of expression quantification. The goal of this study was to prepare and characterize (68)Ga-labelled ABY-002. METHODS: (68)Ga labelling of ABY-002 was optimized. In vitro cell binding and procession of (68)Ga-ABY-002 was evaluated. Biodistribution and tumour targeting of (68)Ga-ABY-002 and (111)In-ABY-002 was compared in vivo by paired-label experiments. RESULTS: ABY-002 was incubated with (68)Ga at 90 degrees C for 10 min resulting in a radiochemical labelling yield of over 95%. Capacity for specific binding to HER2-expressing cells was retained. In vivo, both (68)Ga-ABY-002 and (111)In-ABY-002 demonstrated specific targeting of SKOV-3 xenografts and high-contrast imaging. Background radioactivity in blood, lungs, gastrointestinal tract and muscle fell more rapidly for (68)Ga-ABY-002 compared with (111)In-ABY-002 favouring imaging shortly after injection. For (68)Ga-ABY-002, a tumour uptake of 12.4 +/- 3.8%ID/g and a tumour to blood ratio of 31 +/- 13 were achieved at 2 h post-injection. CONCLUSION: (68)Ga-ABY-002 is easy to label and provides high-contrast imaging within 2 h after injection. This makes it a promising candidate for clinical molecular imaging of HER2 expression in malignant tumours.

  • 172.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wallberg, Helena
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Wennborg, Anders
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    The influence of Bz-DOTA and CHX-AaEuro(3)-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules: implications for In-114m-mediated targeting therapy2009Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 36, nr 9, s. 1460-1468Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules represent a novel class of high-affinity agents for radionuclide tumour targeting. Fusion of the Affibody molecules with an albumin-binding domain (ABD) enables modification of the blood kinetics of the Affibody molecules and reduction of the renal dose. Lu-177-CHX-AaEuro(3)-DTPA-ABD-(Z(HER2:342))(2), an anti-HER2 Affibody molecule-ABD fusion protein has earlier demonstrated promising results in treatment of HER2-expressing micro-xenografts in mice. The use of the in vivo generator In-114m/In-114 as a label for ABD-fused Affibody molecules would create preconditions for efficient treatment of both micrometastases (due to conversion and Auger electrons of In-114m) and bulky tumours (due to high-energy beta particles from the daughter nuclide In-114). The goal of this study was to investigate if different chelators influence the biodistribution of ABD-(Z(HER2:342))(2) and to find an optimal chelator for attachment of In-114m to the Affibody molecule-ABD fusion protein. Isothiocyanate derivatives of Bz-DOTA and CHX-AaEuro(3)-DTPA were coupled to ABD-(Z(HER2:342))(2). The cellular processing of both conjugates was studied in vitro. The influence of chelators on the biodistribution was investigated in mice using double isotope (In-114m and In-111) labelling. The apparent affinity of CHX-AaEuro(3)-DTPA-ABD-(Z(HER2:342))(2) and Bz-DOTA-ABD-(Z(HER2:342))(2) to the extracellular domain of HER2 was similar, 13.5 and 15.0 pM, respectively. It was found that both conjugates were internalized by SKOV-3 cells. The use of CHX-AaEuro(3)-DTPA provided better cellular retention of the radioactivity, better tumour accumulation of radioactivity and better tumour to organ dose ratios than Bz-DOTA-ABD-(Z(HER2:342))(2). CHX-AaEuro(3)-DTPA is more suitable for In-114m labelling of Affibody molecule-ABD fusion proteins for radionuclide therapy.

  • 173.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Wallberg, Helena
    Feldwisch, Joachim
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    HER2 targeting with Tc-99m-labeled second generation synthetic Affibody molecule2010Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, nr 6, s. 705-706Artikkel i tidsskrift (Annet vitenskapelig)
  • 174.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi.
    Winberg, KJ
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi.
    Persson, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sjöberg, S
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi.
    [76Br] p-isothiocycnatobenzyl-undecahydro-bromo-7,8-dicarba-nido-undecaborate (-1) (Br-NBI): preparation and use for labelling of monoclonal antibody2002Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 29, nr Suppl. 1, s. S375-S375Artikkel, omtale (Annet vitenskapelig)
  • 175.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Xu, Heng
    Wållberg, Helena
    KTH, Sthlm.
    Ahlgren, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Hjertman, Magnus
    Sjöberg, Anna
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Abrahmsén, Lars
    Affibody AB.
    Brechbiel, Martin W.
    NCI-NIH, USA.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Evaluation of a maleimido derivative of CHX-A'' DTPA for site-specific labeling of affibody molecules2008Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, nr 8, s. 1579-1587Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are a new class of small targeting proteins based on a common three-helix bundle structure. Affibody molecules binding a desired target may be selected using phage-display technology. An Affibody molecule Z HER2:342 binding with subnanomolar affinity to the tumor antigen HER2 has recently been developed for radionuclide imaging in vivo. Introduction of a single cysteine into the cysteine-free Affibody scaffold provides a unique thiol group for site-specific labeling of recombinant Affibody molecules. The recently developed maleimido-CHX-A'' DTPA was site-specifically conjugated at the C-terminal cysteine of Z HER2:2395-C, a variant of Z HER2:342, providing a homogeneous conjugate with a dissociation constant of 56 pM. The yield of labeling with (111)In was >99% after 10 min at room temperature. In vitro cell tests demonstrated specific binding of (111)In-CHX-A'' DTPA-Z 2395-C to HER2-expressing cell-line SKOV-3 and good cellular retention of radioactivity. In normal mice, the conjugate demonstrated rapid clearance from all nonspecific organs except kidney. In mice bearing SKOV-3 xenografts, the tumor uptake of (111)In-CHX-A'' DTPA-Z 2395-C was 17.3 +/- 4.8% IA/g and the tumor-to-blood ratio 86 +/- 46 (4 h postinjection). HER2-expressing xenografts were clearly visualized 1 h postinjection. In conclusion, coupling of maleimido-CHX-A'' DTPA to cysteine-containing Affibody molecules provides a well-defined uniform conjugate, which can be rapidly labeled at room temperature and provides high-contrast imaging of molecular targets in vivo.

  • 176.
    Tran, Thuy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Molecular Imaging of HER2 Expression using Synthetic Affibody Molecules: Design, Synthesis and Biological Evaluation2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Molecular imaging is an emerging multidisciplinary field that addresses the visualisation of diseases at the cellular and molecular levels. This thesis focuses on the development of a synthetic Affibody molecule-based imaging tracer for the detection of HER2 expression in malignant tumours.

    Papers I-IV report the development of the HER2-specific Affibody molecule, ZHER2:342 by peptide synthesis and the use of different chelators attached to the N-terminus to allow 99mTc-labelling. Paper I described the optimisation of labelling of Affibody molecules using cysteine-based chelator sequences, in which the direct labelling method under alkaline conditions was the most suitable one. Papers II-IV report the development and optimisation of the in vivo properties of the HER2-specific Affibody molecule for high-contrast imaging. By using an array of mercaptoacetyl-based chelators, it was found that the substitution of a single amino acid in a 60 amino acid-long Affibody molecule can dramatically change the pharmacokinetics of the tracer. Strategic approaches that utilised hydrophilic amino acids, such as serine, glutamate and lysine, changed the excretion pathway from hepatobiliary to renal excretion. Problems with the high accumulation of radioactivity in the abdomen area and restricted imaging were resolved by the use of mercaptoacetyl-triglutamyl, maEEE or mercaptoacetyl-seryl-lysyl-seryl, maSKS chelators.

    Paper V reports the re-engineering of the HER2-specific Affibody molecule to provide a C-terminal SECG sequence using peptide synthesis. Incorporation of this sequence provided a multifunctional platform for labelling (with technetium or trivalent radiometals) and a flexible production route (recombinant or chemical synthesis). Combination of a serine, a glutamic acid and a thiol-bearing group in the chelating sequence reduced the renal accumulation of Affibody molecules.

    Altogether, the in vivo efficiency of Affibody molecules to target tumours and their biodistribution properties can be improved by strategic design and suitable chemistry. Hopefully, these observations will be applicable to other small peptide and protein scaffold-based tracers.

    Delarbeid
    1.
    Posten ble ikke funnet. Det kan skyldes at posten ikke lenger er tilgjengelig eller det er feil id i adressefeltet.
    2. 99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule
    Åpne denne publikasjonen i ny fane eller vindu >>99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule
    Vise andre…
    2007 (engelsk)Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 34, nr 11, s. 1843-1853Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    PURPOSE: Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z(HER2:342) binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z(HER2:342) with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with (99m)Tc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z(HER2:342) can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. METHODS: The Affibody molecule Z(HER2:342), carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D: -seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with (99m)Tc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of (99m)Tc-maSSS-Z(HER2:342) was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z(HER2:342). RESULTS: A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of (99m)Tc-maSSS-Z(HER2:342) was 11.5 +/- 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z(HER2:342) were better than those of radioiodinated Z(HER2:342). CONCLUSION: The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z(HER2:342) compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.

    Emneord
    Animals, Chelating Agents/chemistry, Drug Delivery Systems/*methods, Female, Metabolic Clearance Rate, Mice, Inbred BALB C, Mice, Nude, Organ Specificity, Ovarian Neoplasms/*metabolism/radionuclide imaging, Radiopharmaceuticals/chemistry/diagnostic use/pharmacokinetics, Recombinant Fusion Proteins/chemistry/diagnostic use/*pharmacokinetics, Technetium/chemistry/diagnostic use/*pharmacokinetics, Tissue Distribution
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-17041 (URN)10.1007/s00259-007-0474-6 (DOI)000250205400017 ()17565496 (PubMedID)
    Tilgjengelig fra: 2008-06-16 Laget: 2008-06-16 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    3. (99m)Tc-maEEE-Z(HER2:342), an Affibody molecule-based tracer for the detection of HER2 expression in malignant tumors
    Åpne denne publikasjonen i ny fane eller vindu >>(99m)Tc-maEEE-Z(HER2:342), an Affibody molecule-based tracer for the detection of HER2 expression in malignant tumors
    Vise andre…
    2007 (engelsk)Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 18, nr 6, s. 1956-1964Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Detection of HER2-overexpression in tumors and metastases is important for the selection of patients who will benefit from trastuzumab treatment. Earlier investigations showed successful imaging of HER2-positive tumors in patients using indium- or gallium-labeled Affibody molecules. The goal of this study was to evaluate the use of (99m)Tc-labeled Affibody molecules for the detection of HER2 expression. The Affibody molecule Z(HER2:342) with the chelator sequences mercaptoacetyl-Gly-Glu-Gly (maGEG) and mercaptoacetyl-Glu-Glu-Glu (maEEE) was synthesized by peptide synthesis and labeled with technetium-99m. Binding specificity, cellular retention, and in vitro stability were investigated. The biodistribution of (99m)Tc-maGEG-Z(HER2:342) and (99m)Tc-maEEE-Z(HER2:342) was compared with (99m)Tc-maGGG-Z(HER2:342) in normal mice, and the tumor targeting properties of (99m)Tc-maEEE-Z(HER2:342) were determined in SKOV-3 xenografted nude mice. The results showed that the Affibody molecules were efficiently labeled with technetium-99m. The labeled conjugates were highly stable in vitro with preserved HER2-binding capacity. The use of glutamic acid in the chelator sequences for (99m)Tc-labeling of Z(HER2:342) reduced the hepatobiliary excretion 3-fold with a single Gly-to-Glu substitution and 10-fold with three Gly-to-Glu substitutions. (99m)Tc-maEEE-Z(HER2:342) showed a receptor-specific tumor uptake of 7.9 +/- 1.0 %IA/g and a tumor-to-blood ratio of 38 at 4 h pi. Gamma-camera imaging with (99m)Tc-maEEE-Z(HER2:342) could detect HER2-expressing tumors in xenografts already at 1 h pi. It was concluded that peptide synthesis for the coupling of chelator sequences to Affibody molecules for (99m)Tc labeling is an efficient way to modify the in vivo kinetics. Increased hydrophilicity, combined with improved stability of the mercaptoacetyl-triglutamyl chelator, resulted in favorable biodistribution, making (99m)Tc-maEEE-Z(HER2:342) a promising tracer for clinical imaging of HER2 overexpression in tumors.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-17053 (URN)10.1021/bc7002617 (DOI)000251166400035 ()17944527 (PubMedID)
    Tilgjengelig fra: 2008-06-16 Laget: 2009-03-25 Sist oppdatert: 2018-06-26bibliografisk kontrollert
    4. Effects of lysine-containing mercaptoacetyl-based chelators on the biodistribution of 99mTc-labeled anti-HER2 Affibody molecules
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of lysine-containing mercaptoacetyl-based chelators on the biodistribution of 99mTc-labeled anti-HER2 Affibody molecules
    Vise andre…
    2008 (engelsk)Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, nr 12, s. 2568-2576Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The effects of polar (mercaptoacetyl-triseryl) and negatively charged (mercaptoacetyl-triglumatyl) chelators on the biodistribution of 99mTc-labeled anti-HER2 Affibody molecules were previously investigated. With glycine, serine, and glutamate, we demonstrated that substitution with a single amino acid in the chelator can significantly influence the biodistribution properties and the excretion pathways. Here, we have taken this investigation further, by analyzing the effects of introduction of a positive amino acid residue on the in vivo properties of the 99mTc-labeled Affibody molecule. The Affibody molecules with mercaptoacetyl-seryl-lysyl-seryl (maSKS) and mercaptoacetyl-trilysyl (maKKK) extensions were produced by peptide synthesis and labeled with 99mTc in alkaline conditions. A comparative biodistribution was performed in normal mice to evaluate the excretion pathway. A shift toward renal excretion was obtained when serine was substituted with lysine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced 3-fold for the 99mTc-maSKS-Z(HER2:342) and 99mTc-maKKK-Z(HER2: 342) in comparison with the 99mTc-maSSS-Z(HER2:342) conjugate 4 h post injection (p.i.). The radioactivity in the liver was elevated when a triple substitution of positively charged lysine was used. The tumor targeting properties of 99mTc-maSKS-Z(HER2:342) were further investigated in SKOV-3 xenografts. The tumor uptake of 99mTc-maSKS-Z(HER2: 342) was 17+/-7% IA/g 4 h p.i. Tumor xenografts were well-visualized by gamma scintigraphy. In conclusion, the substitution with one single lysine in the chelator results in better tumor imaging properties of the Affibody molecule Z(HER2:342) and is favorable for imaging of tumors and metastases in the abdominal area. Multiple lysine residues in the chelator are, however, undesirable due to elevated uptake both in the liver and kidneys.

    Emneord
    peptide synthesis, imaging, affibody, HER2, technetium, radionuclides, chelator
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-98942 (URN)10.1021/bc800244b (DOI)000261767800036 ()19035668 (PubMedID)
    Tilgjengelig fra: 2009-03-05 Laget: 2009-03-05 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    5. Design, synthesis and biological evaluation of a multifunctional HER2-specific Affibody molecule for molecular imaging
    Åpne denne publikasjonen i ny fane eller vindu >>Design, synthesis and biological evaluation of a multifunctional HER2-specific Affibody molecule for molecular imaging
    Vise andre…
    2009 (engelsk)Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 36, nr 11, s. 1864-1873Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

     Purpose: The purpose of this study was to design and evaluate a novel platform for labelling of Affibody molecules, enabling for both recombinant and synthetic production and for site-specific labelling with 99mTc or trivalent radiometals.

    Methods: The HER2-specific Affibody molecule PEP05352 was made by peptide synthesis. The chelator sequence SECG (serine-glutamic acid-cysteine-glycine) was anchored on the C-terminal to allow 99mTc-labelling. The cysteine can alternatively serve as a conjugation site of the chelator DOTA for indium-labelling. The resulting 99mTc- and 111In-labelled Affibody molecules were evaluated both in vitro and in vivo.

    Results: Both conjugates retained their capacity to bind to HER2 receptors in vitro and in vivo. The tumour-to-blood ratio in LS174T xenografts was 30 at 4 h p.i. for both conjugates. Biodistribution data showed that 99mTc-labelled Affibody molecule had 4-fold lower kidney accumulation compared with 111In-labelled Affibody molecule while the accumulation in other organs was similar. Gamma-camera imaging of the conjugates could clearly visualise the tumours 4 h after injection.

    Conclusions: Incorporation of C-terminal SECG sequence in Affibody molecules provides a general multifunctional platform for site-specific labelling with different nuclides (technetium, indium, gallium, cobalt, or yttrium) and for a flexible production (chemical synthesis or recombinant).

     

    Emneord
    HER2, Affibody molecules, peptide synthesis, imaging, chelator, technetium, indium, SPECT
    HSV kategori
    Forskningsprogram
    Biomedicinsk strålningsvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-99910 (URN)10.1007/s00259-009-1176-z (DOI)000270980400017 ()
    Tilgjengelig fra: 2009-03-23 Laget: 2009-03-23 Sist oppdatert: 2017-12-13bibliografisk kontrollert
  • 177.
    Tran, Thuy A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Rosik, Daniel
    Abrahmsén, Lars
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Sjöberg, Anna
    Wållberg, Helena
    Ahlgren, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Design, synthesis and biological evaluation of a multifunctional HER2-specific Affibody molecule for molecular imaging2009Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 36, nr 11, s. 1864-1873Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

     Purpose: The purpose of this study was to design and evaluate a novel platform for labelling of Affibody molecules, enabling for both recombinant and synthetic production and for site-specific labelling with 99mTc or trivalent radiometals.

    Methods: The HER2-specific Affibody molecule PEP05352 was made by peptide synthesis. The chelator sequence SECG (serine-glutamic acid-cysteine-glycine) was anchored on the C-terminal to allow 99mTc-labelling. The cysteine can alternatively serve as a conjugation site of the chelator DOTA for indium-labelling. The resulting 99mTc- and 111In-labelled Affibody molecules were evaluated both in vitro and in vivo.

    Results: Both conjugates retained their capacity to bind to HER2 receptors in vitro and in vivo. The tumour-to-blood ratio in LS174T xenografts was 30 at 4 h p.i. for both conjugates. Biodistribution data showed that 99mTc-labelled Affibody molecule had 4-fold lower kidney accumulation compared with 111In-labelled Affibody molecule while the accumulation in other organs was similar. Gamma-camera imaging of the conjugates could clearly visualise the tumours 4 h after injection.

    Conclusions: Incorporation of C-terminal SECG sequence in Affibody molecules provides a general multifunctional platform for site-specific labelling with different nuclides (technetium, indium, gallium, cobalt, or yttrium) and for a flexible production (chemical synthesis or recombinant).

     

  • 178.
    Tran, Thuy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Ekblad, Torun
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Feldwisch, Joachim
    Wennborg, Anders
    Abrahmsén, Lars
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eriksson Karlström, Amelie
    Effects of lysine-containing mercaptoacetyl-based chelators on the biodistribution of 99mTc-labeled anti-HER2 Affibody molecules2008Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, nr 12, s. 2568-2576Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effects of polar (mercaptoacetyl-triseryl) and negatively charged (mercaptoacetyl-triglumatyl) chelators on the biodistribution of 99mTc-labeled anti-HER2 Affibody molecules were previously investigated. With glycine, serine, and glutamate, we demonstrated that substitution with a single amino acid in the chelator can significantly influence the biodistribution properties and the excretion pathways. Here, we have taken this investigation further, by analyzing the effects of introduction of a positive amino acid residue on the in vivo properties of the 99mTc-labeled Affibody molecule. The Affibody molecules with mercaptoacetyl-seryl-lysyl-seryl (maSKS) and mercaptoacetyl-trilysyl (maKKK) extensions were produced by peptide synthesis and labeled with 99mTc in alkaline conditions. A comparative biodistribution was performed in normal mice to evaluate the excretion pathway. A shift toward renal excretion was obtained when serine was substituted with lysine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced 3-fold for the 99mTc-maSKS-Z(HER2:342) and 99mTc-maKKK-Z(HER2: 342) in comparison with the 99mTc-maSSS-Z(HER2:342) conjugate 4 h post injection (p.i.). The radioactivity in the liver was elevated when a triple substitution of positively charged lysine was used. The tumor targeting properties of 99mTc-maSKS-Z(HER2:342) were further investigated in SKOV-3 xenografts. The tumor uptake of 99mTc-maSKS-Z(HER2: 342) was 17+/-7% IA/g 4 h p.i. Tumor xenografts were well-visualized by gamma scintigraphy. In conclusion, the substitution with one single lysine in the chelator results in better tumor imaging properties of the Affibody molecule Z(HER2:342) and is favorable for imaging of tumors and metastases in the abdominal area. Multiple lysine residues in the chelator are, however, undesirable due to elevated uptake both in the liver and kidneys.

  • 179.
    Tran, Thuy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Engfeldt, Torun
    School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Abrahmsén, Lars
    Wennborg, Anders
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlström, Amelie Eriksson
    School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden.
    (99m)Tc-maEEE-Z(HER2:342), an Affibody molecule-based tracer for the detection of HER2 expression in malignant tumors2007Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 18, nr 6, s. 1956-1964Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Detection of HER2-overexpression in tumors and metastases is important for the selection of patients who will benefit from trastuzumab treatment. Earlier investigations showed successful imaging of HER2-positive tumors in patients using indium- or gallium-labeled Affibody molecules. The goal of this study was to evaluate the use of (99m)Tc-labeled Affibody molecules for the detection of HER2 expression. The Affibody molecule Z(HER2:342) with the chelator sequences mercaptoacetyl-Gly-Glu-Gly (maGEG) and mercaptoacetyl-Glu-Glu-Glu (maEEE) was synthesized by peptide synthesis and labeled with technetium-99m. Binding specificity, cellular retention, and in vitro stability were investigated. The biodistribution of (99m)Tc-maGEG-Z(HER2:342) and (99m)Tc-maEEE-Z(HER2:342) was compared with (99m)Tc-maGGG-Z(HER2:342) in normal mice, and the tumor targeting properties of (99m)Tc-maEEE-Z(HER2:342) were determined in SKOV-3 xenografted nude mice. The results showed that the Affibody molecules were efficiently labeled with technetium-99m. The labeled conjugates were highly stable in vitro with preserved HER2-binding capacity. The use of glutamic acid in the chelator sequences for (99m)Tc-labeling of Z(HER2:342) reduced the hepatobiliary excretion 3-fold with a single Gly-to-Glu substitution and 10-fold with three Gly-to-Glu substitutions. (99m)Tc-maEEE-Z(HER2:342) showed a receptor-specific tumor uptake of 7.9 +/- 1.0 %IA/g and a tumor-to-blood ratio of 38 at 4 h pi. Gamma-camera imaging with (99m)Tc-maEEE-Z(HER2:342) could detect HER2-expressing tumors in xenografts already at 1 h pi. It was concluded that peptide synthesis for the coupling of chelator sequences to Affibody molecules for (99m)Tc labeling is an efficient way to modify the in vivo kinetics. Increased hydrophilicity, combined with improved stability of the mercaptoacetyl-triglutamyl chelator, resulted in favorable biodistribution, making (99m)Tc-maEEE-Z(HER2:342) a promising tracer for clinical imaging of HER2 overexpression in tumors.

  • 180.
    Tran, Thuy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sivaev, Igor
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Avdelningen för sjukhusfysik.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Comparison of benzoate- and dodecaborate-based linkers for attachment of radioiodine to HER2-targeting Affibody ligand2007Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 19, nr 3, s. 485-493Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The use of radionuclide molecular imaging enables the selection of patients for treatment using molecular medicine. Preclinical studies have demonstrated that a novel low-molecular-weight affinity ligand, Affibody molecule Z(HER2:342) can image the expression of HER2 with high sensitivity and specificity in tumour xenografts and has a potential for the selection of patients for treatment using Herceptin or other anti-HER2 medicine. In this study, we performed a comparative evaluation of two possible linkers for radioiodination of the Affibody molecule Z(HER2:342), 4-iodobenzoate (PIB) and [4-isothiocyanatobenzyl)-amino]-undecahydro-closo-dodecaborate (DABI). It was shown that the use of DABI makes it possible to obtain radioiodinated Z(HER2:342) with preserved capacity for selective binding to HER2-expressing cells. There was no difference between 125I-PIB-Z(HER2:342) and 125I-DABI-Z(HER2:342) in cellular retention of radioactivity after interrupted incubation with radiolabelled Affibody ligands. In vivo, the biodistribution of 125I-PIB-Z(HER2:342) was characterized by a high tumour uptake at 4 h pi (12.7+/-4.6% IA/g) and a quick clearance from blood and normal organs. The tumour uptake of 125I-DABI-Z(HER2:342) was appreciably lower (2.7+/-1.2% IA/g), and a high uptake of this conjugate in the liver was observed. A gamma-camera experiment (at 6 h pi) demonstrated that the use of 125I-PIB-Z(HER2:342) provided a much better contrast of imaging HER2-expressing xenografts than the use of 125I-DABI-Z(HER2:342). In conclusion, 125I-PIB-Z(HER2:342) is superior to 125I-DABI-Z(HER2:342) as an agent for imaging HER2 expression in vivo.

  • 181.
    Velikyan, Irina
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Liljegren Sundberg, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Lindhe, Örjan
    Höglund, A Urban
    Eriksson, Olof
    Werner, Eva
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Bergström, Mats
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Preparation and evaluation of (68)Ga-DOTA-hEGF for visualisation of EGFR expression in malignant tumours2005Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 46, nr 11, s. 1881-1888Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides important diagnostic information, which can influence patient management. The use of PET may enable such detection in vivo by a noninvasive procedure with high sensitivity. The aim of this study was to develop a method for preparation of a positron-emitting tracer based on a natural ligand to EGFR, the recombinant human epidermal growth factor (hEGF), and to perform a preclinical evaluation of the tracer.

    METHODS: DOTA-hEGF (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) was prepared by coupling of a N-sulfosuccinimide ester of DOTA to hEGF. The conjugate was labeled with a generator-produced positron-emitting nuclide, (68)Ga (half-life = 68 min), using microwave heating. Binding specificity, affinity, internalization, and retention of (68)Ga-DOTA-hEGF was studied in 2 EGFR-expressing cell lines, U343 glioma cells and A431 cervical carcinoma cells. Biodistribution and microPET visualization studies were performed in BALB/c nu/nu mice bearing A431 carcinoma xenografts.

    RESULTS: A 1-min-long microwave-assisted labeling provided radioactivity incorporation of 77% +/- 4%. Both cell lines demonstrated receptor-specific uptake of the conjugate, rapid internalization of the tracer, and good retention of radioactivity. Binding to both cell lines occurred with high affinity, approximately 2 nmol/L. The biodistribution study demonstrated accumulation of radioactivity in xenografts and in EGFR-expressing organs. The microPET imaging study enabled visualization of tumors and demonstrated quick--within 5 min--localization of radioactivity in tumors.

    CONCLUSION: (68)Ga-DOTA-hEGF has potential for imaging EGFR overexpression in tumors.

  • 182.
    Vennström, Lina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Bysell, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Björkelund, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Lundqvist, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Real-time viability assay based on 51Cr retention in adherent cells2008Inngår i: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 44, nr 2, s. 237-240Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The chromium (51Cr) release assay has been widely used for viability measurements, even though it has major disadvantages such as high manual workload and poor time resolution. By the use of LigandTracer 51Cr release viability measurements on adherent cells can be significantly simplified and improved. LigandTracer enables a time-resolved detection of 5SCr in target cells, with the result that the effect of toxic material is updated continuously throughout the experiment. Here we explain the principle behind this novel real-time viability assay and show viability curves for known toxic compounds on A431 and U343MGaCl2:6 cell lines.

  • 183. Waldeland, Einar
    et al.
    Hole, Eli Olaug
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Avdelningen för sjukhusfysik.
    Sagstuen, Einar
    Malinen, Eirik
    Radical formation in lithium formate EPR dosimeters after irradiation with protons and nitrogen ions2010Inngår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 174, nr 2, s. 251-257Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radical formation in polycrystalline lithium formate monohydrate after irradiation with gamma rays, protons and nitrogen ions at room temperature was studied by continuous-wave electron paramagnetic resonance (EPR) spectroscopy. The linear energy transfer (LET) of the various radiation beams was 0.2, 0.7-3.9 and 110-164 keV/microm for gamma rays, protons and nitrogen ions, respectively. Doses between 5 and 20 Gy were given. The EPR reading (the area under the EPR absorption resonance) increased linearly with dose for all types of radiation. As the LET increased, the relative effectiveness (the EPR reading per dose relative to that for gamma rays) decreased, while the EPR line width increased. Track structure theory and modeling of detector effectiveness predicted the dosimeter response observed after proton and nitrogen-ion irradiation. A semi-empirical line broadening model including dipolar spin-spin interactions was developed that explained the dependence of the line width on LET. The findings indicate that the local radical density in lithium formate is increased after high-LET irradiation.

  • 184.
    Wei, Q.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Shui, Y.
    Zheng, S.
    Wester, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Nordgren, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    EGFR, HER2 and HER3 expression in primary colorectal carcinomas and corresponding metastases: Implications for targeted radionuclide therapy2011Inngår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 25, nr 1, s. 3-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Members of the epidermal growth factor receptor, EGER, family are interesting as targets for radionuclide therapy using targeting agents labeled with alpha- or beta-emitting radionuclides, especially when EGFR-positive colorectal carcinomas, CRC, are resistant to EGFR inhibiting agents like cetuximab and various tyrosine kinase inhibitors. The expression of EGFR, HER2 and HER3 was therefore analyzed in CRC samples from primary tumors, corresponding lymph node metastases and, in a few cases, liver metastases. The expression of HER2 and EGFR was scored from immunohistochemical preparations using the HercepTest criteria 0, 1+, 2+ or 3+ for cellular membrane staining while HER3 expression was scored as no, weak or strong cytoplasm staining. Material from 60 patients was analyzed. The number of EGFR 2+ or 3+ positive primary tumors was 16 out of 56 (29%) and for lymph node metastases 8 out of 56 (14%) whereas only one out of nine (11%) liver metastases were positive. Thus, there was lower EGFR positivity in the metastases. Only one among 53 patients was strongly HER2 positive and this in both the primary tumor and the metastasis. Eight out of 49 primary tumors (16%) were strongly HER3 positive and the corresponding numbers for lymph node metastases were 9 out of 49 (18%) and for liver metastases 2 out of 9 (22%). The observed number of strongly EGFR positive cases was somewhat low but EGFR might be, for the cases with high EGFR expression in metastases, a target for radionuclide therapy. HER2 seems not to be of such interest due to rare expression, neither HER3 due to mainly expression in the cytoplasm. The requirements for successful EGFR targeted radionuclide therapy are discussed, as well as patient inclusion criteria related to radionuclide therapy.

  • 185.
    Wei, Qichun
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Chen, Lirong
    Sheng, Liming
    Nordgren, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wester, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    EGFR, HER2 and HER3 expression in esophageal primary tumours and corresponding metastases2007Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 31, nr 3, s. 493-499Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The expression of EGFR, HER2 and HER3 receptors were analyzed in immunohistochemical preparations from primary esophageal tumours and corresponding lymph node metastases. The goal was to evaluate whether any of these receptors are suitable as targets for radionuclide based imaging and therapy. The receptor expressions were evaluated in parallel samples, primary tumour and metastasiis, from each patient (n = 51). The majority of the cases were esophageal squamous cell carcinomas, ESCC, (n = 40). The HercepTest scoring was used for the analysis of both HER2 and EGFR expression (0, 1+, 2+ or 3+). HER3 was only evaluated as negative, weak or strong staining. EGFR overexpression (2+/3+) was found in 67.5 % (27/40) of both the ESCC primary tumours and the corresponding lymph node metastases. There were only a few changes in these EGFR-scores;: two cases from 2+/3+ to 0/1+ when the primary tumours were compared to the corresponding metastases and two changes the other way around. HER2 overexpression (2+/3+) was only found only in 3three of the primary ESCC tumours and 2two of the lymph node metastases. EGFR and HER2 stainings were found mainly in the cell membranes. The HER3 staining (weak or strong) was mainly cytoplasmic and granular and was observed in about half (20/39) of the cases, for both the ESCC primary tumours and the corresponding lymph node metastases. It is was concluded that ESCC lymph node metastases generally have a strong expression of EGFR stronglyin their cell membranes and to the same extent as in the primary tumours. The stability in EGFR expression is encouraging for efforts to develop radionuclide based EGFR imaging agents. It is also possible that EGFR targeting agents (e.g. Iressa, Tarceva, Erbitux or radiolabelled antibodies) can be applied for therapy of ESCC.

  • 186.
    Wei, Qichun
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Sheng, Liming
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Shui, Yongjie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för klinisk immunologi och transfusionsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Hu, Qiongge
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Nordgren, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    EGFR, HER2, and HER3 expression in laryngeal primary tumors and corresponding metastases2008Inngår i: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 15, nr 4, s. 1193-1201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: There are several substances available to target members of the epidermal growth factor receptor (EGFR) family, both for imaging in nuclear medicine and for various forms of therapy. The level and stability of expression in both primary tumors and corresponding metastases is crucial in the assessment of a receptor as a target in systemic tumor therapy. To date, the expression of EGFR family members has only been determined in primary laryngeal carcinomas, and we have not found published data regarding the receptor status in corresponding metastatic lesions. METHODS: Expression of EGFR, HER2, and HER3 was investigated immunohistochemically in both lymph node metastases and corresponding primary laryngeal squamous carcinomas (n = 40). RESULTS: EGFR overexpression (2+ or 3+) was found in 87.5% (35/40) of the laryngeal primary tumors and 82.5% (33/40) of the corresponding lymph node metastases. There was a good agreement between the primary tumors and the paired metastases regarding EGFR expression. HER2 overexpression was found in only four cases (10.5%) of the studied primary tumors and in all cases the HER2 expression was retained in the paired metastases. Another two metastases gained HER2 status when compared to the corresponding primary tumors. Strong HER3 staining was found in 26.7% of both the primary tumors and the corresponding metastases. CONCLUSIONS: The high frequency and stability in EGFR expression is encouraging for efforts to use EGFR targeting agents (e.g. Iressa, Tarceva, Erbitux or radiolabeled antibodies) for therapy of laryngeal carcinoma. For a few laryngeal carcinoma patients with HER2 overexpression, anti-HER2 agents could possibly be used.

  • 187.
    Wester, Kenneth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Sjöström, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    de la Torre, Manuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Malmström, Per-Uno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    HER-2: A possible target for therapy of metastatic urinary bladder carcinoma2002Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 41, nr 3, s. 282-288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human epidermal growth factor receptor 2, HER-2, is overexpressed in various tumours, e.g. breast- and bladder tumours. The aim of this study was to predict the potential use of HER-2 receptors as targets in systemic treatment of disseminated bladder tumours. HER-2 expression was assessed in bladder carcinoma metastases and the corresponding primary tumours, and subsequently compared with the EGFR expression. HER-2 and EGFR expression was analysed by immunohistochemistry in formalin-fixed, paraffin-embedded tissues from 21 patients with metastatic bladder carcinoma. HER-2 was overexpressed in 81% of the primary tumours and in 67% of the metastases. All HER-2-positive metastases were from HER-2-positive primary tumours. The results for EG FR were 71% of both primary and metastases-positive tumours. In 90% of the primary tumours and 86% of the metastases, at least one of the receptors was overexpressed. These results suggest that HER-2 targeted therapy can be considered as an alternative or a complement to other modalities in the treatment of metastatic urinary bladder carcinoma.

  • 188.
    Westlin, Jan-Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Ylä-Jääski, J
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nilsson, Sten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Three-dimensional OctreoScan111 SPECT of abdominal manifestation of neuroendocrine tumours1993Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 32, nr 2, s. 171-176Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the present study we have investigated the three-dimensional (3D) reconstruction of OctreoScan111 SPECT (single photon emission tomography) images in 20 patients with neuroendocrine tumours. All patients had at least 2 tumour lesions as assessed from computerized tomography (CT) and SPECT. The 3D rendering was performed using a software, which produces images by implementing direct rendering from voxels without an intermediate surface data structure. The software has options for a free choice of thresholding and possibilities of clipping in coronal, transversal and sagittal planes. The results obtained showed that 3D reconstruction with volume rendering (3Dvr) gave a superior topographical localization of tumour uptakes when compared with SPECT. The 3Dvr technique was also combined with transversal clipping in rendered volumes (3Dvr+c). The major advantage with the 3Dvr+c technique was found to be an improved visualization of anatomical references as well as improved diagnostic information in a particular, selected, transversal slice, thus facilitating the identification and comparison of individual tumour lesions.

  • 189.
    Westlin, Jan-Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Tiensuu Janson, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Arnberg, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nilsson, Sten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Somatostatin receptor scintigraphy of carcinoid tumours using the [111In-DTPA-D-Phe1]-octreotide1993Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 32, nr 7-8, s. 783-786Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Somatostatin-receptor scintigraphy using the 111In-labelled somatostatin-analogue octreotide ([111In-DTPA-D-Phe1]-octreotide) was performed in 40 patients with carcinoid tumours. In 31/40 patients, this scintigraphy proved positive compared with the 33/40 patients whose tumours were disclosed on CT scans. In addition, 18 previously unidentified lesions were detected with this scintigraphy. Two of these lesions represented previously undetectable primary tumours. It is concluded that somatostatin receptor scintigraphy using [111In-DTPA-D-Phe1]-octreotide has a future role in the staging of patients with carcinoid disease.

  • 190. Wikman, Maria
    et al.
    Steffen, Ann-Charlott
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Gunneriusson, Elin
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Adams, Gregory P.
    Fox Chase Cancer Center.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Ståhl, Stefan
    Selection and characterization of HER2/neu-binding affibody ligands2004Inngår i: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 17, nr 5, s. 455-462Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody (affibody) ligands that are specific for the extracellular domain of human epidermal growth factor receptor 2 (HER2/neu) have been selected by phage display technology from a combinatorial protein library based on the 58 amino acid residue staphylococcal protein A-derived Z domain. The predominant variants from the phage selection were produced in Escherichia coli, purified by affinity chromatography, and characterized by biosensor analyses. Two affibody variants were shown to selectively bind to the extracellular domain of HER2/neu (HER2-ECD), but not to control proteins. One of the variants, denoted His6-ZHER2/neu:4, was demonstrated to bind with nanomolar affinity (approximately 50 nM) to the HER2-ECD molecule at a different site than the monoclonal antibody trastuzumab. Furthermore, radiolabeled His6-ZHER2/neu:4 affibody showed specific binding to native HER2/neu, overexpressed on the SKBR-3 tumor cell line. Such affibody ligands might be considered in tumor targeting applications for radionuclide diagnostics and therapy of adenocarcinomas such as breast and ovarian cancers.

  • 191.
    Winberg, Karl Johan
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi II.
    Persson, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Malmström, Per-Uno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Sjöberg, Stefan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi II.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Radiobromination of anti-HER2/neu/ErbB-2 monoclonal antibody using the p-isothiocyanatobenzene derivative of the [76Br]undecahydro-bromo-7,8-dicarba-nido-undecaborate(1-) ion2004Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 31, nr 4, s. 425-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The monoclonal humanized anti-HER2 antibody trastuzumab was radiolabeled with the positron emitter (76)Br (T(1/2) =16.2 h). Indirect labeling was performed using the p-isothiocyanatobenzene derivative of the [(76)Br]undecahydro-bromo-7,8-dicarba-nido-undecaborate(1-) ((76)Br-NBI) as a precursor molecule. (76)Br-NBI was prepared by bromination of the 7-(p-isothiocyanato-phenyl)dodecahydro-7,8-dicarba-nido-undecaborate(1-) ion (NBI) with a yield of 93-95% using Chloramine-T (CAT) as an oxidant. Coupling of radiobrominated NBI to antibody was performed without intermediate purification, in an "one pot" reaction. An overall labeling yield of 55.7 +/- 4.8% (mean +/- maximum error) was achieved when 300 microg of antibody was labeled. The label was stable in vitro in physiological and denaturing conditions. In a cell binding test, trastuzumab remained immunoreactive after labeling.

  • 192.
    Wu, Xuping
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Wanders, Alkwin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wardega, Piotr
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Tinge, B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Gedda, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Bergström, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Sooman, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Hesselius, P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Lennartsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Ekman, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin2009Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, nr 2, s. 334-343Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer. In squamous cell carcinoma, a marked upregulation of Hsp90 could be noted in dysplastic epithelium and invasive cancer compared with normal epithelium. In adenocarcinoma, Hsp90 was expressed in neoplastic epithelium and also in normal non-neoplastic glands weakly. The inhibition of Hsp90 using 17-AAG led to a significant decrease in cell proliferation and viability in human oesophageal cancer cell lines. Using a clonogenic cell survival assay, Hsp90 inhibition significantly sensitised the cells for gamma-photon irradiation. Heat shock protein 90 was found to be critical for proper signalling induced by both epidermal growth factor and insulin-like growthfactor -1, in which the inhibition of signalling by 17-AAG correlated with the observed reduction in cell proliferation and viability. These results showed that Hsp90 was selectively expressed in oesophageal cancer tissue compared with the corresponding normal tissue, and the inhibition of Hsp90 resulted in decreased proliferation and viability as well as radiosensitisation of oesophageal cancer cells. Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy.

  • 193.
    Wållberg, Helena
    et al.
    Affibody AB, Stockholm, Sweden.
    Ahlgren, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Widström, Charles
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Avdelningen för sjukhusfysik.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors2010Inngår i: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 12, nr 1, s. 54-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Imaging using positron emission tomography (PET) in the field of nuclear medicine is becoming increasingly important. The aim of this study was to develop a method for labeling of affibody molecules with radiocobalt for PET applications. PROCEDURES: The human epidermal growth factor receptors type 2 (HER2) binding affibody molecule DOTA-Z(2395)-C was radiolabeled with (57)Co (used as a surrogate of (55)Co). The binding specificity and cellular processing of the labeled compound was studied in vitro followed by in vivo characterization in normal and tumor-bearing mice. Furthermore, a comparative biodistribution study was performed with a (111)In-labeled counterpart. RESULTS: DOTA-Z(2395)-C was successfully labeled with radiocobalt with nearly quantitative yield. The compound displayed good retention on cells over time and high tumor accumulation of radioactivity in animal studies. Imaging studies showed clear visualization of HER2-positive tumors. Furthermore, the radiocobalt label provided better tumor-to-organ ratios than (111)In. CONCLUSIONS: Radiocobalt is a promising label for affibody molecules for future PET applications.

  • 194. Wållberg, Helena
    et al.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Slow internalization of anti-HER2 synthetic affibody monomer 111In-DOTA-ZHER2:342-pep2: implications for development of labeled tracers2008Inngår i: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 23, nr 4, s. 435-442Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are a novel class of targeting proteins, demonstrating promising results in the molecular imaging of tumor markers. The aim of this study was to investigate the cellular processing of Affibody molecules bound to human epidermal growth-factor-receptor type 2 (HER2). Cellular processing of the synthetic Affibody molecule, DOTA-Z(HER2:342-pep2) (K(D) = 65 (p)M) labeled with indium-111, was studied both during continuous and interrupted incubation with HER2-expressing cell lines (SKOV-3, SKBR-3, and BT474). The internalized and membrane bound fractions of Affibody molecule were discriminated by treatment with 4 M of urea solution in 0.2 M of glycine buffer (pH 2.0). Incubation media collected after an interrupted incubation was analyzed for the presence of radiocatabolites. Continuous incubation of tumor cells with (111)In-DOTA-Z(HER2:342-pep2) led to the saturation of HER2 and slow internalization. Sixty (60)- to 80% of the radioactivity remained cell associated 24 hours after interrupted incubation. The rate of Affibody molecule internalization was the same after interrupted incubation, as in the continuous incubation experiments. Internalization of (111) In-DOTA-Z(HER2:342-pep2) was relatively slow. A high level of cellular retention of the tracer was provided by strong binding to cell-surface receptors. These data suggest that good tumor targeting with anti-HER Affibody molecules may be obtained by using short-lived, nonresidualizing labels.

  • 195.
    Yngve, U
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Hedberg, E
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Synthesis of N-succinimidyl-4-76Br-bromobenzoate and its use in conjugation to proteins and 5´modified oligonucleotides1997Inngår i: Journal of Labelled Compounds and Radiopharmaceuticals, ISSN 0362-4803, Vol. 40, s. 120-121Artikkel i tidsskrift (Fagfellevurdert)
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