Sebastian Temme1, Christoph Grapentin1, Christine Quast1, Christoph Jacoby1, Maria Grandoch1, Zhaoping Ding1, Christoph Owenier1, Friederike Mayenfels1, Jens W Fischer1, Rolf Schubert1, Jürgen Schrader1, Ulrich Flögel2. 1. From Institut für Molekulare Kardiologie (S.T., C.Q., C.J., Z.D., C.O., J.S., U.F.), Institut für Pharmakologie und klinische Pharmakologie (M.G., J.W.F.), and Cardiovascular Research Institute Düsseldorf (J.W.F., J.S., U.F.), Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; Institut für Pharmazeutische Technologie und Biopharmazie, Albert-Ludwigs-Universität, Freiburg, Germany (C.G., F.M., R.S.); and Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany (C.Q., C.J., U.F.). 2. From Institut für Molekulare Kardiologie (S.T., C.Q., C.J., Z.D., C.O., J.S., U.F.), Institut für Pharmakologie und klinische Pharmakologie (M.G., J.W.F.), and Cardiovascular Research Institute Düsseldorf (J.W.F., J.S., U.F.), Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; Institut für Pharmazeutische Technologie und Biopharmazie, Albert-Ludwigs-Universität, Freiburg, Germany (C.G., F.M., R.S.); and Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany (C.Q., C.J., U.F.). floegel@uni-duesseldorf.de.
Abstract
BACKGROUND: Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. METHODS AND RESULTS: Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with α2-antiplasmin peptide (α2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. CONCLUSIONS: Our results demonstrate that 1H/19F magnetic resonance imaging, together with α2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging.
BACKGROUND: Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. METHODS AND RESULTS: Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with α2-antiplasmin peptide (α2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. CONCLUSIONS: Our results demonstrate that 1H/19F magnetic resonance imaging, together with α2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging.
Authors: Jeremy K Moore; Junjie Chen; Hua Pan; Joseph P Gaut; Sanjay Jain; Samuel A Wickline Journal: Magn Reson Med Date: 2017-11-16 Impact factor: 4.668
Authors: Dina V Hingorani; Fanny Chapelin; Emma Stares; Stephen R Adams; Hideho Okada; Eric T Ahrens Journal: Magn Reson Med Date: 2019-10-21 Impact factor: 4.668
Authors: Pascal Bouvain; Vera Flocke; Wolfgang Krämer; Rolf Schubert; Jürgen Schrader; Ulrich Flögel; Sebastian Temme Journal: MAGMA Date: 2018-11-29 Impact factor: 2.310
Authors: Lindsay K Hill; Joseph A Frezzo; Priya Katyal; Dung Minh Hoang; Zakia Ben Youss Gironda; Cynthia Xu; Xuan Xie; Erika Delgado-Fukushima; Youssef Z Wadghiri; Jin Kim Montclare Journal: ACS Nano Date: 2019-02-19 Impact factor: 15.881
Authors: Gregory M Lanza; Grace Cui; Anne H Schmieder; Huiying Zhang; John S Allen; Michael J Scott; Todd Williams; Xiaoxia Yang Journal: J Nucl Cardiol Date: 2017-06-12 Impact factor: 5.952