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  • 151.
    Orlova, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Andersson, K. G.
    Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Imaging contrast of HER3 expression using monomeric affibody-based imaging probe can be improved by co-injection of affibody trimer2018Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, nr Supplement 1, s. S673-S673Artikkel i tidsskrift (Annet vitenskapelig)
  • 152.
    Orlova, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Influence of chelators on targeting properties of In-111 and Ga-68 labeled GRPR antagonist2015Inngår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, s. S88-S88Artikkel i tidsskrift (Annet vitenskapelig)
  • 153.
    Oroujeni, Maryam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Abouzayed, Ayman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Lundmark, Fanny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Evaluation of Tumor-Targeting Properties of an Antagonistic Bombesin Analogue RM26 Conjugated with a Non-Residualizing Radioiodine Label Comparison with a Radiometal-Labelled Counterpart2019Inngår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, nr 8, artikkel-id 380Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radiolabelled antagonistic bombesin analogues are successfully used for targeting of gastrin-releasing peptide receptors (GRPR) that are overexpressed in prostate cancer. Internalization of antagonistic bombesin analogues is slow. We hypothesized that the use of a non-residualizing radioiodine label might not affect the tumour uptake but would reduce the retention in normal organs, where radiopharmaceutical would be internalized. To test this hypothesis, tyrosine was conjugated via diethylene glycol linker to N-terminus of an antagonistic bombesin analogue RM26 to form Tyr-PEG(2)-RM26. [In-111]In-DOTA-PEG(2)-RM26 was used as a control with a residualizing label. Tyr-PEG(2)-RM26 was labelled with I-125 with 95% radiochemical purity and retained binding specificity to GRPR. The IC50 values for Tyr-PEG(2)-RM26 and DOTA-PEG(2)-RM26 were 1.7 +/- 0.3 nM and 3.3 +/- 0.5 nM, respectively. The cellular processing of [I-125]I-Tyr-PEG(2)-RM26 by PC-3 cells showed unusually fast internalization. Biodistribution showed that uptake in pancreas and tumour was GRPR-specific for both radioconjugates. Blood clearance of [I-125]I-Tyr-PEG(2)-RM26 was appreciably slower and activity accumulation in all organs was significantly higher than for [In-111]In-DOTA-PEG(2)-RM26. Tumor uptake of [In-111]In-DOTA-PEG(2)-RM26 was significantly higher than for [I-125]I-Tyr-PEG(2)-RM26, resulting in higher tumour-to-organ ratio for [In-111]In-DOTA-PEG(2)-RM26 at studied time points. Incorporation of amino acids with hydrophilic side-chains next to tyrosine might overcome the problems associated with the use of tyrosine as a prosthetic group for radioiodination.

  • 154.
    Oroujeni, Maryam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Anderson, K. G.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Steinhardt, X.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Ståhl, S.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Influence of composition of cysteine-containing peptide based chelators on biodistribution of Tc-99m-labelled anti-EGFR affibody molecules2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, s. S347-S348Artikkel i tidsskrift (Annet vitenskapelig)
  • 155.
    Oroujeni, Maryam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Andersson, K.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Imaging of EGFR Expression Using 99mTC-Labelled ZEGFR:2377 Affibody Molecule2016Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, s. S238-S238Artikkel i tidsskrift (Fagfellevurdert)
  • 156.
    Oroujeni, Maryam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Andersson, Ken G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Steinhardt, Xenia
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules2018Inngår i: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 50, nr 8, s. 981-994Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epidermal growth factor receptor (EGFR) is overexpressed in a number of cancers and is the molecular target for several anti-cancer therapeutics. Radionuclide molecular imaging of EGFR expression should enable personalization of anti-cancer treatment. Affibody molecule is a promising type of high-affinity imaging probes based on a non-immunoglobulin scaffold. A series of derivatives of the anti-EGFR affibody molecule ZEGFR:2377, having peptide-based cysteine-containing chelators for conjugation of Tc-99m, was designed and evaluated. It was found that glutamate-containing chelators Gly-Gly-Glu-Cys (GGEC), Gly-Glu-Glu-Cys (GEEC) and Glu-Glu-Glu-Cys (EEEC) provide the best labeling stability. The glutamate containing conjugates bound to EGFR-expressing cells specifically and with high affinity. Specific targeting of EGFR-expressing xenografts in mice was demonstrated. The number of glutamate residues in the chelator had strong influence on biodistribution of radiolabeled affibody molecules. Increase of glutamate content was associated with lower uptake in normal tissues. The Tc-99m-labeled variant containing the EEEC chelator provided the highest tumor-to-organ ratios. In conclusion, optimizing the composition of peptide-based chelators enhances contrast of imaging of EGFR-expression using affibody molecules.

  • 157.
    Oroujeni, Maryam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Andersson, K.
    Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    Royal Inst Technol, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala Univ, Uppsala, Sweden.
    Comparative evaluation of anti-EFGR affibody molecules labelled with gallium-68 and zirconium-89 using desferrioxamine B as a chelator2018Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, nr Supplement 1, s. S674-S675Artikkel i tidsskrift (Annet vitenskapelig)
  • 158.
    Oroujeni, Maryam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Andersson, Ken G.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Lofblom, John
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Preclinical Evaluation of [Ga-68]Ga-DFO-ZEGFR:2377: A Promising Affibody-Based Probe for Noninvasive PET Imaging of EGFR Expression in Tumors2018Inngår i: CELLS, E-ISSN 2073-4409, Vol. 7, nr 9, artikkel-id 141Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.

  • 159. Pater, P.
    et al.
    Backstrom, G.
    Enger, S.
    Villegas, Fernanda Navarro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Seuntjens, J.
    El Naqa, I.
    On the Value of LET as a Radiation Quality Descriptor for RBE2015Inngår i: Medical physics (Lancaster), ISSN 0094-2405, Vol. 42, nr 6, s. 3469-3469Artikkel i tidsskrift (Annet vitenskapelig)
  • 160. Pater, P.
    et al.
    Backstrom, G.
    Enger, S.
    Villegas, F.Fernanda Navarro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Seuntjens, J.
    El Naga, I.
    Influence of Proton Track-Cell Nucleus Incidence Angle On Relative Biological Effectiveness2015Inngår i: Medical physics (Lancaster), ISSN 0094-2405, Vol. 42, nr 6, s. 3448-3448Artikkel i tidsskrift (Annet vitenskapelig)
  • 161.
    Pater, Piotr
    et al.
    McGill Univ, Med Phys Unit, Montreal, PQ H4A 3J1, Canada..
    Backstom, Gloria
    McGill Univ, Med Phys Unit, Montreal, PQ H4A 3J1, Canada..
    Villegas, Fernanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Enger, Shirin A.
    McGill Univ, Med Phys Unit, Montreal, PQ H4A 3J1, Canada..
    Seuntjens, Jan
    McGill Univ, Med Phys Unit, Montreal, PQ H4A 3J1, Canada..
    El Naqa, Issam
    McGill Univ, Med Phys Unit, Montreal, PQ H4A 3J1, Canada..
    Proton and light ion RBE for the induction of direct DNA double strand breaks2016Inngår i: Medical physics (Lancaster), ISSN 0094-2405, Vol. 43, nr 5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To present and characterize a Monte Carlo (MC) tool for the simulation of the relative biological effectiveness for the induction of direct DNA double strand breaks (RBEDSBdirect) for protons and light ions. Methods: The MC tool uses a pregenerated event-by-event tracks library of protons and light ions that are overlaid on a cell nucleus model. The cell nucleus model is a cylindrical arrangement of nucleosome structures consisting of 198 DNA base pairs. An algorithm relying on k-dimensional trees and cylindrical symmetries is used to search coincidences of energy deposition sites with volumes corresponding to the sugar-phosphate backbone of the DNA molecule. Strand breaks (SBs) are scored when energy higher than a threshold is reached in these volumes. Based on the number of affected strands, they are categorized into either single strand break (SSB) or double strand break (DSB) lesions. The number of SBs composing each lesion (i.e., its size) is also recorded. RBEDSBdirect is obtained by taking the ratio of DSB yields of a given radiation field to a Co-60 field. The MC tool was used to obtain SSB yields, DSB yields, and RBEDSBdirect as a function of linear energy transfer (LET) for protons (H-1(+)), He-4(2+), Li-7(3+), and C-12(6+) ions. Results: For protons, the SSB yields decreased and the DSB yields increased with LET. At approximate to 24.5 keV mu m(-1), protons generated 15% more DSBs than 12C6+ ions. The RBEDSBdirect varied between 1.24 and 1.77 for proton fields between 8.5 and 30.2 keV mu m(-1), and it was higher for iso-LET ions with lowest atomic number. The SSB and DSB lesion sizes showed significant differences for all radiation fields. Generally, the yields of SSB lesions of sizes >= 2 and the yields of DSB lesions of sizes >= 3 increased with LET and increased for iso-LET ions of lower atomic number. On the other hand, the ratios of SSB to DSB lesions of sizes 2-4 did not show variability with LET nor projectile atomic number, suggesting that these metrics are independent of the radiation quality. Finally, a variance of up to 8% in the DSB yields was observed as a function of the particle incidence angle on the cell nucleus. This simulation effect is due to the preferential alignment of ion tracks with the DNA nucleosomes at specific angles. Conclusions: The MC tool can predict SSB and DSB yields for light ions of various LET and estimate RBEDSBdirect. In addition, it can calculate the frequencies of different DNA lesion sizes, which is of interest in the context of biologically relevant absolute dosimetry of particle beams.

  • 162.
    Persson, Emilia
    et al.
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Klinikgatan 5, S-22185 Lund, Sweden.;Lund Univ, Dept Med Phys, Malmo, Sweden..
    Gustafsson, Christian
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Klinikgatan 5, S-22185 Lund, Sweden.;Lund Univ, Dept Med Phys, Malmo, Sweden..
    Nordström, Fredrik
    Sahlgrens Univ Hosp, Dept Med Phys & Biomed Engn, Gothenburg, Sweden..
    Sohlin, Maja
    Sahlgrens Univ Hosp, Dept Med Phys & Biomed Engn, Gothenburg, Sweden..
    Gunnlaugsson, Adalsteinn
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Klinikgatan 5, S-22185 Lund, Sweden..
    Petruson, Karin
    Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden..
    Rintelä, Niina
    Karolinska Univ Hosp, Med Radiat Phys & Nucl Med, Stockholm, Sweden..
    Hed, Kristoffer
    Karolinska Univ Hosp, Med Radiat Phys & Nucl Med, Stockholm, Sweden..
    Blomqvist, Lennart
    Karolinska Univ Hosp, Dept Diagnost Radiol, Stockholm, Sweden.;Umea Univ, Dept Radiat Sci, Umea, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Zackrisson, Björn
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Nyholm, Tufve
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Umea Univ, Dept Radiat Sci, Umea, Sweden.
    Olsson, Lars E.
    Lund Univ, Dept Med Phys, Malmo, Sweden..
    Siversson, Carl
    Spectron Med AB, Helsingborg, Sweden..
    Jonsson, Joakim
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    MR-OPERA: A Multicenter/Multivendor Validation of Magnetic Resonance Imaging-Only Prostate Treatment Planning Using Synthetic Computed Tomography Images2017Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 99, nr 3, s. 692-700Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To validate the dosimetric accuracy and clinical robustness of a commercially available software for magnetic resonance (MR) to synthetic computed tomography (sCT) conversion, in an MR imaginge-only workflow for 170 prostate cancer patients.

    Methods and Materials: The 4 participating centers had MriPlanner (Spectronic Medical), an atlas-based sCT generation software, installed as a cloud-based service. A T2-weighted MR sequence, covering the body contour, was added to the clinical protocol. The MR images were sent from the MR scanner workstation to theMriPlanner platform. The sCT was automatically returned to the treatment planning system. Four MR scanners and 2 magnetic field strengths were included in the study. For each patient, a CT-treatment plan was created and approved according to clinical practice. The sCT was rigidly registered to the CT, and the clinical treatment plan was recalculated on the sCT. The dose distributions from the CT plan and the sCT plan were compared according to a set of dose-volume histogram parameters and gamma evaluation. Treatment techniques included volumetric modulated arc therapy, intensity modulated radiation therapy, and conventional treatment using 2 treatment planning systems and different dose calculation algorithms.

    Results: The overall (multicenter/multivendor) mean dose differences between sCT and CT dose distributions were below 0.3% for all evaluated organs and targets. Gamma evaluation showed a mean pass rate of 99.12% (0.63%, 1 SD) in the complete body volume and 99.97% (0.13%, 1 SD) in the planning target volume using a 2%/ 2-mm global gamma criteria.

    Conclusions: Results of the study show that the sCT conversion method can be used clinically, with minimal differences between sCT and CT dose distributions for target and relevant organs at risk. The small differences seen are consistent between centers, indicating that an MR imagingeonly workflow using MriPlanner is robust for a variety of field strengths, vendors, and treatment techniques.

  • 163.
    Philippot, Gaetan
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Sundell-Bergman, Synnöve
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Buratovic, Sonja
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice2019Inngår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 39, nr 4, s. 582-589Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radiological methods for screening, diagnostics and therapy are often used in healthcare; however, it has recently been reported that developmental exposure to low-dose ionizing radiation (IR) causes neurotoxicity. Environmental chemicals also have the potential to affect the developing brain and the concomitant effects caused by IR and chemicals are of high interest today. We therefore aim to investigate if low-dose IR can interact with the known neurotoxicant paraquat to induce neurotoxicity in the neonatal mouse model. Using the same model, we also aim to investigate if fractionated low-dose IR can be as neurotoxic as higher acute doses. Male mice were exposed to a single dose of paraquat (0.2 or 0.02 mg/kg) on postnatal day 10 and 11. Two hours following paraquat exposure, mice were whole body irradiated with 100 or 300 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2 and 3 months of age. Following behavioural testing, we evaluated striatal dopaminergic gene transcription. Animals co-exposed to IR and paraquat generally displayed altered spontaneous behaviour compared to controls and single agent exposed mice. Stronger effects by combined exposure were also observed on adult memory and learning. However, dopaminergic gene transcript levels remained unchanged by treatment. Co-exposure to low-dose IR and paraquat can interact to exacerbate neurotoxic effects and to impair cognitive function. Furthermore, fractionation of the radiation dose was observed to be as potent as higher acute exposure for induction of developmental neurotoxicity.

  • 164.
    Reijmar, Karin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Ridgeview Instruments AB, Skillsta 4, 740 20 Vänge, Sweden.
    Agmo Hernández, Víctor
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Characterizing and controlling the loading and release of cationic amphiphilic peptides onto and from PEG-stabilized lipodisks2016Inngår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 32, nr 46, s. 12091-12099Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies have identified PEG-stabilized lipid nanodisks (lipodisks) as promising carriers for cationic amphiphilic peptides with antimicrobial and anticancer activity. Using fluorimetric and nanogravimetric methods, we have in this work characterized the parameters describing and controlling the binding of three selected peptides (melittin, LL37, and magainin 2) onto lipodisks. It was found that the affinity of melittin for lipodisks is independent of the disk size and rim charge. On the other hand, the number of binding sites is strongly dependent on both parameters, with the highest loading being obtained for small disks with a negatively charged rim. An optimized composition of the lipodisks was utilized to study the loading of antimicrobial peptides magainin 2 and human LL37. It was observed that although magainin 2 can be loaded in large amounts, it is released very fast upon dilution, which limits future therapeutic applications. In contrast, LL37 can be loaded at relevant concentrations and the formulation is stable. This opens up for applications of LL37-loaded lipodisks as antibiotics and in anticancer treatments.

  • 165.
    Rinne, Sara S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Leitao, Charles Dahlsson
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Bass, Tarek Z.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Andersson, Ken G.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stahl, Stefan
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Lofblom, John
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Optimization of HER3 expression imaging using affibody molecules: Influence of chelator for labeling with indium-1112019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 655Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radionuclide molecular imaging of human epidermal growth factor receptor 3 (HER3) expression using affibody molecules could be used for patient stratification for HER3-targeted cancer therapeutics. We hypothesized that the properties of HER3-targeting affibody molecules might be improved through modification of the radiometal-chelator complex. Macrocyclic chelators NOTA (1,4,7-triazacyclononane-N,N',N ''-triacetic acid), NODAGA (1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid), and DOTAGA (1,4,7,10-tetraazacyclododececane, 1-(glutaric acid)-4,7,10-triacetic acid) were conjugated to the C-terminus of anti-HER3 affibody molecule Z(08698) and conjugates were labeled with indium-111. All conjugates bound specifically and with picomolar affinity to HER3 in vitro. In mice bearing HER3-expressing xenografts, no significant difference in tumor uptake between the conjugates was observed. Presence of the negatively charged In-111-DOTAGA-complex resulted in the lowest hepatic uptake and the highest tumor-to-liver ratio. In conclusion, the choice of chelator influences the biodistribution of indium-111 labeled anti-HER3 affibody molecules. Hepatic uptake of anti-HER3 affibody molecules could be reduced by the increase of negative charge of the radiometal-chelator complex on the C-terminus without significantly influencing the tumor uptake.

  • 166.
    Rinne, Sara S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Leitao, C. Dahlsson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Ståhl, S.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Optimization of affibody molecule for imaging of HER3 expression: negatively charged metal-chelator complex increases imaging contrast2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, s. S539-S540Artikkel i tidsskrift (Annet vitenskapelig)
  • 167.
    Rinne, Sara S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Leitao, C. Dahlsson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Andersson, K.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Löfblom, J.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Optimization of molecular design of Ga-68-labeled affibody molecule for PET imaging of HER3 expression2018Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, nr Supplement 1, s. S109-S109Artikkel i tidsskrift (Annet vitenskapelig)
  • 168.
    Rosestedt, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Andersson, Ken G
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, John
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Ståhl, Stefan
    Evaluation of radiocobalt-labelled affibody molecule for imaging of human epidermal growth factor receptor 3 expression2017Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 51, nr 6, s. 1765-1774Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated. Preclinical studies have shown that the contrast when imaging using anti-HER3 affibody molecules can be improved over time. We aim to develop an agent for PET imaging of HER3 expression using the long-lived positron-emitting radionuclide cobalt-55 (55Co) (T1/2=17.5 h). A long-lived cobalt isotope 57Co was used as a surrogate for 55Co in this study. The anti-HER3 affibody molecule HEHEHE-ZHER3-NOTA was labelled with radiocobalt with high yield, purity and stability. Biodistribution of 57Co-HEHEHE-ZHER3-NOTA was measured in mice bearing DU145 (prostate carcinoma) and LS174T (colorectal carcinoma) xenografts at 3 and 24 h post injection (p.i.). Tumour-to-blood ratios significantly increased between 3 and 24 h p.i. (p<0.05). At 24 h p.i., tumour-to-blood ratios were 6 for DU145 and 8 for LS174T xenografts, respectively. HER3‑expressing xenografts were clearly visualized in a preclinical imaging setting already 3 h p.i., and contrast further improved at 24 h p.i. In conclusion, the radiocobalt-labelled anti-HER3 affibody molecule, HEHEHE-ZHER3-NOTA, is a promising tracer for imaging of HER3 expression in tumours.

  • 169.
    Rosestedt, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Andersson, Ken G.
    KTH Royal Inst Technol, Div Prot Technol, Stockholm, Sweden..
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lofblom, John
    KTH Royal Inst Technol, Div Prot Technol, Stockholm, Sweden..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Stahl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, Stockholm, Sweden..
    Affibody-mediated PET imaging of HER3 expression in malignant tumours2015Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 15226Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human epidermal growth factor receptor 3 (HER3) is involved in the progression of various cancers and in resistance to therapies targeting the HER family. In vivo imaging of HER3 expression would enable patient stratification for anti-HER3 immunotherapy. Key challenges with HER3-targeting are the relatively low expression in HER3-positive tumours and HER3 expression in normal tissues. The use of positron-emission tomography (PET) provides advantages of high resolution, sensitivity and quantification accuracy compared to SPECT. Affibody molecules, imaging probes based on a non-immunoglobulin scaffold, provide high imaging contrast shortly after injection. The aim of this study was to evaluate feasibility of PET imaging of HER3 expression using Ga-68-labeled affibody molecules. The anti-HER3 affibody molecule HEHEHE-Z08698-NOTA was successfully labelled with Ga-68 with high yield, purity and stability. The agent bound specifically to HER3-expressing cancer cells in vitro and in vivo. At 3 h pi, uptake of Ga-68-HEHEHE-Z08698-NOTA was significantly higher in xenografts with high HER3 expression (BT474, BxPC-3) than in xenografts with low HER3 expression (A431). In xenografts with high expression, tumour-to-blood ratios were >20, tumour-to-muscle >15, and tumour-to-bone >7. HER3-positive xenografts were visualised using microPET 3 h pi. In conclusion, PET imaging of HER3 expression is feasible using Ga-68-HEHEHE-Z08698-NOTA shortly after administration.

  • 170.
    Rosestedt, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Andersson, Ken G.
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Leitao, Charles Dahlsson
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Improved contrast of affibody-mediated imaging of HER3 expression in mouse xenograft model through co-injection of a trivalent affibody for in vivo blocking of hepatic uptake2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 6779Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human epidermal growth factor receptor type 3 (HER3) plays a crucial role in the progression of many cancer types. In vivo radionuclide imaging could be a reliable method for repetitive detection of HER3-expression in tumors. The main challenge of HER3-imaging is the low expression in tumors together with endogenous receptor expression in normal tissues, particularly the liver. A HER3-targeting affibody molecule labeled with radiocobalt via a NOTA chelator [Co-57]Co-NOTA-Z(08699) has demonstrated the most favorable biodistribution profile with the lowest unspecific hepatic uptake and high activity uptake in tumors. We hypothesized that specific uptake of labeled affibody monomer might be selectively blocked in the liver but not in tumors by a co-injection of non-labeled corresponding trivalent affibody (Z(08699))(3). Biodistribution of [Co-57]Co-NOTA-Z(08699) and [In-111]ln-DOTA-(Z(08699))(3) was studied in BxPC-3 xenografted mice. [Co-57]Co-NOTA-Z(08699) was co-injected with unlabeled trivalent affibody DOTA-(Z(08699))(3) at different monomer:trimer molar ratios. HER3-expression in xenografts was imaged using [Co-57]Co-NOTA-Z(08699) and [Co-57]Co-NOTA-Z(08699): DOTA-(Z(08699))(3). Hepatic activity uptake of [Co-57] Co-NOTA-Z(08699): DOTA-(Z(08699))(3) decreased with increasing monomer:trimer molar ratio. The tumor activity uptake and tumor-to-liver ratios were the highest for the 1:3 ratio. SPECT/CT images confirmed the biodistribution data. Imaging of HER3 expression can be improved by co-injection of a radiolabeled monomeric affi body-based imaging probe together with a trivalent affibody.

  • 171.
    Rosestedt, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala Univ, Dept Med Chem, Div Mol Imaging, Uppsala, Sweden..
    Andersson, K. G.
    Royal Inst Technol, KTH, Div Prot Technol, Stockholm, Sweden..
    Löfblom, J.
    Royal Inst Technol, KTH, Div Prot Technol, Stockholm, Sweden..
    Ståhl, S.
    Royal Inst Technol, KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Development and Evaluation of Radiocobalt-labelled Affibody Molecule for Next Day PET Imaging of HER3 Expression2016Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, s. S37-S38Artikkel i tidsskrift (Fagfellevurdert)
  • 172.
    Ryttlefors, Mats
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Danfors, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Latini, Francesco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Montelius, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Blomquist, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Gudjonsson, Olafur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Long-term evaluation of the effect of hypofractionated high-energy proton treatment of benign meningiomas by means of (11)C-L-methionine positron emission tomography2016Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, nr 8, s. 1432-1443Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To determine if (11)C-L-methionine PET is a useful tool in the evaluation of the long-term effect of proton beam treatment in patients with meningioma remnant.

    METHODS: Included in the study were 19 patients (4 men, 15 women) with intracranial meningioma remnants who received hypofractionated high-energy proton beam treatment. Patients were examined with (11)C-L-methionine PET and MRI prior to treatment and after 6 months, and 1, 2, 3, 5, 7 and 10 years. Temporal changes in methionine uptake ratio, meningioma volume, meningioma regrowth and clinical symptoms throughout the follow-up period were evaluated.

    RESULTS: In 17 patients the tumour volume was unchanged throughout the follow-up. The methionine uptake ratio on PET decreased over the years in most patients. In two patients the tumour remnant showed progression on MRI. In these patients, prior to the volume increase on MRI, the methionine uptake ratio increased. One patient experienced transient clinical symptoms and showed radiological evidence of a radiation-induced reaction close to the irradiated field.

    CONCLUSION: Proton beam treatment is a safe and effective treatment for achieving long-term growth arrest in meningioma remnants. Follow-up with (11)C-L-methionine PET may be a valuable adjunct to, but not a replacement for, standard radiological follow-up.

  • 173.
    Sandberg, Dan T
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wennborg, Anders
    Affibody AB, Solna, Sweden.
    Feldwisch, Joachim
    Affibody AB, Solna, Sweden.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, nr 8, s. 1337-1346Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: In phase I/II-studies radiolabelled ABY-025 Affibody molecules identified human epidermal growth factor receptor 2 (HER2) expression in breast cancer metastases using PET and SPECT imaging. Here, we wanted to investigate the utility of a simple intra-image normalization using tumour-to-reference tissue-ratio (T/R) as a HER2 status discrimination strategy to overcome potential issues related to cross-calibration of scanning devices.

    METHODS: Twenty-three women with pre-diagnosed HER2-positive/negative metastasized breast cancer were scanned with [(111)In]-ABY-025 SPECT/CT (n = 7) or [(68)Ga]-ABY-025 PET/CT (n = 16). Uptake was measured in all metastases and in normal spleen, lung, liver, muscle, and blood pool. Normal tissue uptake variation and T/R-ratios were established for various time points and for two different doses of injected peptide from a total of 94 whole-body image acquisitions. Immunohistochemistry (IHC) was used to verify HER2 expression in 28 biopsied metastases. T/R-ratios were compared to IHC findings to establish the best reference tissue for each modality and each imaging time-point. The impact of shed HER2 in serum was investigated.

    RESULTS: Spleen was the best reference tissue across modalities, followed by blood pool and lung. Spleen-T/R was highly correlated to PET SUV in metastases after 2 h (r = 0.96, P < 0.001) and reached an accuracy of 100% for discriminating IHC HER2-positive and negative metastases at 4 h (PET) and 24 h (SPECT) after injection. In a single case, shed HER2 resulted in intense tracer retention in blood. In the remaining patients shed HER2 was elevated, but without significant impact on ABY-025 biodistribution.

    CONCLUSION: T/R-ratios using spleen as reference tissue accurately quantify HER2 expression with radiolabelled ABY-025 imaging in breast cancer metastases with SPECT and PET. Tracer binding to shed HER2 in serum might affect quantification in the extreme case.

  • 174.
    Sandgren, Kristina
    et al.
    Umea Univ, Dept Radiat Sci, S-90185 Umea, Sweden.
    Westerlinck, Philippe
    Iridium Canc Network, Dept Radiat Oncol, Antwerp, Belgium.
    Jonsson, Joakim H.
    Umea Univ, Dept Radiat Sci, S-90185 Umea, Sweden.
    Blomqvist, Lennart
    Umea Univ, Dept Radiat Sci, S-90185 Umea, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Karlsson, Camilla Thellenberg
    Umea Univ, Dept Radiat Sci, S-90185 Umea, Sweden.
    Nyholm, Tufve
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Umea Univ, Dept Radiat Sci, S-90185 Umea, Sweden.
    Dirix, Piet
    Iridium Canc Network, Dept Radiat Oncol, Antwerp, Belgium;Ctr Oncol Res CORE, Dept Mol Imaging Pathol Radiotherapy & Oncol MIPR, Antwerp, Belgium.
    Imaging for the Detection of Locoregional Recurrences in Biochemical Progression After Radical Prostatectomy: A Systematic Review2019Inngår i: EUROPEAN UROLOGY FOCUS, ISSN 2405-4569, Vol. 5, nr 4, s. 550-560Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Context

    Local and regional recurrence after radical prostatectomy (RP) can be treated using salvage radiotherapy (SRT). If the recurrence can be delineated on diagnostic imaging, this could allow for increasingly individualized SRT.

    Objective

    This systematic review aimed at evaluating the evidence regarding the usefulness of positron emission tomography (PET) and magnetic resonance imaging (MRI) in identifying local and regional recurrences, with the aim to further individualize the SRT treatment.

    Evidence acquisition

    A systematic PubMed/Medline search was conducted in December 2015. Studies included were imaging studies of post-RP patients focusing on local and/or regional recurrence where sensitivity and specificity of MRI or PET were the primary end points. Only studies using biopsy, other histological analysis, and/or treatment follow-up as reference standard were included. Quality Assessment of Diagnostic Accuracy Studies-2 was used to score the study quality. Twenty-five articles were deemed of sufficient quality and included in the review.

    Evidence synthesis

    [11C]Acetate had the highest pooled sensitivity (92%), while [11C]choline and [18F]choline had pooled sensitivities of 71% and 84%, respectively. The PET tracer with highest pooled specificity was [11C]choline (86%). Regarding MRI, MR spectroscopy combined with dynamic contrast enhanced (DCE) MRI showed the highest pooled sensitivity (89%). High pooled sensitivities were also seen using multiparametric MRI (84%), diffusion-weighted MRI combined with T2-weigthed (T2w) imaging (82%), and DCE MRI combined with T2w imaging (82%). These also showed high pooled specificities (85%, 89%, and 92%, respectively).

    Conclusions

    Both MRI and PET have adequate sensitivity and specificity for the detection of prostate cancer recurrences post-RP. Multiparametric MRI, using diffusion-weighted and/or DCE imaging, and the choline-labeled tracers showed high pooled sensitivity and specificity, although their ranges were broad.

    Patient summary

    After reviewing imaging studies of recurrent prostate cancer after prostatectomy, we concluded that choline positron emission tomography and diffusion-weighted magnetic resonance imaging can be proposed as the current standard, with high sensitivity and specificity.

  • 175.
    Sandström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lindskog, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Velikyan, Irma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Wennborg, Anders
    Affibody AB, Solna, Sweden..
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna, Sweden..
    Sandberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients2016Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, nr 6, s. 867-871Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ga-68-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of Ga-68-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD Ga-68-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 +/- 0.003 mSv/MBq for LD and 0.028 +/- 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of Ga-68-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other Ga-68-labeled tracers, such as 0.021 +/- 0.003 mSv/MBq for Ga-68-DOTATATE and Ga-68-DOTATOC, mainly because of higher uptake in liver and kidney.

  • 176.
    Spiegelberg, Diana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    HSP90 inhibition in angiosarcoma2017Inngår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 177, nr 2, s. 343-344Artikkel i tidsskrift (Annet vitenskapelig)
  • 177.
    Spiegelberg, Diana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Towards Personalized Cancer Therapy: New Diagnostic Biomarkers and Radiosensitization Strategies2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis focuses on the evaluation of biomarkers for radio-immunodiagnostics and radio-immunotherapy and on radiosensitization strategies after HSP90 inhibition, as a step towards more personalized cancer medicine. There is a need to develop new tracers that target cancer-specific biomarkers to improve diagnostic imaging, as well as to combine treatment strategies to potentiate synergistic effects. Special focus has been on the cell surface molecule CD44 and its oncogenic variants, which were found to exhibit unique expression patterns in head and neck squamous cell carcinoma (HNSCC). The variant CD44v6 seems to be a promising target, because it is overexpressed in this cancer type and is associated with radioresistance. Two new radioconjugates that target CD44v6, namely, the Fab fragment AbD15179 and the bivalent fragment AbD19384, were investigated with regard to specificity, biodistribution and imaging performance. Both conjugates were able to efficiently target CD44v6-positive tumors in vitro and in vivo. PET imaging of CD44v6 with 124I-AbD19384 revealed many advantages compared with the clinical standard 18F-FDG. Furthermore, the efficacy of the novel HSP90 inhibitor AT13387 and its potential use in combination with radiation treatment were evaluated. AT13387 proved to be a potent new cancer drug with favorable pharmacokinetics. Synergistic combination effects at clinically relevant drug and radiation doses are promising for both radiation dose reduction and minimization of side effects, or for an improved therapeutic response. The AT13387 investigation indicated that CD44v6 is not dependent on the molecular chaperone HSP90, and therefore, radio-immunotargeting of CD44v6 in combination with the HSP90 inhibitor AT13387 might potentiate treatment outcomes. However, EGFR expression levels did correlate with HSP90 inhibition, and therefore, molecular imaging of EGFR-positive tumors may be used to assess the treatment response to HSP90 inhibitors.

    In conclusion, these results demonstrate how tumor targeting with radiolabeled vectors and chemotherapeutic compounds can provide more specific and sensitive diagnostic tools and treatment options, which can lead to customized treatment decisions and a functional diagnosis that provides more precise and safer drug prescribing, as well as a more effective treatment for each patient.

    Delarbeid
    1. Characterization of CD44 variant expression in head and neck squamous cell carcinomas
    Åpne denne publikasjonen i ny fane eller vindu >>Characterization of CD44 variant expression in head and neck squamous cell carcinomas
    2014 (engelsk)Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, nr 3, s. 2053-2062Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    CD44 is a complex family of molecules, associated with aggressive malignancies and cancer stem cells. However, the role of CD44 variants in tumor progression and treatment resistance is not clear. In this study, the expression of CD44 and its variants was assessed in head and neck squamous cell carcinomas (HNSCC). Furthermore, subpopulations of cells expressing high amounts of CD44 variants were identified and characterized, for e.g., cell cycle phase and radioresistance. Results revealed high and homogenous CD44 and CD44v7 expression in four cell lines and CD44v4 and CD44v6 in three cell lines. CD44v3 was highly expressed in two cell lines, whereas CD44v5, CD44v7/8, CD44v10, CD133, and CD24 demonstrated no or moderate expression. Moreover, a subpopulation of very high CD44v4 expression was identified, which is independent of cell phase, demonstrating increased proliferation and radioresistance. In cell starvation experiments designed to enrich for cancer stem cells, a large population with dramatically increased expression of CD44, CD44v3, CD44v6, and CD44v7 was formed. Expression was independent of cell phase, and cells demonstrated increased radioresistance and migration rate. Our results demonstrate that the heterogeneity of tumor cells has important clinical implications for the treatment of HNSCC and that some of the CD44 variants may be associated with increased radioresistance. Highly expressed CD44 variants could make interesting candidates for selective cancer targeting.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-221093 (URN)10.1007/s13277-013-1272-3 (DOI)000333536300041 ()24122205 (PubMedID)
    Tilgjengelig fra: 2014-03-25 Laget: 2014-03-25 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    2. In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study
    Åpne denne publikasjonen i ny fane eller vindu >>In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study
    Vise andre…
    2014 (engelsk)Inngår i: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, artikkel-id 11Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Patients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours.

    METHODS: The fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup.

    RESULTS: Both species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys.

    CONCLUSIONS: We conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies.

    Emneord
    Radio-immunodiagnostics, Antibody fragment, CD44v6, Molecular imaging, Fab, I-125, In-111
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-221094 (URN)10.1186/2191-219X-4-11 (DOI)000357859200001 ()24598405 (PubMedID)
    Tilgjengelig fra: 2014-03-25 Laget: 2014-03-25 Sist oppdatert: 2017-12-05bibliografisk kontrollert
    3. Molecular imaging of CD44v6-expressing squamous cell carcinoma using a novel engineered bivalent antibody fragment
    Åpne denne publikasjonen i ny fane eller vindu >>Molecular imaging of CD44v6-expressing squamous cell carcinoma using a novel engineered bivalent antibody fragment
    Vise andre…
    (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Emneord
    Head and neck cancer, 125I, 124I, F(ab´)2, AbD19384, CD44v6, small animal studies, PET imaging
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-247056 (URN)
    Tilgjengelig fra: 2015-03-12 Laget: 2015-03-12 Sist oppdatert: 2015-07-07
    4. The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells
    Åpne denne publikasjonen i ny fane eller vindu >>The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells
    Vise andre…
    2015 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 34, s. 35652-35666Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Overexpression of heat shock protein 90 (HSP90) is associated with increased tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor AT13387 and examined its radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts. AT13387 induced effective cytotoxic activity and radiosensitized cancer cells in monolayer and tumor spheroid models, where low drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore, AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8-24 h. These results were confirmed in vivo where AT13387 treated tumors displayed effective downregulation of HSP90 and its oncogenic client proteins. In conclusion, our results demonstrate that AT13387 is a potent new cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy. AT13387 treatment has the potential to improve external beam therapy and radionuclide therapy outcomes and restore treatment efficacy in cancers that are resistant to initial therapeutic regimes.

    Emneord
    HSP90 inhibitors, radiation, DNA repair, EGFR, CD44, Radioresistance, Radio-­immuno targeting
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-247054 (URN)10.18632/oncotarget.5363 (DOI)000366111900051 ()26452257 (PubMedID)
    Tilgjengelig fra: 2015-03-12 Laget: 2015-03-12 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    5. Evaluation of biomarkers for imaging and radio-immunotherapy in combination with HSP90 inhibition in squamous cell carcinomas
    Åpne denne publikasjonen i ny fane eller vindu >>Evaluation of biomarkers for imaging and radio-immunotherapy in combination with HSP90 inhibition in squamous cell carcinomas
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    HSP90 inhibitor, Head and neck cancer, F(ab´)2, AbD19384, CD44v6, PET imaging, AT13387, 124I, EGFR, CD44v6, radio-­immunotherapy, treatment response
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-247055 (URN)
    Tilgjengelig fra: 2015-03-12 Laget: 2015-03-12 Sist oppdatert: 2015-07-07
  • 178.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Dascalu, Adrian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mortensen, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Abramenkovs, Andris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Kuku, Gamze
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells2015Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 34, s. 35652-35666Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Overexpression of heat shock protein 90 (HSP90) is associated with increased tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor AT13387 and examined its radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts. AT13387 induced effective cytotoxic activity and radiosensitized cancer cells in monolayer and tumor spheroid models, where low drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore, AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8-24 h. These results were confirmed in vivo where AT13387 treated tumors displayed effective downregulation of HSP90 and its oncogenic client proteins. In conclusion, our results demonstrate that AT13387 is a potent new cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy. AT13387 treatment has the potential to improve external beam therapy and radionuclide therapy outcomes and restore treatment efficacy in cancers that are resistant to initial therapeutic regimes.

  • 179.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lundsten, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mortensen, Anja C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Abramenkovs, Andris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    In Vitro and In Vivo Growth Inhibitory and Radiosensitizing Effects of the Anti-HSP90 agent Onalespib2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, s. S182-S182Artikkel i tidsskrift (Annet vitenskapelig)
  • 180.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Mortensen, Anja C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lundsten, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Brown, C. J.
    ASTAR, P53Lab, 8A Biomed Grove,06-04-05 Neuros Immunos, Singapore, Singapore.
    Lane, D. P.
    ASTAR, P53Lab, 8A Biomed Grove,06-04-05 Neuros Immunos, Singapore, Singapore; Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    First in vivo study of the MDM2/MDMX-p53 antagonist PM2 as potentiator of external radiotherapy in wt p53 cancer2018Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, nr Supplement: 1, s. S30-S30Artikkel i tidsskrift (Annet vitenskapelig)
  • 181.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mortensen, Anja C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Selvaraju, Ram K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för Preklinisk PET-MRI.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model.2016Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, nr 5, s. 974-982Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition.

    METHODS: Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining.

    RESULTS: AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment.

    CONCLUSION: We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.

  • 182.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mortensen, Anja C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Selvaraju, Ram Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Scott, A.
    Olivia Newton John Canc Res Inst, Ludwig Inst Canc Res, Melbourne, Vic, Australia.;La Trobe Univ, Melbourne, Vic, Australia..
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Molecular imaging of EGFR and EGFRvIII for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model2015Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, nr S1, s. S263-S264Artikkel i tidsskrift (Annet vitenskapelig)
  • 183.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mortensen, Anja C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Selvaraju, Ram Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Stenberg, J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Scott, A.
    Olivia Newton John Canc Res Inst, Ludwig Inst Canc Res, Melbourne, Vic, Australia.;La Trobe Univ, Melbourne, Vic, Australia..
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Improving EGFR imaging by use of an anti-EGFRvIII monoclonal antibody: characterizations in an in vivo squamous cell carcinoma model2015Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, nr S1, s. S467-S467Artikkel i tidsskrift (Annet vitenskapelig)
  • 184.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Mortensen, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lundsten, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Brown, Christopher J.
    ASTAR, p53Lab, Singapore, Singapore.
    Lane, David P.
    ASTAR, p53Lab, Singapore, Singapore;Karolinska Inst, Sci Life Lab, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors2018Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 17, s. 5084-5093Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radiotherapy amplifies p53 expression in cancer cells with wild-type (wt) p53. Blocking the negative regulators MDM2 and MDMX stabilizes p53 and may therefore potentiate radiotherapy outcomes. In this study, we investigate the efficacy of the novel anti-MDM2/X stapled peptide PM2 alone and in combination with externalgamma radiation in vitro and in vivo. PM2 therapy combined with radiotherapy elicited synergistic therapeutic effects compared with monotherapy in cells with wt p53 in both in vitro and in vivo assays, whereas these effects did not manifest in p53(-/-) cells. Biodistribution and autoradiography of 125I-PM2 revealed high and retained uptake homogenously distributed throughout the tumor. In mice carrying wt p53 tumors, PM2 combined with radiother-apy significantly prolonged the median survival by 50%, whereas effects of PM2 therapy on mutant and p53(-/-) tumors were negligible. PM2-dependent stabilization of p53 was confirmed with ex vivo immunohistochemistry. These data demonstrate the potential of the stapled peptide PM2 as a radiotherapy potentiator in vivo and suggest that clinical application of PM2 with radiotherapy in wt p53 cancers might improve tumor control.

    Significance: These findings contribute advances to cancer radiotherapy by using novel p53-reactivating stapled peptides as radiosensitizers in wild-type p53 cancers.

  • 185.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mortensen, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Selvaraju, Ram Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Evaluation of biomarkers for imaging and radio-immunotherapy in combination with HSP90 inhibition in squamous cell carcinomasManuskript (preprint) (Annet vitenskapelig)
  • 186.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nilvebrant, Johan
    Royal Inst Technol, Div Prot Technol, Sch Biotechnol, Stockholm, Sweden..
    CD44v6-Targeted Imaging of Head and Neck Squamous Cell Carcinoma: Antibody-Based Approaches2017Inngår i: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, Vol. 2017, artikkel-id 2709547Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) is a common and severe cancer with low survival rate in advanced stages. Noninvasive imaging of prognostic and therapeutic biomarkers could provide valuable information for planning and monitoring of the different therapy options. Thus, there is amajor interest in development of new tracers towards cancer-specific molecular targets to improve diagnostic imaging and treatment. CD44v6, an oncogenic variant of the cell surface molecule CD44, is a promising molecular target since it exhibits a unique expression pattern in HNSCC and is associated with drug-and radio-resistance.

    In this review we summarize results from preclinical and clinical investigations of radiolabeled anti-CD44v6 antibody-based tracers: full-length antibodies, Fab, F(ab')(2) fragments, and scFvs with particular focus on the engineering of various antibody formats and choice of radiolabel for the use as molecular imaging agents in HNSCC. We conclude that the current evidence points to CD44v6 imaging being a promising approach for providing more specific and sensitive diagnostic tools, leading to customized treatment decisions and functional diagnosis. Improved imaging tools hold promise to enable more effective treatment for head and neck cancer patients.

  • 187.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenberg, J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Haylock, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    A real-time in vitro assay as a potential predictor of in vivo tumour imaging properties2015Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, nr S1, s. S306-S307Artikkel i tidsskrift (Annet vitenskapelig)
  • 188.
    Spiegelberg, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Ridgeview Instruments AB, Vange, Sweden..
    Haylock, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    A real-time in vitro assay as a potential predictor of in vivo tumor imaging properties2016Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 43, nr 1, s. 12-18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Selective tumor targeting strategies based on cell surface molecules enable new personalized diagnosis and treatments, potentially lowering adverse effects and increasing efficacy. Radio-immunotargeting generally relies on a molecule binding to a cancer-specific target. It is therefore important to understand the properties of molecular interactions in their working environment and how to translate these properties measured in vitro into the in vivo molecular imaging situation. Methods: Time resolved interaction analysis in vitro was compared with a corresponding in vivo xenograft mouse model. The antibody fragment AbD15179 was labeled with I-125 or In-111, and analyzed on cell lines with differing CD44v6 expression in vitro, and in a dual tumor xenograft model derived from the same cell lines. In vitro LigandTracer measurements were analyzed with TraceDrawer and Interaction Map. Conjugate sensitivity, kinetics, and signal-to-background ratios were assessed for both tumor cells in vitro and xenograft tumors in vivo. Results: In vitro results revealed a general biphasic appearance of a high- and a low-affinity interaction event. The In-111-labeled fragment displayed the largest proportion of the high-affinity interaction with increased sensitivity and retention compared to I-125-Fab. In vivo results were in agreement with in vitro data, with increased retention, higher sensitivity and better contrast for the In-111-labeled fragment compared to I-125. Conclusions: Time resolved binding characteristics measured in vitro largely matched the in vivo performance for the conjugates, which is promising for future studies. In vitro time-resolved LigandTracer assays are efficient, rapid, and in this study shown to be able to predict in vivo outcomes. Advances in Knowledge and Implications for Patient Care: Further studies are needed to confirm these findings, but the method is promising considering the ethical need to reduce the use of laboratory animals, as well as reducing costs for the development of tumor targeting compounds in the future.

  • 189.
    Strand, Joanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Site-Specific Radioiodination of HER2-Targeting Affibody Molecules using 4-Iodophenethylmaleimide Decreases Renal Uptake of Radioactivity2015Inngår i: ChemistryOpen, ISSN 2191-1363, Vol. 4, nr 2, s. 174-182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small scaffold-based affinity proteins with promising properties as probes for radionuclide-based molecular imaging. However, a high reabsorption of radiolabeled Affibody molecules in kidneys is an issue. We have shown that the use of I-125-3-iodo-((4-hydroxyphenyl)ethyl)maleimide (IHPEM) for site-specific labeling of cysteine-containing Affibody molecules provides high tumor uptake but low radioactivity retention in kidneys. We hypothesized that the use of 4-iodophenethylmaleimide (IPEM) would further reduce renal retention of radioactivity because of higher lipophilicity of radiometabolites. An anti-human epidermal growth factor receptor type2 (HER2) Affibody molecule (Z(HER2:2395)) was labeled using I-125-IPEM with an overall yield of 45 +/- 3%. I-125-IPEM-Z(HER2:2395) bound specifically to HER2-expressing human ovarian carcinoma cells (SKOV-3 cell line). In NMRI mice, the renal uptake of I-125-IPEM-Z(HER2:2395) (24 +/- 2 and 5.7 +/- 0.3%IAg(-1)at 1 and 4 h after injection, respectively) was significantly lower than uptake of I-125-IHPEM-Z(HER2:2395) (50 +/- 8 and 12 +/- 2%IAg(-1)at 1 and 4 h after injection, respectively). In conclusion, the use of a more lipophilic linker for the radioiodination of Affibody molecules reduces renal radioactivity.

  • 190.
    Ståhl, Stefan
    et al.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Karlström, Amelie Eriksson
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Frejd, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Gunnar Asplunds Alle 24, SE-17169 Solna, Sweden..
    Nygren, Per-Åke
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Affibody Molecules in Biotechnological and Medical Applications2017Inngår i: Trends in Biotechnology, ISSN 0167-7799, E-ISSN 1879-3096, Vol. 35, nr 8, s. 691-712Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small (6.5-kDa) affinity proteins based on a three-helix bundle domain framework. Since their introduction 20 years ago as an alternative to antibodies for biotechnological applications, the first therapeutic affibody molecules have now entered clinical development and more than 400 studies have been published in which affibody molecules have been developed and used in a variety of contexts. In this review, we focus primarily on efforts over the past 5 years to explore the potential of affibody molecules for medical applications in oncology, neurodegenerative, and inflammation disorders, including molecular imaging, receptor signal blocking, and delivery of toxic payloads. In addition, we describe recent examples of biotechnological applications, in which affibody molecules have been exploited as modular affinity fusion partners.

  • 191.
    Summer, D
    et al.
    Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Andersson, K. G.
    Division of Protein Technology, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, J.n
    Division of Protein Technology, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Decristoforo, C
    Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
    PP15 89Zr-Siderophore-Affibody conjugates for imaging EGFR expression2018Inngår i: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, nr S1, artikkel-id 5Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Aim: Zirconium-89 has gained great interest for PET, when imaging at late time points is required. Desferrioxamine B (DFO), is mostly used for this radionuclide as bifunctional chelator (BFC) and we recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study reports on the comparison of FSC and DFO as BFCs for 89Zr labelling of the affibody ZEGFR:2377 targeting Epidermal Growth Factor Receptors (EGFR).

    Methods: FSC-ZEGFR:2377 and DFO-ZEGFR:2377 were evaluated regarding labeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution and microPET-CT imaging.

    Results: Both conjugates showed increased labelling yields at elevated temperature (85°C). Both conjugates revealed remarkable specificity, affinity and slow cell-line dependent internalisation. Labeling at 85°C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake but clear improvement as compared to 89Zr-DFO-ZEGFR:2377, labeled at room temperature, which was confirmed by MicroPET-CT imaging.

    Conclusion: We were able to show that FSC is a suitable alternative to DFO for labeling of biomolecules with zirconium-89. Furthermore our findings indicate that 89Zr- labeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

  • 192.
    Summer, Dominik
    et al.
    Med Univ Innsbruck, Dept Nucl Med, Anichstr 35, A-6020 Innsbruck, Austria..
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Andersson, Ken G.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Decristoforo, Clemens
    Med Univ Innsbruck, Dept Nucl Med, Anichstr 35, A-6020 Innsbruck, Austria..
    Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression2018Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, nr 1, s. 175-185Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow e pharmacokinetics as due to its longer half-life, in comparison to fluorine 18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to head as bifunctional chelators for "Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFOZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 degrees C. Both 89Zr-FSC-ZEGFR:2377 and Zr-89-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 degrees C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89ZrDFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of Zr-89-FSC-ZEGFR:2377 as well as Zr-89-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that Zr-89-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

  • 193.
    Sörensen, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Sandberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Wennborg, Anders
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [(68)Ga]ABY-025 Affibody PET/CT2016Inngår i: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 6, nr 2, s. 262-271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with (68)Ga-gallium ([(68)Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology.

    EXPERIMENTAL DESIGN: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [(68)Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [(68)Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [(68)Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization.

    RESULTS: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [(68)Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients.

    CONCLUSION: [(68)Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer.

  • 194.
    Sörensen, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wennborg, Anders
    Feldwisch, Joachim
    Sandberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Carlsson, Jorgen
    Lindman, Henrik
    Accuracy of [Ga-68]ABY-025 PET/CT for determination of HER2-expression in metastatic breast cancer2015Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, nr 3Artikkel i tidsskrift (Annet vitenskapelig)
  • 195.
    Tilly, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Probabilistic treatment planning based on dose coverage: How to quantify and minimize the effects of geometric uncertainties in radiotherapy2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Traditionally, uncertainties are handled by expanding the irradiated volume to ensure target dose coverage to a certain probability. The uncertainties arise from e.g. the uncertainty in positioning of the patient at every fraction, organ motion and in defining the region of interests on the acquired images. The applied margins are inherently population based and do not exploit the geometry of the individual patient. Probabilistic planning on the other hand incorporates the uncertainties directly into the treatment optimization and therefore has more degrees of freedom to tailor the dose distribution to the individual patient. The aim of this thesis is to create a framework for probabilistic evaluation and optimization based on the concept of dose coverage probabilities. Several computational challenges for this purpose are addressed in this thesis.

    The accuracy of the fraction by fraction accumulated dose depends directly on the accuracy of the deformable image registration (DIR). Using the simulation framework, we could quantify the requirements on the DIR to 2 mm or less for a 3% uncertainty in the target dose coverage.

    Probabilistic planning is computationally intensive since many hundred treatments must be simulated for sufficient statistical accuracy in the calculated treatment outcome. A fast dose calculation algorithm was developed based on the perturbation of a pre-calculated dose distribution with the local ratio of the simulated treatment’s fluence and the fluence of the pre-calculated dose. A speedup factor of ~1000 compared to full dose calculation was achieved with near identical dose coverage probabilities for a prostate treatment.

    For some body sites, such as the cervix dataset in this work, organ motion must be included for realistic treatment simulation. A statistical shape model (SSM) based on principal component analysis (PCA) provided the samples of deformation. Seven eigenmodes from the PCA was sufficient to model the dosimetric impact of the interfraction deformation.

    A probabilistic optimization method was developed using constructs from risk management of stock portfolios that enabled the dose planner to request a target dose coverage probability. Probabilistic optimization was for the first time applied to dataset from cervical cancer patients where the SSM provided samples of deformation. The average dose coverage probability of all patients in the dataset was within 1% of the requested.

    Delarbeid
    1. Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy – applied to prostate proton treatments
    Åpne denne publikasjonen i ny fane eller vindu >>Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy – applied to prostate proton treatments
    2013 (engelsk)Inngår i: BMC Medical Physics, ISSN 1756-6649, E-ISSN 1756-6649, Vol. 13, nr 2Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background

    Calculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.

    A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths.

    Results

    The planning parameter most sensitive to the DIR uncertainty was found to be the targetD95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk.

    Conclusions

    The DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.

    Emneord
    Radiotherapy; Adaptive radiotherapy; Dose tracking; Dose mapping; Dose accumulation; Dose accumulation accuracy; Deformable image registration; Non-rigid image registration; Protons
    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-224059 (URN)10.1186/1756-6649-13-2 (DOI)
    Tilgjengelig fra: 2014-04-30 Laget: 2014-04-30 Sist oppdatert: 2017-12-05bibliografisk kontrollert
    2. Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy
    2015 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 60, nr 14, s. 5439-5454Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan.For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel.Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso-probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable.

    Emneord
    Radiotherapy dose calculation
    HSV kategori
    Forskningsprogram
    Fysik
    Identifikatorer
    urn:nbn:se:uu:diva-258095 (URN)10.1088/0031-9155/60/14/5439 (DOI)000357620400008 ()26118844 (PubMedID)
    Tilgjengelig fra: 2015-07-10 Laget: 2015-07-10 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    3. Dose coverage calculation using a statistical shape model: applied to cervical cancer radiotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Dose coverage calculation using a statistical shape model: applied to cervical cancer radiotherapy
    Vise andre…
    2017 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 62, nr 10, s. 4140-4159Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A comprehensive methodology for treatment simulation and evaluation of dose coverage probabilities is presented where a population based statistical shape model (SSM) provide samples of fraction specific patient geometry deformations.The learning data consists of vector fields from deformable image registration of repeated imaging giving intra-patient deformations which are mapped to an average patient serving as a common frame of reference. The SSM is created by extracting the most dominating eigenmodes through principal component analysis of the deformations from all patients. The sampling of a deformation is thus reduced to sampling weights for enough of the most dominating eigenmodes that describe the deformations.For the cervical cancer patient datasets in this work, we found seven eigenmodes to be sufficient to capture 90% of the variance in the deformations of the, and only three eigenmodes for stability in the simulated dose coverage probabilities. The normality assumption of the eigenmode weights was tested and found relevant for the 20 most dominating eigenmodes except for the first. Individualization of the SSM is demonstrated to be improved using two deformation samples from a new patient. The probabilistic evaluation provided additional information about the trade-offs compared to the conventional single dataset treatment planning.

    Emneord
    Radiotherapy, probabilistic, statistical shape model, principal component analysis, deformable image registration, cervix
    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-304979 (URN)10.1088/1361-6560/aa64ef (DOI)000425818300003 ()28266348 (PubMedID)
    Tilgjengelig fra: 2016-10-11 Laget: 2016-10-11 Sist oppdatert: 2018-05-04bibliografisk kontrollert
    4. Probabilistic optimization of the dose coverage – applied to radiotherapy treatment planning of cervical cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Probabilistic optimization of the dose coverage – applied to radiotherapy treatment planning of cervical cancer
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Probabilistic (or robust) optimization is an alternative to margins for handling geometrical uncertainties in treatment planning of radiotherapy where the uncertainties are explicitly incorporated in the optimization through sampling of treatment scenarios. We present a probabilistic method based on statistical measures close to those behind conventional margin based planning. The dose planner requests a dose coverage to a specified probability, which the algorithm then attempts to fulfil.

    We define the Percentile UnderDosage (PUD) as a measure of the target minimum dose coverage probability, i.e. the dose coverage that a treatment plan meet or exceed to a given probability. Margin based planning commonly use the implicit probabilistic treatment criteria that the 90th PUD is at least 95% of the intended dose. For optimization we use the Expected Percentile UnderDosage (EPUD) defined as the average dose coverage below a given PUD. The EPUD is, in contrast to PUD, a convex measure and hence standard optimization techniques can be used to find the optimal treatment plan. We propose an iterative method where a treatment optimization is performed at each iteration and the EPUD tolerance is adjusted gradually until a desired PUD is met.

    We demonstrate our proposed probabilistic planning method for cervical cancer patients. The uncertainty caused by organ deformation is explicitly included in the probabilistic optimization where a statistical shape model is used to sample scenarios with different deformations. For all patients in this work, the iterative process of finding the EPUD tolerance converged in less than 10 iterations to within 0.1Gy of the requested PUD even though a conservative update scheme was used. The resulting estimated PUD was validated based on 1000 simulated scenarios not part of the optimization yielding an agreement within 1.2% of the requested PUD.

    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-304982 (URN)
    Tilgjengelig fra: 2016-10-11 Laget: 2016-10-11 Sist oppdatert: 2016-10-11
  • 196.
    Tilly, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy2015Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 60, nr 14, s. 5439-5454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan.For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel.Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso-probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable.

  • 197.
    Tilly, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Probabilistic optimization of the dose coverage – applied to radiotherapy treatment planning of cervical cancerManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Probabilistic (or robust) optimization is an alternative to margins for handling geometrical uncertainties in treatment planning of radiotherapy where the uncertainties are explicitly incorporated in the optimization through sampling of treatment scenarios. We present a probabilistic method based on statistical measures close to those behind conventional margin based planning. The dose planner requests a dose coverage to a specified probability, which the algorithm then attempts to fulfil.

    We define the Percentile UnderDosage (PUD) as a measure of the target minimum dose coverage probability, i.e. the dose coverage that a treatment plan meet or exceed to a given probability. Margin based planning commonly use the implicit probabilistic treatment criteria that the 90th PUD is at least 95% of the intended dose. For optimization we use the Expected Percentile UnderDosage (EPUD) defined as the average dose coverage below a given PUD. The EPUD is, in contrast to PUD, a convex measure and hence standard optimization techniques can be used to find the optimal treatment plan. We propose an iterative method where a treatment optimization is performed at each iteration and the EPUD tolerance is adjusted gradually until a desired PUD is met.

    We demonstrate our proposed probabilistic planning method for cervical cancer patients. The uncertainty caused by organ deformation is explicitly included in the probabilistic optimization where a statistical shape model is used to sample scenarios with different deformations. For all patients in this work, the iterative process of finding the EPUD tolerance converged in less than 10 iterations to within 0.1Gy of the requested PUD even though a conservative update scheme was used. The resulting estimated PUD was validated based on 1000 simulated scenarios not part of the optimization yielding an agreement within 1.2% of the requested PUD.

  • 198.
    Tilly, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Elekta Instruments AB, Stockholm, Sweden.
    van de Schoot, Agustinus J A J
    Academic Medical Center, Univesity of Amsterdam, Amsterdam, The Netherlands.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Bel, Arjan
    Academic Medical Center, Univesity of Amsterdam, Amsterdam, The Netherlands.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Dose coverage calculation using a statistical shape model: applied to cervical cancer radiotherapy2017Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 62, nr 10, s. 4140-4159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A comprehensive methodology for treatment simulation and evaluation of dose coverage probabilities is presented where a population based statistical shape model (SSM) provide samples of fraction specific patient geometry deformations.The learning data consists of vector fields from deformable image registration of repeated imaging giving intra-patient deformations which are mapped to an average patient serving as a common frame of reference. The SSM is created by extracting the most dominating eigenmodes through principal component analysis of the deformations from all patients. The sampling of a deformation is thus reduced to sampling weights for enough of the most dominating eigenmodes that describe the deformations.For the cervical cancer patient datasets in this work, we found seven eigenmodes to be sufficient to capture 90% of the variance in the deformations of the, and only three eigenmodes for stability in the simulated dose coverage probabilities. The normality assumption of the eigenmode weights was tested and found relevant for the 20 most dominating eigenmodes except for the first. Individualization of the SSM is demonstrated to be improved using two deformation samples from a new patient. The probabilistic evaluation provided additional information about the trade-offs compared to the conventional single dataset treatment planning.

  • 199.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Grönroos, Tove J
    Turku PET Centre, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland; Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.
    Yim, Cheng-Bin
    Turku PET Centre, University of Turku, Turku, Finland; Turku PET Centre, Åbo Akademi University, Turku, Finland.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Yue, Ying
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Grimm, Sebastian
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Rajander, Johan
    Turku PET Centre, Åbo Akademi University, Turku, Finland.
    Perols, Anna
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Haaparanta-Solin, Merja
    Turku PET Centre, University of Turku, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland.
    Solin, Olof
    Turku PET Centre, University of Turku, Turku, Finland; Turku PET Centre, Åbo Akademi University, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland.
    Ferdani, Riccardo
    Washington University, St. Louis, MO, USA.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Anderson, Carolyn J
    Departments of Medicine, Radiology, Bioengineering and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15203, USA.
    Karlström, Amelie Eriksson
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Molecular design of radiocopper-labelled Affibody molecules2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, nr 1, artikkel-id 6542Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cu-CB-TE2A-GEEE-ZHER2:342 was 16 ± 6%ID/g and tumor-to-blood ratio was 181 ± 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu-Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption.

  • 200.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Yim, C.
    Turku PET Ctr, Turku, Finland.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Yue, Y.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Grimm, S.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Rajander, J.
    Turku PET Ctr, Turku, Finland.
    Perols, A.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Haaparanta-Solin, M.
    Turku PET Ctr, Turku, Finland.
    Grönroos, T. J.
    Turku PET Ctr, Turku, Finland.
    Solin, O.
    Turku PET Ctr, Turku, Finland.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Anderson, C.
    Univ Pittsburgh, Pittsburgh, PA USA.
    Karlström, A. Eriksson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Optimal molecular design of radiocopper-labelled affibody molecules2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, s. S549-S549Artikkel i tidsskrift (Annet vitenskapelig)
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