| 1. |
- Hagberg, Carolina E, et al.
(författare)
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Vascular endothelial growth factor B controls endothelial fatty acid uptake.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 464:7290, s. 917-21
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Tidskriftsartikel (refereegranskat)abstract
- The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.
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| 2. |
- Samén, Erik
(författare)
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Targeting EGFR and VEGFR2 tyrosine kinases with positron emission tomography : evaluation of two radiotracers
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Receptor tyrosine kinases (RTKs) are commonly involved in the development, growth and spread of cancer. Targeted therapy with tyrosine kinase inhibitors (TKIs) has proven a successful treatment strategy against cancers in which growth is dependent on the expression of these receptors. Increased effectiveness of treatment can potentially be achieved by individual characterizations of the disease, enabling tailoring of the therapy directed at the specific targets found. Positron emission tomography (PET) is a non-invasive imaging technique that allows characterization of biochemical processes and quantification of targets such as RTKs. In PET, the distribution of radiolabeled molecules in the body is traced by the emission of photons produced after the decay of the radionuclide that is incorporated in the tracer molecule. Drugs and other xenobiotics are often metabolized in the body to facilitate excretion. A PET tracer can be metabolized into radioactive metabolites, which often display pharmacokinetic behaviors different than that of the parent molecule. It is therefore pivotal to characterize the metabolism of novel PET tracers before accurate estimations of biological target levels, based on radioactivity uptakes, can be performed. This doctoral thesis focuses on the preclinical evaluation of two tracer molecules, [11C]PD153035 and [11C]PAQ, each targeting a specific RTK known to play important roles in cancerogenesis. Both tracers are based on TKIs and have been proven to be potent RTK inhibitors in vitro. In papers I and III, the in vitro and in vivo metabolism, respectively, of [11C]PD153035 was investigated. We found that the tracer was extensively metabolized by cytochrome P450 enzymes into several different radioactive metabolites. Furthermore, the results indicate that the metabolism impairs quantification of the target RTK, the epidermal growth factor receptor (EGFR). In papers II and IV the pharmacokinetics and angiogenesis detection properties of (R,S)-[11C]PAQ and (R)-[11C]PAQ were assessed in various models of cancer in mice. The results show that the tracer is metabolically stable and that areas with increased angiogenic activity, based on vascular endothelial growth factor receptor 2 expression (VEGFR2), can be visualized with PET. Uptake of radioactivity correlated well to areas with high expression of the receptor both with the labeled racemate and the R-isomer. In addition, high focal uptake was observed with (R)-[11C]PAQ in lungs with metastases that exhibited high expression levels of the VEGFR2. In summary, we conclude that [11C]PD153035 is metabolized very rapidly in rat and that a similar metabolism in humans would imply serious limitations if the tracer is used in patient stratification for EGFR targeted therapy. (R)-[11C]PAQ, on the other hand, is a promising tracer that, pending positive results in further validation studies, can prove to be a valuable tool for personalizing cancer treatment based on expression levels of VEGFR2.
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| 3. |
- Wållberg, Helena, et al.
(författare)
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HER2-Positive Tumors Imaged Within 1 Hour Using a Site-Specifically C-11-Labeled Sel-Tagged Affibody Molecule
- 2012
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Ingår i: Journal of Nuclear Medicine. - Stockholm : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:9, s. 1446-1453
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Tidskriftsartikel (refereegranskat)abstract
- A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for individualizing therapy and predicting prognoses. In vivo imaging methods are available but not yet in clinical practice; new methodologies improving speed, sensitivity, and specificity are required. Methods: A HER2-binding Affibody molecule, Z(HER2:342), was recombinantly fused with a C-terminal selenocysteine-containing tetrapeptide Sel-tag, allowing site-specific labeling with either C-11 or Ga-68, followed by biodistribution studies with small-animal PET. Dosimetry data for the 2 radiotracers were compared. Imaging of HER2-expressing human tumor xenografts was performed using the C-11-labeled Affibody molecule. Results: Both the C-11- and Ga-68-labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4-5 percentage injected dose per gram of tissue at 1 h. Final retention in the kidneys was much lower (>5-fold) for the C-11-labeled protein, and its overall absorbed dose was considerably lower. C-11-Z(HER2:342) showed excellent tumor-targeting capability, with almost 10 percentage injected dose per gram of tissue in HER2-expressing tumors within 1 h. Specificity was demonstrated by preblocking binding sites with excess ligand, yielding significantly reduced radiotracer uptake (P = 0.002), comparable to uptake in tumors with low HER2 expression. Conclusion: To our knowledge, the Sel-tagging technique is the first that enables site-specific C-11-radiolabeling of proteins. Here we present the finding that, in a favorable combination between radionuclide half-life and in vivo pharmacokinetics of the Affibody molecules, C-11-labeled Set-tagged Z(HER2:342) can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.
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| 4. |
- Wållberg, Helena, et al.
(författare)
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Specific in vivo imaging of HER2-positive tumors within one hour using a site-specifically 11C-labeled Sel-tagged Affibody molecule
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for improvement of cancer care. In v ivo imaging methods are available, but are not yet in clinical practice; new methodologies improving speed, sensitivity and specificity are required. Here we describe promising results with a HER2‐binding Affibody molecule, ZHER2:342, recombinantly fused with a C‐terminal selenocysteine‐containing tetrapeptide Sel‐tag and site‐specifically labeled with either 11C or 68Ga for molecular imaging applications with positron emissiontomography (PET). In mice, both the 11C‐ and 68Ga‐labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4‐5 %ID/g at 1 h. Final uptake in kidneys was much lower (> 5‐fold) for the 11C‐labeled protein, leading to markedly reduced background radioactivity in the abdomen. Furthermore, 11C‐labeled Sel‐tagged ZHER2:342 showed excellent tumor targeting capability, with almost 10 %ID/g in HER2 expressing tumors within the first hour. High specificity was demonstrated by preblocking the binding sites with excess ligand, which yielded low radiotracer uptakes, comparable to those in tumors with low endogenous HER2 expression. To our knowledge the Sel‐tagging technique is the first that enables site‐specific 11C radiolabelingof proteins. Here we present that, in a favorable combination between radionuclide half‐life and in vivo pharmacokinetics of the Affibody molecules, 11C‐labeled Sel taggedZHER2:342 can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.
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