Autoradiography, MALDI-MS, and SIMS-MS Imaging in Pharmaceutical Discovery and Development

Solon, Eric; Schweitzer, A.; Stoeckli, Markus; Prideaux, Brendan

doi:10.1208/s12248-009-9158-4

Cited by 230 publications

(208 citation statements)

References 83 publications

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“…While a 0.1 mg/kg dose in the monkey is 2.5-fold higher than the human starting dose of 0.04 mg/kg administered every 4 weeks, the 5 mg/kg dose is 125-fold higher than the human starting dose. The nonclinical doses were selected to obtain a recommended targeted radioactive dose of 16-300 mCi/kg (Solon et al, 2010) and based on the achievable specific activity of [ 14 C]peginesatide. Administration of lower clinically relevant doses would not have delivered adequate radioactivity for the determination of tissue distribution using both QWBA and MARG analyses.…”

Section: Discussionmentioning

confidence: 99%

Peginesatide Clearance, Distribution, Metabolism, and Excretion in Monkeys following Intravenous Administration

Woodburn

Fong

Wilson³

et al. 2013

Drug Metab Dispos

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Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine.

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Section: Discussionmentioning

confidence: 99%

Peginesatide Clearance, Distribution, Metabolism, and Excretion in Monkeys following Intravenous Administration

Woodburn

Fong

Wilson³

et al. 2013

Drug Metab Dispos

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“…26 SIMS with high mass and lateral resolution capabilities and parts per million or parts per billion detection limit is widely applied in biology. In SIMS analysis (Fig.…”

Section: Secondary Ion Mass Spectrometry Imagingmentioning

confidence: 99%

Review of combined isotopic and optical nanoscopy

et al. 2017

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Abstract. Investigating the detailed substructure of the cell is beyond the ability of conventional optical microscopy. Electron microscopy, therefore, has been the only option for such studies for several decades. The recent implementation of several super-resolution optical microscopy techniques has rendered the investigation of cellular substructure easier and more efficient. Nevertheless, optical microscopy only provides an image of the present structure of the cell, without any information on its long-temporal changes. These can be investigated by combining super-resolution optics with a nonoptical imaging technique, nanoscale secondary ion mass spectrometry, which investigates the isotopic composition of the samples. The resulting technique, combined isotopic and optical nanoscopy, enables the investigation of both the structure and the "history" of the cellular elements. The age and the turnover of cellular organelles can be read by isotopic imaging, while the structure can be analyzed by optical (fluorescence) approaches. We present these technologies, and we discuss their implementation for the study of biological samples. We conclude that, albeit complex, this type of technology is reliable enough for mass application to cell biology. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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“…• In matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI), and secondary ion mass spectrometric imaging (SIMS-MSI) for pharmaceutical discovery and development [20].…”

Section: Disadvantagesmentioning

confidence: 99%