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Estrada, Sergio
Publications (10 of 31) Show all publications
Nordling, S., Brännström, J., Carlsson, F., Lu, B., Salvaris, E., Wanders, A., . . . Magnusson, P. U. (2018). Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse. Scientific Reports, 8, Article ID 5220.
Open this publication in new window or tab >>Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5220Article in journal (Refereed) Published
Abstract [en]

Ischemia reperfusion injury is one of the major complications responsible for delayed graft function in kidney transplantation. Applications to reduce reperfusion injury are essential due to the widespread use of kidneys from deceased organ donors where the risk for delayed graft function is especially prominent. We have recently shown that coating of inflamed or damaged endothelial cells with a unique heparin conjugate reduces thrombosis and leukocyte recruitment. In this study we evaluated the binding capacity of the heparin conjugate to cultured human endothelial cells, to kidneys from brain-dead porcine donors, and to murine kidneys during static cold storage. The heparin conjugate was able to stably bind cultured endothelial cells with high avidity, and to the renal vasculature of explanted kidneys from pigs and mice. Treatment of murine kidneys prior to transplantation reduced platelet deposition and leukocyte infiltration 24 hours post-transplantation, and significantly improved graft function. The present study thus shows the benefits of enhanced protection of the renal vasculature during cold storage, whereby increasing the antithrombotic and anti-adhesive properties of the vascular endothelium yields improved renal function early after transplantation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Surgery Urology and Nephrology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-354353 (URN)10.1038/s41598-018-21463-1 (DOI)000428235200024 ()29581529 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 602699VINNOVA
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
Hulsart Billström, G., Selvaraju, R., Estrada, S., Lubberink, M., Asplund, V., Bergman, K., . . . Antoni, G. (2018). Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept. Journal of Controlled Release, 285, 178-186
Open this publication in new window or tab >>Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept
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2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 285, p. 178-186Article in journal (Refereed) Published
Abstract [en]

Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.

Keywords
Bone morphogenetic protein 2, Bone tissue engineering, Hydrogel, Micro computed tomography, Positron emission tomography, Single-photon emission computed tomography
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-356465 (URN)10.1016/j.jconrel.2018.07.012 (DOI)000441737400015 ()30005906 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 262948
Note

G. Hulsart-Billström and R. K. Selvaraju contributed equally to this work and should be regarded as joint first authors.

Available from: 2018-07-28 Created: 2018-07-28 Last updated: 2018-10-10Bibliographically approved
Tovedal, T., Lubberink, M., Morell, A., Estrada, S., Golla, S. S., Myrdal, G., . . . Lennmyr, F. (2017). Blood Flow Quantitation by Positron Emission Tomography During Selective Antegrade Cerebral Perfusion. Annals of Thoracic Surgery, 103(2), 610-616
Open this publication in new window or tab >>Blood Flow Quantitation by Positron Emission Tomography During Selective Antegrade Cerebral Perfusion
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2017 (English)In: Annals of Thoracic Surgery, ISSN 0003-4975, E-ISSN 1552-6259, Vol. 103, no 2, p. 610-616Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Perfusion strategies during aortic surgery usually comprise hypothermic circulatory arrest (HCA), often combined with selective antegrade cerebral perfusion (SACP) or retrograde cerebral perfusion. Cerebral blood flow (CBF) is a fundamental parameter for which the optimal level has not been clearly defined. We sought to determine the CBF at a pump flow level of 6 mL/kg/min, previously shown likely to provide adequate SACP at 20°C in pigs.

METHODS: Repeated positron emission tomography (PET) scans were used to quantify the CBF and glucose metabolism throughout HCA and SACP including cooling and rewarming. Eight pigs on cardiopulmonary bypass were assigned to either HCA alone (n = 4) or HCA+SACP (n = 4). The CBF was measured by repeated [(15)O]water PET scans from baseline to rewarming. The cerebral glucose metabolism was examined by [(18)F]fluorodeoxyglucose PET scans after rewarming to 37°C.

RESULTS: Cooling to 20°C decreased the cortical CBF from 0.31 ± 0.06 at baseline to 0.10 ± 0.02 mL/cm(3)/min (p = 0.008). The CBF was maintained stable by SACP of 6 mL/kg/min during 45 minutes. After rewarming to 37°C, the mean CBF increased to 0.24 ± 0.07 mL/cm(3)/min, without significant differences between the groups at any time-point exclusive of the HCA period. The net cortical uptake (Ki) of [(18)F]fluorodeoxyglucose after rewarming showed no significant difference between the groups.

CONCLUSIONS: Cooling autoregulated the CBF to 0.10 mL/cm(3)/min, and 45 minutes of SACP at 6 mL/kg/min maintained the CBF in the present model. Cerebral glucose metabolism after rewarming was similar in the study groups.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-302609 (URN)10.1016/j.athoracsur.2016.06.029 (DOI)000397165400067 ()27592601 (PubMedID)
Available from: 2016-09-07 Created: 2016-09-07 Last updated: 2018-09-03Bibliographically approved
Nordeman, P., Johansson, L. B. G., Back, M., Estrada, S., Hall, H., Sjölander, D., . . . Antoni, G. (2016). C-11 and F-18 Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates. ACS Medicinal Chemistry Letters, 7(4), 368-373
Open this publication in new window or tab >>C-11 and F-18 Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates
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2016 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 4, p. 368-373Article in journal (Refereed) Published
Abstract [en]

Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

Keywords
Positron emission tomography, amyloidosis, amyloid-beta, transthyretin, AL amyloidosis, oligothiophenes
National Category
Pharmacology and Toxicology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-296858 (URN)10.1021/acsmedchemlett.5b00309 (DOI)000374436700007 ()27096043 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyEU, European Research Council
Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2019-03-29Bibliographically approved
Estrada, S., Lubberink, M., Thibblin, A., Sprycha, M., Buchanan, T., Mestdagh, N., . . . Antoni, G. (2016). [C-11]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A. Nuclear Medicine and Biology, 43(6), 325-332
Open this publication in new window or tab >>[C-11]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A
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2016 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 43, no 6, p. 325-332Article in journal (Refereed) Published
Abstract [en]

Introduction: Development of a selective and specific high affinity PET tracer, [C-11]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine V-T. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. Results: 3-5 GBq of [C-11]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65 GBq/mu mol. In vitro binding showed high selective binding towards SV2A. [C-11]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the V-T could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [C-11]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. Conclusions: We have developed the novel PET tracer, [C-11]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400 MBq of [C-11]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline V-T values. This will have to be further validated in human studies.

Keywords
SV2A, Epilepsy, [C-11]UCB-A, Preclinical PET
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-299599 (URN)10.1016/j.nucmedbio.2016.03.004 (DOI)000378011300001 ()27260773 (PubMedID)
Available from: 2016-07-25 Created: 2016-07-25 Last updated: 2017-11-28Bibliographically approved
Stevens, M., Chow, C., Estrada, S., Eriksson, J., Asplund, V., Orlova, A., . . . Odell, L. (2016). Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO. ChemistryOpen, 58(3), 566-573
Open this publication in new window or tab >>Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO
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2016 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 58, no 3, p. 566-573Article in journal (Refereed) Accepted
Abstract [en]

Herein we describe the development of new methodologyfocusing on 11C-labelling of sulfonyl carbamates in a multicomponentreaction comprising a sulfonyl azide, an alkyl alcohol and [11C]CO. Anumber of 11C-labelled sulfonyl carbamates were synthesised andisolated, and the developed methodology was then applied in thepreparation of a biologically active molecule. The target compoundwas obtained in 18±8% isolated radiochemical yield and wasevaluated for binding properties in a tumor cell assay, as well asundergoing in vivo biodistribution and imaging studies. Thisrepresents the first successful radiolabelling of C21, a non-peptideangiotensin II receptor subtype 2 agonist currently in clinical trials.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-296406 (URN)
Available from: 2016-06-16 Created: 2016-06-16 Last updated: 2017-11-28
Stevens, M. Y., Chow, S. Y., Estrada, S., Eriksson, J., Asplund, V., Orlova, A., . . . Odell, L. R. (2016). Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO. ChemistryOpen, 5(6), 566-573
Open this publication in new window or tab >>Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO
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2016 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 5, no 6, p. 566-573Article in journal (Refereed) Published
Abstract [en]

We describe the development of a new methodology focusing on C-11-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [C-11] CO. A number of C-11-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24 +/- 10% isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.

Keywords
AT(2)R agonists, multicomponent reactions, radiochemistry, sulfonyl azides, sulfonyl carbamates
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-316971 (URN)10.1002/open.201600091 (DOI)000393071500012 ()28032026 (PubMedID)
Funder
Carl Tryggers foundation , CTS13:333 CTS14:356Swedish Cancer Society, 2014/474Swedish Research Council, 2015-02509
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-01-13Bibliographically approved
Velikyan, I., Selvaraju, R. K., Bulenga, T., Espes, D., Lubberink, M., Sörensen, J., . . . Eriksson, O. (2015). Dosimetry of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 in rodents, pigs, non-human primates and human. Journal of labelled compounds & radiopharmaceuticals, 58, S95-S95
Open this publication in new window or tab >>Dosimetry of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 in rodents, pigs, non-human primates and human
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2015 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, p. S95-S95Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-284896 (URN)000369950200096 ()
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Yngve, U., Nordeman, P., Estrada, S., Marklund, N., Auberson, Y., Machauer, R., . . . Antoni, G. (2015). Tracing BACE: Synthesis and evaluation of beta-secretase inhibitors as ligands for PET imaging. Journal of labelled compounds & radiopharmaceuticals, 58, S51-S51
Open this publication in new window or tab >>Tracing BACE: Synthesis and evaluation of beta-secretase inhibitors as ligands for PET imaging
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2015 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, p. S51-S51Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-284900 (URN)000369950200052 ()
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Nordeman, P., Estrada, S., Odell, L. R., Larhed, M. & Antoni, G. (2014). 11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo. Nuclear Medicine and Biology, 41(6), 536-543
Open this publication in new window or tab >>11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
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2014 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, p. 536-543Article in journal (Refereed) Published
Abstract [en]

Introduction: The enzyme beta-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-p, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo. Methods: (11)[C]-N-1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-y1)-5-(N-methylmethylsulfonamido)-N-3-((R)-1-phenylethyl)isophthalamide, a p-secretase inhibitor, denoted here as [C-11]BSIIV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [C-11]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats. Results: The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21-26%. [C-11]BSI-IV was obtained in 29 +/- 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 +/- 155 GBq/umol at the end of synthesis with a radiochemical purity of >99%. The predinical studies showed that [C-11]BSI-IV has a rapid metabolism in rat with excretion to the small intestines. Conclusion: [C-11]BSI-IV was obtained in sufficient amount and purity to enable predinical investigation. The predinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [C-11]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-213860 (URN)10.1016/j.nucmedbio.2014.03.024 (DOI)000336946400014 ()
Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2018-01-11Bibliographically approved
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