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With more than 30 million medical applications annually, 99mTc is the most widely used radioisotope. Nevertheless, the discharge of 99mTc and its radioactive nuclear isomer 99Tc through medical facilities into the aqueous environments is mostly unknown. This is related to the low absolute Tc mass used in medical examinations and consequent trace levels of Tc emitted from respective facilities. In this work, a new approach employing automated on-line extraction chromatography and anion-exchange chromatography was developed and coupled to inductively coupled plasma-mass spectrometry. The extraction column was filled with TK201 resin to preconcentrate, purify and elute pertechnetate ([99Tc]TcO4−) as the most relevant Tc species. The eluting 99Tc fraction was focused and separated on an anion-exchange chromatography column and directly calibrated into a mass flow using an on-line isotope dilution-like approach named isobaric dilution analysis. To accommodate ultra-trace levels in strong matrices with high grades of particulate contamination, the automated method was complemented by a newly developed manual filtration and preconcentration workflow with TK201 impregnated filter disks, reaching a combined preconcentration factor as high as 4615. An aerosol desolvation nebulization system was used additionally to boost sensitivity, achieving an ultimate limit of detection (LOD) as low as 0.70 ± 0.02 fg kg−1. As proof of concept, a wastewater sample from a retention basin of a local university hospital was collected. This wastewater contained 99Tc emitted in diagnostic procedures and levels were determined to be as low as 89 ± 4 fg kg−1. [ABSTRACT FROM AUTHOR]

To sensitively determine 99Tc, a new method for internal quantification of its most common and stable species, [99Tc]Tc O 4 - , was developed. Anion-exchange chromatography (IC) was coupled to inductively coupled plasma–mass spectrometry (ICP-MS) and equipped with an aerosol desolvation system to provide enhanced detection power. Due to a lack of commercial Tc standards, an isotope dilution-like approach using a Ru spike and called isobaric dilution analysis (IBDA) was used for internal quantification of 99Tc. This approach required knowledge of the sensitivities of 99Ru and 99Tc in ICP-MS. The latter was determined using an in-house prepared standard manufactured from decayed medical 99mTc-generator eluates. This standard was cleaned and preconcentrated using extraction chromatography with TEVA resin and quantified via total reflection X-ray fluorescence (TXRF) analysis. IC coupled to ICP-MS enabled to separate, detect and quantify [99Tc]Tc O 4 - as most stable Tc species in complex environments, which was demonstrated in a proof of concept. We quantified this species in untreated and undiluted raw urine collected from a patient, who previously underwent scintigraphy with a 99mTc-tracer, and determined a concentration of 19.6 ± 0.5 ng L−1. The developed method has a high utility to characterize a range of Tc-based radiopharmaceuticals, to determine concentrations, purity, and degradation products in complex samples without the need to assess activity parameters of 99(m)Tc. [ABSTRACT FROM AUTHOR]

Its easy accessibility, ideal physical properties and the multifaceted redox chemistry made 99mTc the most important radionuclide for SPECT (single-photon emission computed tomography) in nuclear medicine. Unfortunately, small concentrations used in scintigraphy are also limiting analytical techniques to perform routine quality controls and to support the development of novel tracers. In this work, speciation analysis via liquid chromatography (LC) coupled with elemental and molecular mass spectrometry is developed for novel and established Tc radiopharmaceuticals to enable direct identification, characterization, and quantification. Here, an Orbitrap-based ESI-MS method was used to attain high mass resolutions and high mass accuracies for compound identification. RP-HPLC-ICP-MS was employed for the separation and sensitive detection of Tc species. Due to a lack of Tc standards, the previously introduced "isobaric dilution analysis" was modified and applied in an on-line post-column dilution approach. Besides the expected tracers, various Tc impurities were detected and calibrated in a non-target approach. The presented methods allow fast on-site quality controls of commercially available tracers, but further promote the characterization of novel experimental tracers in nuclear medicine without the need of "cold" reference compounds. [ABSTRACT FROM AUTHOR]

Introduction: Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity in vivo promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders in vivo. To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity in vivo.Methods: Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated in vitro and in vivo. Biodistribution and radiotracer elimination were determined in C57/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. In vivo data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry.Results: We prepared three new 99mTc-labeled MMP inhibitors, bearing either a glycine ([99mTc]MEA39), lysine ([99mTc]MEA61), or the ligand HYNIC with the ionic co-ligand TPPTS ([99mTc]MEA223) yielding gradually increasing hydrophilicity. [99mTc]MEA39 and [99mTc]MEA61 were rapidly eliminated via hepatobiliary pathways. In contrast, [99mTc]MEA223 showed delayed in vivo clearance and primary renal elimination. In a thyroid tumor xenograft model, only [99mTc]MEA223 exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images.Conclusion: Introduction of HYNIC/TPPTS into the barbiturate lead structure ([99mTc]MEA223) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model. [ABSTRACT FROM AUTHOR]

Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell‐targeted, internalizing antibody. To this end, we synthesized a poly‐anionic derivate, ibrutinib‐Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti‐CD20‐protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. In vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune‐compromised mice and a significantly better response to lower doses compared to the original drug. [ABSTRACT FROM AUTHOR]

Ibrutinib ist ein Inhibitor der Bruton‐Tyrosinkinase, der für die Behandlung von Patienten mit chronischer lymphatischer Leukämie, Mantelzell‐Lymphom und Waldenström‐Makroglobulinämie zugelassen und mit Nebenwirkungen verbunden ist. Um seine Toxizität zu minimieren, haben wir Ibrutinib mit einem zellgerichteten, internalisierenden Antikörper verbunden. Dazu synthetisierten wir ein polyanionisches Derivat, Ibrutinib‐Cy3.5, das seine volle Funktionalität beibehält. Dieser anionische Inhibitor wird durch unser Anti‐CD20‐Protamin‐Targeting‐Konjugat und freies Protamin komplexiert und assembliert dadurch spontan zu einem elektrostatisch stabilisierten vesikulären Nanoträger. Die Komplexierung führte zu einer Akkumulation des Wirkstoffs, der durch die CD20‐Antigen‐Internalisierung in die Zellen aufgenommen und in seiner Wirksamkeit verstärkt wurde. In vivo beobachteten wir eine signifikante Anreicherung des Wirkstoffs in Xenotransplantat‐Lymphom‐Tumoren bei Mäusen mit defizientem Immunsystem und eine signifikant verbesserte Reaktion auf niedrigere Dosen im Vergleich zum ursprünglichen Wirkstoff. [ABSTRACT FROM AUTHOR]