Johan Hygum Dam
Odense University Hospital
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Featured researches published by Johan Hygum Dam.
The Journal of Nuclear Medicine | 2014
Helge Thisgaard; Birgitte Brinkmann Olsen; Johan Hygum Dam; Peter Bollen; Jan Mollenhauer; Poul Flemming Høilund-Carlsen
The somatostatin receptor, which is overexpressed by many neuroendocrine tumors, is a well-known target for molecular imaging and peptide receptor radionuclide therapy. Recently, 57Co-labeled DOTATOC, an octreotide analog, was shown to have the highest affinity yet found for somatostatin receptor subtype 2. The aim of this study was to evaluate the biologic effects of novel cobalt-labeled octreotide analogs targeting the somatostatin receptor to identify promising candidates for molecular imaging and Auger electron–based radionuclide therapy. Methods: Cobalt-labeled DOTATATE, DOTATOC, and DOTANOC were prepared with 57Co or 58mCo for SPECT or Auger electron–based therapy, respectively. The cellular uptake and intracellular distribution of the radioligands were characterized with the pancreatic tumor cell line AR42J in vitro, including assessment of the therapeutic effects of 58mCo-DOTATATE via DNA double-strand break and proliferation assays. Comparisons with the therapeutic effects of 111In- and 177Lu-DOTATATE were also performed. Tumor uptake and normal tissue uptake were characterized in a subcutaneous pancreatic tumor mouse model. Results: All 3 cobalt-conjugated peptides resulted in time-dependent and receptor-specific uptake, with a high level (≥88%) of cellular internalization in vitro of the total cell-associated radioactivity. The DNA double-strand break yield showed a dose-dependent increase with activity, whereas cell survival showed a dose-dependent decrease. 58mCo-DOTATATE was significantly more efficient in cell killing per cumulated decay than 111In- and 177Lu-DOTATATE. The in vivo pharmacokinetic studies showed a high level of receptor-specific tumor uptake. Conclusion: All cobalt-labeled radioligands showed a high level of receptor-specific uptake both in vitro and in vivo in tumor-bearing mice. Furthermore, 58mCo-DOTATATE showed considerable therapeutic effects in vitro and, thus, could be an effective agent for eradicating disseminated tumor cells and micrometastases.
Contrast Media & Molecular Imaging | 2017
Bogdan Mitran; Helge Thisgaard; Ulrika Rosenström; Johan Hygum Dam; Mats Larhed; Vladimir Tolmachev; Anna Orlova
High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a 55Co-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with 57Co and 55Co, stability, binding specificity, and in vitro and in vivo characteristics of 57Co-NOTA-PEG2-RM26 were studied. NOTA-PEG2-RM26 was successfully radiolabeled with 57Co and 55Co with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. 57Co-NOTA-PEG2-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG2-RM26 translated into high contrast preclinical PET/CT (using 55Co) and SPECT/CT (using 57Co) images of PC-3 xenografts. The initial biological results suggest that 55Co-NOTA-PEG2-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.
Nuclear Medicine and Biology | 2016
Johan Hygum Dam; Dirk Bender; Dan Peters; Kjell Någren
INTRODUCTION NS9531, NS9762 and NS6417 are nitroquinolinyl-diazabicyclo-alkane derivatives that have been developed as inhibitors of serotonin reuptake transporters (SERT) by NeuroSearch A/S. METHODS IC50 was measured on the up-take of serotonin, dopamine and noradrenaline in synaptosomes prepared from selected rat brain regions. For the pre-clinical evaluation in pigs, [(11)C]NS9531, [(11)C]NS9762 and [(11)C]NS6417 were prepared by N-methylation using [(11)C]methyl iodide. These syntheses were later on optimized regarding: 1) choice of labelled precursor; 2) HPLC purification conditions; and 3) formulation using SPE columns. The synthesis protocols were then fully automated on a GE FXc Pro. Preclinical evaluation was performed by PET studies in landrace pigs before and after treatment with citalopram. RESULTS IC50 measurements showed that all three compounds have low nanomolar affinity for SERT, and micromolar affinity for DAT and NET. The radiochemical yield (r.y.) of all three ligands from [(11)C]methyl iodide was higher than 30%. From [(11)C]methyl triflate, the r.y. of [(11)C]NS9531 and [(11)C]NS9762 were higher than 80% whereas the r.y. of [(11)C]NS6417 was 65%. Residual precursor amounts in final products could be significantly reduced by the use of [(11)C]methyl triflate, <0.2 μg compared with <10 μg, calculated for a 300 MBq injection at 20 minutes EOS. The optimized conditions gave 2.5-4.5 GBq of products with a specific radioactivity of 20-70 MBq/nmol, residual acetonitrile 15-30 ppm, and pH 6.5-7.1. All three compounds showed a rapid and comparable high pig brain uptake of about 3%, producing PET images of good contrast, and uptake was reduced after pre-administration with citalopram. CONCLUSION The three (11)C labelled PET tracers could be prepared in medium to high yield and high purity. IC50 measurements showed that the three NS compounds were highly selective, high affinity SERT inhibitors. PET studies in pig showed high brain uptake that could be blocked by citalopram pre-treatment.
Journal of Controlled Release | 2018
Pablo Hervella; Johan Hygum Dam; Helge Thisgaard; Christina Baun; Birgitte Brinkmann Olsen; Poul Flemming Høilund-Carlsen; David Needham
Background and motivation: While small molecules can be used in cancer diagnosis there is a need for imageable diagnostic NanoParticles (NPs) that act as surrogates for the therapeutic NPs. Many NPs are composed of hydrophobic materials so the challenge is to formulate hydrophobic imaging agents. To develop individualized medical treatments based on NP, a first step should be the selection of patients who are likely responders to the treatment as judged by imaging tumor accumulation of NPs. This requires NPs with the same size and structure as the subsequent therapeutic NPs but labelled with a long‐lived radionuclide. Cobalt isotopes are good candidates for NP labelling since 55Co has half‐life of 17.5h and positron energy of 570keV while 57Co (t1/2 271.6 d) is an isotope suited for preclinical single photon emission tomography (SPECT) to visualize biodistribution and pharmacokinetics of NPs. We used the hydrophobic octaethyl porphyrin (OEP) to chelate cobalt and to encapsulate it inside hydrophobic liquid NPs (LNPs). We hypothesized that at least two additional hydrophobic axial ligands (oleylamine, OA) must be provided to the OEP‐Co complex in order to encapsulate and retain Co inside LNP. Results: 1. Cobalt chelation by OEP and OA. The association constant of cobalt to OEP was 2.49×105 M−1 and the formation of the hexacoordinate complex OEP‐Co‐4OA was measured by spectroscopy. 2. NP formulation and characterization: LNPs were prepared by the fast ethanol injection method and were composed of a liquid core (triolein) surrounded by a lipid monolayer (DSPC:Cholesterol:DSPE‐PEG2000). The size of the LNPs loaded with the cobalt complex was 40±5nm, 3. Encapsulation of OEP‐Co‐OA: The loading capacity of OEP‐Co‐OA in LNP was 5mol%. 4. Retention of OEP‐57Co‐4OA complex in the LNPs: the positive effect of the OA ligands was demonstrated on the stability of the OEP‐57Co‐4OA complex, providing a half‐life for retention in PBS of 170h (7days) while in the absence of the axial OA ligands was only 22h. 5 Biodistribution Study: the in vivo biodistribution of LNP was studied in AR42J pancreatic tumor‐bearing mice. The estimated half‐life of LNPs in blood was about 7.2h. Remarkably, the accumulation of LNPs in the tumor was as high as 9.4% ID/g 24h after injection with a doubling time for tumor accumulation of 3.22h. The most important result was that the nanoparticles could indeed accumulate in the AR42J tumors up to levels greater than those of other NPs previously measured in the same tumor model, and at about half the values reported for the molecular agent 57Co‐DOTATATE. Conclusions: The additional hydrophobic chelator OA was indeed needed to obtain a stable octahedral OEP‐Co‐4OA. Cobalt was actually well‐retained inside LNP in the OEP‐Co‐4OA complex. The method described in the present work for the core‐labelling of LNPs with cobalt is now ready for labeling of NPs with 55Co, or indeed other hexadentate radionuclides of interest for preclinical in vivo PET‐imaging and radio‐therapeutics.
European Journal of Nuclear Medicine and Molecular Imaging | 2017
Pablo Hervella; Johan Hygum Dam; Helge Thisgaard; Christina Baun; Birgitte Brinkmann Olsen; Poul Flemming Høilund-Carlsen; David Needham
European Journal of Nuclear Medicine and Molecular Imaging Volume 44, Supplement 2 10.1007/s00259-017-3822-1 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources DOI 10.1007/s00259-017-3822-1 S119 Eur J Nucl Med Mol Imaging (2017) 44 (Suppl 2):S119–S956
European Journal of Nuclear Medicine and Molecular Imaging | 2016
Kjell Någren; Johan Hygum Dam; Christina Baun; Thomas Emil Andersen; Algirdas Šačkus; Osvaldas Paliulis; Dan Peters
Hypothesis: We assessed in in vitro and in vivo models of ovarian cancer the therapeutic efficacy of 16F12 mAbs directed against Mullerian Inhibiting Substance type II receptor (MISRII) radiolabeled with 213Bi Methods: In vitro, both direct and bystander cytotoxic effects were measured using clonogenic assay and standard medium transfer protocol. Typically, Clonogenic survival was assessed in SK-OV-3 donor cells expressing MISRII and exposed for 90 min to 0.06-0.5MBq/mL of 16F12 213Bi-mAbs. Bystander cytotoxicity was measured in recipient cells grown in non-radioactive culture medium preconditioned for 2 hours in the presence of donor cells. DNA double strand breaks (DSBs) were measured in both donor and recipients cells using immunofluorescent detection of gamma-H2AX and of 53BP1. In vivo we explored in athymic nude mice bearing intraperitoneal (IP) MISRII-expressing AN3CA tumor the therapeutic efficacy of brief-intraperitoneal radioimmunotherapy (BIP-RIT, 12.95 37 MBq; 37MBq/mg) or of intraperitoneal RIT (IP-RIT; 2.96-12.95 MBq; 37MBq/mg) using 213Bi-16F12. BIP-RIT mimics hyperthermic intraperitoneal chemotherapy as used in clinic. It consists of intraperitoneal injection of high activities of radiolabeled mAbs followed 30 min later by wash of the peritoneal cavity with saline solution to remove unbound radioactivity. The biodistribution of radiolabeled antibodies following IP-RIT (12.95 MBq; 37MBq/mg) or BIP-RIT (37 MBq; 37MBq/mg) was assessed. Results: In vitro we showed in donor cells a strong direct cytotoxicity of 16F12 213Bi-mAbs. A significant bystander cytotoxicity was also measured in recipient cells. Genotoxic effects were also demonstrated as measured by the formation of DNA DSBs in both donor and recipient cells. In vivo, results of biodistribution indicated that tumour uptake of 213Bi-16F12 during BIP RIT was higher than after IP RIT. The tumour-to-blood uptake ratio was 9 versus 3, respectively, one hour post RIT while it decreased down to 3 and 1, respectively, three hours post-RIT. Finally, a similar delay in tumor growth was observed in mice treated with 12.95 MBq of 213Bi-16F12 following IP-RIT or treated with 37 MBq using BIP-RIT. Conclusions: We confirmed in vitro the therapeutic efficacy of newly developed 16F12 213Bi-mAbs. in vivo results indicate that similar therapeutic efficacy and lower toxicity could be obtained with BIP-RIT compared with IP-RIT. BIP-RIT could be a new tool in the therapy of peritoneal carcinomatosis. URI: Authors: LADJOHOUNLOU Riad PICHARD Alexandre DEHAYES E BOUDOUSQ Vincent BRUCHERTSEIFER Frank MORGENSTERN Alfred NAVARRO-TEULON Isabelle POUGET Jean-Pierre Publication Year: 2016 Science Areas: Health and consumer protection [1]European Journal of Nuclear Medicine and Molecular Imaging Volume 43, Supplement 1 10.1007/s00259-016-3484-4 This supplement was not sponsored by outside commercial interests. It was funded entirely by the association’s own resources. ABSTRACT DOI 10.1007/s00259-016-3484-4 Eur J Nucl Med Mol Imaging (2016) 43 (Suppl 1):S1–S734Background: In the context of the EORTC LungTech trial, a QA procedure including a PET/CT credentialing has been developed. This procedure will ultimately allow us to pool data from 23 institutions with the overall goal of investigating the impact of tumour motion on quantification. As no standardized procedure exists under respiratory conditions, we investigated the variability of 14 SUV metrics to assess their robustness over respiratory noise. Methods: The customized CIRS-008A phantom was scanned at 13 institutions. This phantom consists of a 18 cm long body, a rod attached to a motion actuator, and a sphere of either 1.5 or 2.5cm diameters. Body, rods and spheres were filled with homogeneous 18FDG solutions representative of activity concentrations in mediastinum, lung and tumour for a 70kg patient. Three respiratory patterns with peak-to-peak amplitudes and periods of 15mm/3sec, 15mm/6sec and 25mm/4sec were tested. Prior to scanning in respiratory condition, a 3D static PET/CT was acquired as reference. During motion, images were acquired using 3D or 4D gated PET(average image) according to institutional settings. 14 SUV(mean) metrics were obtained per acquisition varying VOI/ ROI shape and location. Three ROIs and three VOIs with respective radii of 0.5, 0.6 and 0.8cm were investigated. These ROIs/VOIs were first centred on the maximum activity voxel; a second analysis was made changing the location from the voxel to the region (ROI5voxels) or the volume (VOI7voxels) with the maximum value. Two additional VOIs were defined as 3D isocontours respectively at 70% and 50% of the maximum voxel value. The SUV metrics were normalized by the corresponding 3D static SUV. Converting to recovery coefficients (RC) allowed us to pool data from all institutions, while maintaining focus solely on motion. For each RC from each motion setting we calculated the mean over institutions, we then looked at the standard deviation (Sd) and spread of each averaged RC over each motion setting (formula [1], [2], Figure1). Results: For the institutions visited we found that RCVOI70% and RCVOI50%, yielded over the 14 metrics the lowest variability to motion with Sd of 0.04 and 0.03 respectively. The RCs based on ROIs/VOIs centered on a single voxel were less impacted by motion (Sd: 0.08) compared to region RCs (Sd: 0.14). The averaged Sd over the RCs based on VOIs and ROIs was 0.12 and 0.11 respectively. Conclusion: Quantification over breathing types depends on ROI/VOI definition. Variables based on SUV max thresholds were found the most robust against respiratory noise.
Journal of Labelled Compounds and Radiopharmaceuticals | 2011
Helge Thisgaard; Marie Louise Olesen; Johan Hygum Dam
Molecular Imaging and Biology | 2016
Johan Hygum Dam; Birgitte Brinkmann Olsen; Christina Baun; Poul Flemming Høilund-Carlsen; Helge Thisgaard
Theranostics | 2016
Helge Thisgaard; Bo Halle; Charlotte Aaberg-Jessen; Birgitte Brinkmann Olsen; Anne Sofie Nautrup Therkelsen; Johan Hygum Dam; Niels Langkjær; Sune Munthe; Kjell Någren; Poul Flemming Høilund-Carlsen; Bjarne Winther Kristensen
Molecular Imaging and Biology | 2017
Johan Hygum Dam; Birgitte Brinkmann Olsen; Christina Baun; Poul Flemming Høilund-Carlsen; Helge Thisgaard