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Guus A M S Van Dongen - One of the best experts on this subject based on the ideXlab platform.
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noise induced variability of immuno pet with Zirconium 89 labeled antibodies an analysis based on count reduced clinical images
Molecular Imaging and Biology, 2018Co-Authors: Yvonne W S Jauw, Danielle J Vugts, Guus A M S Van Dongen, Ronald Boellaard, Dennis F R Heijtel, Josee M Zijlstra, Otto S Hoekstra, Henk M W Verheul, Sonja Zweegman, Willemien Menkevan Der Houven C Van OordtAbstract:PURPOSE: Positron emission tomography (PET) with Zirconium-89 (Zr-89)-labeled antibodies can be used for in vivo quantification of antibody uptake. Knowledge about measurement variability is required to ensure correct interpretation. However, no clinical studies have been reported on measurement variability of Zr-89 immuno-PET. As variability due to low signal-to-noise is part of the total measurement variability, the aim of this study was to assess noise-induced variability of Zr-89 -immuno-PET using count-reduced clinical images. PROCEDURES: Data were acquired from three previously reported clinical studies with [89Zr]antiCD20 (74 MBq, n = 7), [89Zr]antiEGFR (37 MBq, n = 7), and [89Zr]antiCD44 (37 MBq, n = 13), with imaging obtained 1 to 6 days post injection (D0-D6). Volumes of interest (VOIs) were manually delineated for liver, spleen, kidney, lung, brain, and tumor. For blood pool and bone marrow, fixed-size VOIs were used. Original PET list mode data were split and reconstructed, resulting in two count-reduced images at 50 % of the original injected dose (e.g., 37 MBq74inj). Repeatability coefficients (RC) were obtained from Bland-Altman analysis on standardized uptake values (SUV) derived from VOIs applied to these images. RESULTS: The RC for the combined manually delineated organs for [89Zr] antiCD20 (37 MBq74inj) increased from D0 to D6 and was less than 6 % at all time points. Blood pool and bone marrow had higher RC, up to 43 % for 37 MBq74inj at D6. For tumor, the RC was up to 42 % for [89Zr]antiCD20 (37 MBq74inj). For [89Zr]antiCD20, (18 MBq74inj), [89Zr]antiEGFR (18 MBq37inj), and [89Zr]antiCD44 (18 MBq37inj), measurement variability was independent of the investigated antibody. CONCLUSIONS: Based on this study, noise-induced variability results in a RC for Zr-89-immuno-PET (37 MBq) around 6 % for manually delineated organs combined, increasing up to 43 % at D6 for blood pool and bone marrow, assuming similar biodistribution of antibodies. The signal-to-noise ratio leads to tumor RC up to 42 %.
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Cerebral rituximab uptake in multiple sclerosis: A 89Zr-immunoPET pilot study.
Multiple Sclerosis Journal, 2017Co-Authors: Marloes Hagens, Guus A M S Van Dongen, Joep Killestein, Maqsood Yaqub, Adriaan A. Lammertsma, Frederik Barkhof, Bart N.m. Van BerckelAbstract:Previous studies have demonstrated that the chimeric monoclonal antibody rituximab significantly reduces clinical and radiological disease activity in relapsing-remitting multiple sclerosis as early as 4 weeks after the first administration. The exact mechanisms leading to this rapid effect have not yet been clarified. The aim of this positron emission tomography study was to assess central nervous system penetration as a possible explanation, using Zirconium-89-labelled rituximab. No evidence was found for cerebral penetration of [89Zr]rituximab.
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b cell imaging with Zirconium 89 labelled rituximab pet ct at baseline is associated with therapeutic response 24 weeks after initiation of rituximab treatment in rheumatoid arthritis patients
Arthritis Research & Therapy, 2016Co-Authors: Stefan T G Bruijnen, Danielle J Vugts, Guus A M S Van Dongen, Otto S Hoekstra, Marc C Huisman, M Tsangasjoe, Hennie G Raterman, T H Ramwadhdoebe, Alexandre E Voskuyl, Conny J Van Der LakenAbstract:B cells are key players in the pathogenesis of rheumatoid arthritis (RA). Although successful in 50–60% of patients with RA, anti-B-cell therapy given as rituximab could be more efficient by identifying potential responders prior to treatment. Positron emission tomography (PET) using radiolabeled rituximab for B-cell imaging might provide the means to fulfil this unmet clinical need. The objective of this study was to investigate the association between biodistribution of Zirconium-89 (89Zr)-rituximab on PET-computed tomography (CT) and clinical response in patients with RA. We included 20 patients with RA who were starting rituximab treatment. At the first intravenous (i.v.) therapeutic dose, patients were also injected with 89Zr-rituximab, followed by PET-CT. European League Against Rheumatism (EULAR) response criteria were applied to determine response at week 24. PET-CT was analyzed visually and quantitatively. Lymph node (LN) biopsies were performed at 0 and 4 weeks to correlate B-cell counts with imaging data. PET-positive hand joints (range 1–20) were observed in 18/20 patients. Responders had significantly higher 89Zr-rituximab uptake in PET-positive hand joints than non-responders (median target-to-background (T/B)) ratios (IQR) were 6.2 (4.0–8.8) vs. 3.1 (2.2–3.9), p = 0.02). At T/B ≥4.0, positive and negative predictive values for clinical response were respectively 90% and 75%. Quantitative 89Zr-rituximab hand joint uptake on PET correlated inversely with CD22+ B-cell count in LN tissue at 4 weeks of treatment (r = 0.6, p = 0.05). In addition, the CD22+ B-cell count in LN correlated positively with quantitative LN PET data at baseline, supporting the specificity of B-cell imaging on PET. Non-invasive B-cell imaging by 89Zr-rituximab PET-CT has promising clinical value to select RA responders to rituximab at baseline. 89Zr-rituximab PET-CT may also hold promise for monitoring anti-B-cell therapies in other B-cell driven autoimmune diseases, such as systemic lupus erythematosus and Sjogren’s disease.
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immuno positron emission tomography with Zirconium 89 labeled monoclonal antibodies in oncology what can we learn from initial clinical trials
Frontiers in Pharmacology, 2016Co-Authors: Yvonne W S Jauw, Danielle J Vugts, Josee M Zijlstra, Otto S Hoekstra, Willemien Menkevan Der Houven C Van Oordt, Harry N Hendrikse, Marc C Huisman, Guus A M S Van DongenAbstract:Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using Zirconium-89 (89Zr)-labeled monoclonal antibodies also known as 89Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with 89Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with 89Zr-immuno-PET two requirements should be met for each 89Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the 89Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of 89Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed towards the development of 89Zr-immuno-PET as an imaging biomarker by showing association between uptake of 89Zr-labeled mAbs on PET and target expression levels in biopsies. However, no definitive proof has been reported that 89Zr-immuno-PET reflects specific, antigen-mediated binding. 89Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop 89Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.
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inert coupling of irdye800cw and Zirconium 89 to monoclonal antibodies for single or dual mode fluorescence and pet imaging
Nature Protocols, 2013Co-Authors: Ruth Cohen, Gerard W M Visser, Danielle J Vugts, Marijke Stigtervan Walsum, Guus A M S Van DongenAbstract:Inert coupling of IRDye800CW and Zirconium-89 to monoclonal antibodies for single- or dual-mode fluorescence and PET imaging
Todd E. Barnhart - One of the best experts on this subject based on the ideXlab platform.
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chelator free labeling of metal oxide nanostructures with Zirconium 89 for positron emission tomography imaging
ACS Nano, 2017Co-Authors: Liang Cheng, Shreya Goel, Emily B Ehlerding, Sida Shen, Dawei Jiang, Paul A Ellison, Guosheng Song, Peng Huang, Todd E. BarnhartAbstract:Radiolabeling of molecules or nanoparticles to form imaging probes is critical for positron emission tomography (PET) imaging, which, with high sensitivity and the ability for quantitative imaging, has been widely used in the clinic. While conventional radiolabeling often employs chelator molecules, a general method for chelator-free radiolabeling of a wide range of materials remains to be developed. Herein, we determined that 10 different types of metal oxide (MxOy, M = Gd, Ti, Te, Eu, Ta, Er, Y, Yb, Ce, or Mo, x = 1–2, y = 2–5) nanomaterials with polyethylene glycol (PEG) modification could be labeled with 89Zr, a PET tracer, via a simple yet general chelator-free radiolabeling method upon simple mixing. High-labeling yields and good serum stabilities are achieved with this method, owing to the strong bonding between oxyphilic 89Zr4+ with oxygen atoms on the MxOy surface. Selecting 89Zr–Gd2O3–PEG as a multimodal imaging probe, we have successfully demonstrated in vivo PET imaging of draining lymph nodes...
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engineering intrinsically Zirconium 89 radiolabeled self destructing mesoporous silica nanostructures for in vivo biodistribution and tumor targeting studies
Advanced Science, 2016Co-Authors: Shreya Goel, Fanrong Ai, Feng Chen, Hector F. Valdovinos, Todd E. Barnhart, Shijie Luan, Stephen A Graves, Charles P TheuerAbstract:: A systematic study of in vitro and in vivo behavior of biodegradable mesoporous silica nanoparticles (bMSNs), designed to carry multiple cargos (both small and macromolecular drugs) and subsequently self-destruct following release of their payloads, is presented. Complete degradation of bMSNs is seen within 21 d of incubation in simulated body fluid. The as-synthesized bMSNs are intrinsically radiolabeled with oxophilic Zirconium-89 (89Zr, t1/2 = 78.4 h) radionuclide to track their in vivo pharmacokinetics via positron emission tomography imaging. Rapid and persistent CD105 specific tumor vasculature targeting is successfully demonstrated in murine model of metastatic breast cancer by using TRC105 (an anti-CD105 antibody)-conjugated bMSNs. This study serves to illustrate a simple, versatile, and readily tunable approach to potentially overcome the current challenges facing nanomedicine and further the goals of personalized nanotheranostics.
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Spot-welding solid targets for high current cyclotron irradiation.
Applied Radiation and Isotopes, 2016Co-Authors: Paul A Ellison, Hector F. Valdovinos, Todd E. Barnhart, Stephen A Graves, Robert J. NicklesAbstract:Abstract Zirconium-89 finds broad application for use in positron emission tomography. Its cyclotron production has been limited by the heat transfer from yttrium targets at high beam currents. A spot welding technique allows a three-fold increase in beam current, without affecting 89Zr quality. An yttrium foil, welded to a jet-cooled tantalum support base accommodates a 50 µA proton beam degraded to 14 MeV. The resulting activity yield of 48±4 MBq/(μA∙hr) now extends the outreach of 89Zr for a broader distribution.
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intrinsically Zirconium 89 labeled gd2o2s eu nanoprobes for in vivo positron emission tomography and gamma ray induced radioluminescence imaging
Small, 2016Co-Authors: Yonghua Zhan, Fanrong Ai, Feng Chen, Hector F. Valdovinos, Hakan Orbay, Jimin Liang, Haiyan Sun, Todd E. BarnhartAbstract:The engineering of a novel dual-modality imaging probe is reported here by intrinsically labeling Zirconium-89 ((89) Zr, a positron emission radioisotope with a half-life of 78.4 h) to PEGylated Gd2 O2 S:Eu nanophorphors, forming [(89) Zr]Gd2 O2 S:Eu@PEG for in vivo positron emission tomography/radioluminescence lymph node mapping.
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Intrinsically Zirconium‐89 Labeled Gd2O2S:Eu Nanoprobes for In Vivo Positron Emission Tomography and Gamma‐Ray‐Induced Radioluminescence Imaging
Small, 2016Co-Authors: Yonghua Zhan, Fanrong Ai, Feng Chen, Hector F. Valdovinos, Hakan Orbay, Jimin Liang, Todd E. Barnhart, Jie TianAbstract:: The engineering of a novel dual-modality imaging probe is reported here by intrinsically labeling Zirconium-89 ((89) Zr, a positron emission radioisotope with a half-life of 78.4 h) to PEGylated Gd2 O2 S:Eu nanophorphors, forming [(89) Zr]Gd2 O2 S:Eu@PEG for in vivo positron emission tomography/radioluminescence lymph node mapping.
Thaddeus J Wadas - One of the best experts on this subject based on the ideXlab platform.
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A comprehensively revised strategy that improves the specific activity and long-term stability of clinically relevant 89Zr-immuno-PET agents
Dalton Transactions, 2018Co-Authors: Nikunj Bhatt, Darpan N Pandya, Stephanie Rideout-danner, H. D. Gage, Frank C. Marini, Thaddeus J WadasAbstract:Zirconium-89 is currently being used in numerous clinical trials involving monoclonal antibodies and positron emission tomography. This report describes a revised strategy that reduces preparation time while increasing the specific activity of clinically relevant immuno-PET agents. Additionally, it demonstrates that n-acetyl-L-cysteine acts as a superior radioprotective agent that improves long-term stability without compromising antigen affinity in vivo.
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recent advances in Zirconium 89 chelator development
Molecules, 2018Co-Authors: Nikunj Bhatt, Darpan N Pandya, Thaddeus J WadasAbstract:The interest in Zirconium-89 (89Zr) as a positron-emitting radionuclide has grown considerably over the last decade due to its standardized production, long half-life of 78.2 h, favorable decay characteristics for positron emission tomography (PET) imaging and its successful use in a variety of clinical and preclinical applications. However, to be utilized effectively in PET applications it must be stably bound to a targeting ligand, and the most successfully used 89Zr chelator is desferrioxamine B (DFO), which is commercially available as the iron chelator Desferal®. Despite the prevalence of DFO in 89Zr-immuno-PET applications, the development of new ligands for this radiometal is an active area of research. This review focuses on recent advances in Zirconium-89 chelation chemistry and will highlight the rapidly expanding ligand classes that are under investigation as DFO alternatives.
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evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for Zirconium 89
PLOS ONE, 2017Co-Authors: Nikunj Bhatt, Darpan N Pandya, Jide Xu, David Tatum, Darren Magda, Thaddeus J WadasAbstract:The development of bifunctional chelators (BFCs) for Zirconium-89 immuno-PET applications is an area of active research. Herein we report the synthesis and evaluation of octadentate hydroxyisophthalamide ligands (1 and 2) as Zirconium-89 chelators. While both radiometal complexes could be prepared quantitatively and with excellent specific activity, preparation of 89Zr-1 required elevated temperature and an increased reaction time. 89Zr-1 was more stable than 89Zr-2 when challenged in vitro by excess DTPA or serum proteins and in vivo during acute biodistribution studies. Differences in radiometal complex stability arise from structural changes between the two ligand systems, and suggest further ligand optimization is necessary to enhance 89Zr chelation.
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composes compositions et procedes associes mettant en œuvre du Zirconium 89 dans l immuno tomographie par emission de positrons
2017Co-Authors: Thaddeus J Wadas, Darpan N Pandya, Nikunj BhattAbstract:L'invention concerne de nouveaux composes, complexes, compositions et procedes mettant en œuvre du Zirconium-89 combines a des chelatants azamacrocycliques en relation avec du PET. Les compositions et les procedes devraient fournir de meilleurs traitements oncologiques de diagnostic, de pronostic et therapeutiques par rapport aux compositions de chelatants actuellement disponibles en raison d'une variete de proprietes superieures des compositions decrites. La presente invention concerne egalement un procede superieur de fabrication de ces composes, complexes, compositions qui permet de fabriquer des composes/complexes (et donc, des compositions) qui ne pouvaient etre obtenus auparavant.
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Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for Zirconium 89 based radiopharmaceutical development
Chemical Science, 2017Co-Authors: Darpan N Pandya, Nikunj Bhatt, Hong Yuan, Brandie M Ehrmann, Marcus W Wright, Ulrich Bierbach, Thaddeus J WadasAbstract:We report our initial investigations into the use of tetraazamacrocycles as Zirconium-89 chelators. We describe the synthesis and complete characterization of several Zr tetraazamacrocycle complexes, and definitively describe the first crystal structure of Zirconium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Zr–DOTA) using single crystal X-ray diffraction analysis. After evaluating several radioactive analogs, we found that 89Zr–DOTA is superior to 89Zr–DFO, the only 89Zr-complex to be used clinically in 89Zr-radiopharmaceutical applications. Finally, we provide a rationale for the unanticipated and extraordinary stability of these complexes in vitro and in vivo. These results may inform the development of safer and more robust immuno-PET agents for precision medicine applications.
Carleen Cullinane - One of the best experts on this subject based on the ideXlab platform.
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bivalent inhibitors of prostate specific membrane antigen conjugated to desferrioxamine b squaramide labeled with Zirconium 89 or gallium 68 for diagnostic imaging of prostate cancer
Journal of Medicinal Chemistry, 2020Co-Authors: Asif Noor, Stacey E Rudd, Peter Roselt, Rodney J Hicks, Jessica Van Zuylekom, Kelly Waldeck, Mohammad B Haskali, Michael P Wheatcroft, Carleen CullinaneAbstract:Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (H3DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H3DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or Zirconium-89 (t1/2 = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or Zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.
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a desferrioxamine b squaramide ester for the incorporation of Zirconium 89 into antibodies
Chemical Communications, 2016Co-Authors: Stacey E Rudd, Peter Roselt, Carleen Cullinane, Rodney J Hicks, Paul S DonnellyAbstract:A squaramide ester derivative of desferrioxamine B (H3DFO) that is compatible with aqueous solvents and does not induce antibody aggregation is used to attach the siderophore to the antibody trastuzumab. The new conjugates were radiolabeled with Zirconium-89 to give complexes that are more resistant to ligand exchange when compared to currently used H3DFO derivatives and result in high quality positron emission tomography images in mouse models of HER2 positive breast cancer.
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correction a desferrioxamine b squaramide ester for the incorporation of Zirconium 89 into antibodies
Chemical Communications, 2016Co-Authors: Stacey E Rudd, Peter Roselt, Carleen Cullinane, Rodney J Hicks, Paul S DonnellyAbstract:Correction for ‘A desferrioxamine B squaramide ester for the incorporation of Zirconium-89 into antibodies’ by Stacey E. Rudd et al., Chem. Commun., 2016, DOI: 10.1039/c6cc05961a.
Rodney J Hicks - One of the best experts on this subject based on the ideXlab platform.
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bivalent inhibitors of prostate specific membrane antigen conjugated to desferrioxamine b squaramide labeled with Zirconium 89 or gallium 68 for diagnostic imaging of prostate cancer
Journal of Medicinal Chemistry, 2020Co-Authors: Asif Noor, Stacey E Rudd, Peter Roselt, Rodney J Hicks, Jessica Van Zuylekom, Kelly Waldeck, Mohammad B Haskali, Michael P Wheatcroft, Carleen CullinaneAbstract:Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (H3DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H3DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or Zirconium-89 (t1/2 = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or Zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.
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a desferrioxamine b squaramide ester for the incorporation of Zirconium 89 into antibodies
Chemical Communications, 2016Co-Authors: Stacey E Rudd, Peter Roselt, Carleen Cullinane, Rodney J Hicks, Paul S DonnellyAbstract:A squaramide ester derivative of desferrioxamine B (H3DFO) that is compatible with aqueous solvents and does not induce antibody aggregation is used to attach the siderophore to the antibody trastuzumab. The new conjugates were radiolabeled with Zirconium-89 to give complexes that are more resistant to ligand exchange when compared to currently used H3DFO derivatives and result in high quality positron emission tomography images in mouse models of HER2 positive breast cancer.
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correction a desferrioxamine b squaramide ester for the incorporation of Zirconium 89 into antibodies
Chemical Communications, 2016Co-Authors: Stacey E Rudd, Peter Roselt, Carleen Cullinane, Rodney J Hicks, Paul S DonnellyAbstract:Correction for ‘A desferrioxamine B squaramide ester for the incorporation of Zirconium-89 into antibodies’ by Stacey E. Rudd et al., Chem. Commun., 2016, DOI: 10.1039/c6cc05961a.
