Molekulare Bildgebung - eine zukünftige diagnostische Methode für die Neuroonkologie?

Zusammenfassung

Unter Molekularer Bildgebung versteht man die bildliche Darstellung biologischer Prozesse auf zellulärer und molekularer Ebene in vivo mit Hilfe der PET, SPECT, MRT, Nahinfrarotreflexionsbildgebungen und Szintigraphie. Die Methoden befinden sich größtenteils noch im tierexperimentellen Stadium. Sie werden weiterentwickelt um mögliche Gentherapien (z. B: Herpes-simplex-Virus-Thymidinkinase beim Glioblastom) in der MRT und PET darzustellen und damit zu überwachen. Durch die Darstellung von Matrix-Metalloproteinasen mit der Nahinfrarotreflexionsbildgebung können die Agressivität von Tumoren und die Therapie mit Angiogenesehemmern besser beurteilt werden. Mit speziellen Eisenkontrastmitteln kann man Lymphozyten und Makrophagen, die zum Randgebiet des Glioblastoms wandern, markieren und so dieses in der MRT genauer abgrenzen. Apoptose könnte über die Darstellung der Caspase 3 in der Nahinfrarotreflexionsbildgebung erkannt werden. In dieser Übersicht wird der Stand der Forschung zu diesem Thema zusammengefasst. Zudem werden eigene Ergebnisse auf dem Gebiet der onkogenspezifischen molekularen MR-Bildgebung vorgestellt.

Abstract

Molecular imaging is the depiction of biological processes at the cellular or molecular level using PET, SPECT, MRI, near-infrared optical imaging, and scintigraphy in vivo. The majority of these methods are still at an experimental stage. Of primary interest is the development of methods using MRI and PET with which to monitor and graphically display the progress of gene-therapy in glioblastoma (herpes simplex virus-thymidinkinase). The use of near-infrared optical imaging techniques to visualize matrix-metalloproteinases can improve the assessment of tumour aggressiveness and angiogenesis-inhibitory therapy. Lymphocytes and macrophages can be marked with certain iron-containing contrast agents which, through accumulation at the margin of glioblastomas, ameliorate the visual demarcation in MRI. Apoptosis could be detected using near-infrared optical imaging representation of caspase 3 activity. This review will summarize the current state of research in molecular imaging and the results our study group obtained during investigations on oncogene specific molecular imaging in MRI.

Schlüsselwörter:

Molekulare Bildgebung - Molecular Imaging - Gentherapie - Magnetresonanztomographie - Nuklearmedizin - Gadolinium - Antisense

Key words:

Molecular imaging - gene therapy - magnetic resonance imaging - nuclear imaging - antisense - gadolinium

Literatur

• 1 Tjuvajev J G, Avril N, Oku T, Sasajima T, Miyagawa T, Joshi R, Safer M, Beattie B, DiResta G, Daghighian F, Augensen F, Koutcher J, Zweit J, Humm J, Larson S M, Finn R, Blasberg R. Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography.  Cancer Res. 1998;  58 (19) 4333-4341
• 2 Jacobs A, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, Kaestle C, Wagner R, Wienhard K, Heiss W D. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas.  Lancet. 2001;  358 727-729
• 3 Adachi M, Sampath J, Lan L B, Sun D, Hargrove P, Flatley R M, Tatum A, Ziegelmeier M Z, Wezeman M, Matherly L H, Drake R R, Schuetz J D. Expression of MRP4 confers resistance to ganciclovir and compromises bystander cell killing.  J Biol Chem. 2002;  277 (41) 38998-90004
• 4 Rainov N G. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme.  Hum Gene Ther. 2000;  11 2389-2401
• 5 Louie A Y, Huber M M, Ahrens E T, Rothbächer U, Moats R, Jacobs R E, Fraser S E, Meade T J. In vivo visualisation of gene expression using magnetic resonance imaging.  Nature Biotechnology. 1999;  18 321-325
• 6 Bogdanov A, Weissleder R. The development of in vivo imaging systems to study gene expression.  TIBTECH. 1998;  16 5-10
• 7 Weissleder R, Simonova M, Bogdanova A, Bredow S, Enochs W S, Bogdanov A. MR imaging and scintigraphy of gene expression through melanin induction.  Radiology. 1997;  204 417-423
• 8 Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocco E A, Basilion J P. In vivo magnetic resonance imaging of transgene expression.  Nature Medicine. 2000;  6 351-354
• 9 Shen T, Weissleder R, Papisov M, Bogdanov A, Brady T J. Monocrystalline iron oxide nanocompounds (MION): physico-chemical properties.  Magn Reson Med. 1993;  29 (5) 599-604
• 10 Högemann D, Josephson L, Weissleder R, Basilion J P. Improvement of MRI probes to allow efficient detection of gene expression.  Bioconjug Chem. 2000;  11 941-946
• 11 Högemann D, Ntziachristos V, Josephson L, Weissleder R. High throughput magnetic resonance imaging for evaluating targeted nanoparticle probes.  Bioconjug Chem. 2002;  13 (1) 116-121
• 12 Zimmer C, Weissleder R, Poss K, Bogdanova A, Wright S C, Enochs W S. MR imaging of phagocytosis in experimental gliomas.  Radiology. 1995;  1197 533-538
• 13 Fleige G, Nolte C, Synowitz M, Seeberger F, Kettenmann H, Zimmer C. Magnetic labeling of activated microglia in experimental gliomas.  Neoplasia. 2001;  3 (6) 489-499
• 14 Egelhof T, Delbeck N, Hartmann M, Roth S U, Elste V, Heiland S, Sartor K. Can superparamagnetic contrast media improve MRI-tomographic images of experimental gliomas?.  Radiologe. 1998;  38 (11) 943-947
• 15 Knauth M, Egelhof T, Roth S U, Wirtz C R, Sartor K. Monocrystalline iron oxide nanoparticles: possible solution to the problem of surgically induced intracranial contrast enhancement in intraoperative MR imaging.  Am J Neuroradiol. 2001;  22 (1) 99-102
• 16 Josephson K, Tung C, Melder R, Moore A, Weissleder R. High efficiency magnetic cell labeling through Tat peptides.  Bioconjug Chem. 1999;  10 186-191
• 17 Lewin M, Carlesso N, Tung C H, Cory D, Scadden D T, Weissleder R. Tat peptide derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.  Nature Biotechnology. 2000;  18 410-414
• 18 Jöbsis F F. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters.  Science. 1977;  198 1264-1267
• 19 Smielewski P, Czosnyka M, Pickard J D, Kirkpatrick P. Clinical evaluation of near-infrared spetroscopy for testing cerebrovascular reactivity in patients with carotid artery disease.  Stroke. 1997;  28 (2) 331-338
• 20 Giller C A, Maureen J, Hanli L. Use of an intracranial near-infrared probe for localization during stereotactic surgery for movement disorders. Technical note.  J Neurosurg. 2000;  93 498-505
• 21 Weissleder R. A clearer vision for in vivo imaging.  Nature Biotechnology. 2001;  19 316-317
• 22 Bremer C, Ntziachristos V, Mahmood U, Tung C H, Weissleder R. Fortschritte in der optischen Bildgebung.  Der Radiologe. 2001;  2 131-138
• 23 Becker A, Hessenius C, Licha K, Ebert B, Sukowski U, Semmler W, Wiedenmann B, Grötzinger C. Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands.  Nature Biotechnology. 2001;  19 327-331
• 24 Guyotat J, Champier J, Jouvet A, Signorelli F, Houzard C, Bret P, Saint Pierre G, Fevre Montagne M. Differential expression of somatostatin receptors in ependymoma: Implications for diagnosis.  Int J Cancer. 2001;  95 144-151
• 25 Guyotat J, Champier J, Pierre G S, Jouvet A, Bret P, Brisson C, Belin M F, Signorelli F, Montagne M F. Differential expression of somatostatin receptors in medulloblastoma.  J Neurooncol. 2001;  51 (2) 93-103
• 26 Papos M, Pekrun A, Herms J W, Behr T M, Meller J, Rustenbeck H H, Kretzschmar H A, Becker W. Somatostatin receptor scintigraphy in the management of cerebral malignant ecto-mesenchymoma: a case report.  Pediatr Radiol. 2001;  31 169-172
• 27 Öberg K. Established clinical use of octreotide and lanreotide in oncology.  Chemotherapy. 2001;  47 (Suppl 2) 40-53
• 28 Bremer C, Tung C H, Weissleder R. In vivo molecular target assessment of matrix metalloproteinase inhibition.  Nat Med. 2001;  7 (6) 743-748
• 29 Bremer C, Tung C H, Bogdanov A, Weissleder R. Imaging of differential protease expression in breast cancers for detection of aggressive tumor phenotypes.  Radiology. 2002;  222 (3) 814-818
• 30 Marten K, Bremer C, Khazaie K, Sameni M, Sloane B, Tung C H, Weissleder R. Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice.  Gastroenterology. 2002;  122 (2) 406-414
• 31 Weissleder R, Tung C H, Mahmood U, Bogdanov A. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.  Nature Biotechnology. 1999;  17 (4) 375-378
• 32 Tung C H, Mahmood U, Bredow S, Weissleder R. In vivo imaging of proteolytic enzyme activity using a novel molecular reporter.  Cancer Res. 2000;  60 (17) 4953-4958
• 33 Mahmood U, Tung C H, Bogdanov A, Weissleder R. Near-Infrared Optical Imaging of protease activity for tumor detection.  Radiology. 1999;  213 866-870
• 34 Koblinski J E, Ahram M, Sloane B F. Unraveling the role of proteases in cancer.  Clinical Chimica Acta. 2000;  291 113-135
• 35 Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W. Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma.  Cancer Research. 2001;  61 2744-2750
• 36 Weissleder R, Mahmood U. Molecular imaging.  Radiology. 2001;  19 (2) 316-333
• 37 Kown M H, Strauss H W, Blankenberg F G, Berry G J, Stafford-Cecil S, Tait J F, Goris M L, Robbins R C. In vivo imaging of acute cardiac rejection in human patients using (99m) technetium labeled annexin V.  Am J Transplant. 2001;  3 270-277
• 38 Hessenius C, Bäder M, Meinhold H, Böhmig M, Faiss S, Reubi J C, Wiedenmann B. Vasoactive intestinal peptide receptor scintigraphy in patients with pancreatic adenocarcinomas or neuroendocrine tumors.  Europ J Nucl Med. 2000;  27 1684-1693
• 39 Brix G, Bellemann M E, Gerlach L, Haberkorn U. Direct detection of intratumoral 5-fluorouracil trapping using metabolic 19F MR imaging.  Magn Reson Imaging. 1999;  17 (1) 151-155
• 40 Brix G, Bellemann M E, Haberkorn U, Gerlach L, Lorenz W J. Assessment of the biodistribution and metabolism of 5-fluorouracil as monitored by 18F PET and 19F MRI: a comparative animal study.  Nucl Med Biol. 1996;  23 (7) 897-906
• 41 Haberkorn U, Oberdorfer F, Gebert J, Morr I, Haack K, Weber K, Lindauer M, van Kaick G, Schackert H K. Monitoring gene therapy with cytosine deaminase: in vitro studies using triated-5-fluorocytosine.  J Nucl Med. 1996;  37 (1) 87-94
• 42 Wu A M, Yazaki P J, Tsai S W, Nguyen K, Anderson A L, McCarthy D W, Welch M J, Shively J E, Wiliams L E, Raubitschek A A, Wong J Y, Toyokuni T, Phelps M E, Gambhir S S. High-resolution micro PET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled engineered antibody fragment.  Proc Natl Acad Sci USA. 2000;  97 (15) 8495-8500
• 43 Haberkorn U, Henze M, Altmann A, Jiang S, Morr I, Mahmut M, Peschke P, Kubler W, Debus J, Eisenhut M. Transfer of the human NaI symporter gene enhances iodide uptake in hepatoma cells.  J Nucl Med. 2001;  42 (2) 317-325
• 44 Bernard B F, Krenning E, Breeman W A, Visser T J, Bakker W H, Srinivasan A, de Jong M. Use of the rat pancreatic CA20948 cell line for the comparison of radiolabelled peptides for receptor-targeted scintigraphy and radionuclide therapy.  Nucl Med Commun. 2000;  21 (11) 1079-1085
• 45 Heppeler A, Froidevaux S, Eberle A N, Maecke H R. Receptor targeting for tumor localisation and therapy with radiopeptides.  Curr Med Chem. 2000;  7 (9) 971-994
• 46 Krenning E P, Kwekkeboom D J, Bakker W H, Breeman W A, Kooij P P, Oei H Y, van Hagen M, Postema P T, de Jong M, Reubi J C. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients.  Eur J Nucl Med. 1993;  20 (8) 716-731
• 47 Högemann D, Josephson L, Perez J M, Loughlin T, Weissleder R. Detektion des Bombesin/Gastrin-Rezeptors in der MRT.  Fortschr Röntgenstr. 2001;  173 81
• 48 Chaudhry A, Carrasquillo J A, Avis I L, Shuke N, Reynolds J C, Bartholomew R, Larson S M, Cuttitta F, Johnson B E, Mulshine J L. Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer.  Clin Cancer Res. 1999;  5 (11) 3385-3393
• 49 Van der Wiele C, Dumont F, Vanden Broecke R, Oosterlinck W, Cocquyt V, Serreyn R, Peers S, Thornback J, Slegers G, Dierckx R A. Technetium-99m RP527, a GRP analogue for visualisation of GRP receptor-expressing malignancies: a feasibility study.  Eur J Nucl Med. 2000;  27 (11) 1694-1699
• 50 Karra S R, Schibli R, Gali H, Katti K V, Hoffman T J, Higginbotham C, Sieckman G L, Volkert W A. 99mTc-labeling and in vivo studies of a bombesin analogue with a novel water-soluble dithiadiphosphine-based bifunctional chelating agent.  Bioconjug Chem. 1999;  10 (2) 254-260
• 51 Tung C H, Gerszten R E, Jaffer F A, Weissleder R. A novel near-infrared fluorescence sensor for detection of thrombin activation in blood.  Chembiochem. 2002;  1; 3 (2 - 3) 207-211
• 52 Klem J A, Schaffer J V, Crane P D, Barrett J A, Henry G A, Canestri L, Ezekowitz M D. Detection of deep venous thrombosis by DMP 444, a platelet IIb/IIIa antagonist: a preliminary report.  J Nucl Cardiol. 2000;  7 (4) 359-364
• 53 Anderson S A, Rader R K, Westlin W F, Null C, Jackson D, Lanza G M, Wickline S A, Kotyk J J. Magnetic resonance contrast enhancement of neovasculature with alpha (v) beta (3)-targeted nanoparticles.  Magn Reson Med. 2000;  44 (3) 433-439
• 54 Bredow S, Lewin M, Hofman B, Marecos E, Weissleder R. Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin.  Eur J Cancer. 2000;  36 675-681
• 55 Brower V. Tumor angiogenesis: new drugs on the block.  Nature Biotechnology. 1999;  17 963-968
• 56 Neri D, Carnemolla B, Nissim A, Leprini A, Querze G, Balza E, Pini A, Tarli L, Halin C, Neri P, Zardi L, Winter G. Targeting by affinity-matured recombinant antibody fragments of an angiogenesis associated fibronectin isoform.  Nature Biotechnology. 1997;  15 1271-1275
• 57 Posey J A, Khazaeli M B, Del Grosso A, Saleh M N, Lin C Y, Huse W, LoBuglio A F. A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha (v) beta (3)) antibody in patients with metastatic cancer.  Cancer Biother Radiopharm. 2001;  16 (2) 125-132
• 58 Sipkins D A, Cheresh D A, Kazemi M R, Nevin L M, Bednarski M D, Li K C. Detection of tumor angiogenesis in vivo by alpha (V) beta (3)-targeted magnetic resonance imaging.  Nature Medicine. 1998;  4 623-626
• 59 Moore A, Zhe Sun P, Cory D, Weissleder R, Lipes M A. MRI of insulitis in autoimmune diabetes.  Magn Reson Med. 2002;  47 (4) 751-758
• 60 Artemov D, Mori N, Ravi R, Bhujwalla Z. MR molecular imaging of HER-2/NEU Receptor with targeted nanoparticles.  Proc Intl Soc Mag Reson Med. 2001;  9 53
• 61 Hemminki A, Belousova N, Zinn K R, Liu B, Wang M, Chaudhuri T R, Rogers B E, Buchsbaum D J, Siegal G P, Barnes M N, Gomez-Navarro J, Curiel D T, Alvarez R D. Adenovirus with enhanced infectivity mediates molecular chemotherapy of ovarian cancer cells and allows imaging of gene expression.  Mol Ther. 2001;  4 (3) 223-231
• 62 Yu Y, Annala A J, Barrio J R, Toyokuni T, Satyamurthy N, Namavari M, Cherry S R, Phelps M E, Herschman H R, Gambhir S S. Quantification of target gene expression by imaging reporter gene expression in living animals.  Nat Med. 2000;  6 (8) 933-937
• 63 Siders W M, Halloran P J, Fenton R G. Menaloma-specific cytotoxicity induced by a tyrosinase promoter-enhancer/herpes simplex virus thymidine kinase adenovirus.  Cancer Gene Ther. 1998;  5 (5) 281-291
• 64 Emiliusen L, Gough M, Bateman A, Ahmed A, Voellmy R, Chester J, Diaz R M, Harrington K, Vile R. A transcriptional feedback loop for tissue-specific expression of highly cytotoxic genes which incorporates an immunostimulatory component.  Gene Ther. 2001;  8 (13) 987-998
• 65 De Stasio G, Casalbore P, Pallini R, Gilbert B, Sanita F, Ciotti M T, Rosi G, Festinesi A, Larocca L M, Rinelli A, Perret D, Mogk D W, Perfetti P, Mehta M P, Mercanti D. Gadolinium in human glioblastoma cells for gadolinium neutron capture therapy.  Cancer Res. 2001;  61 4272-4277
• 66 Bhorade R, Weissleder R, Nakakoshi T, Moore A, Tung C H. Macrocyclic chelators with paramagnetic cations are internalized into mammalian cells via a HIV-Tat derived membrane translocation peptide.  Bioconjug Chem. 2000;  11 301-305
• 67 Efthymiadis A, Briggs L J, Jans D A. The HIV-1 tat nuclear localization sequence confers novel nuclear import properties.  J Biol Chem. 1998;  273 1623-1628
• 68 Ntziachristos V, Yodh A G, Schnall M, Chance B. Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement.  Proc Natl Acad Sci USA. 2000;  97 2766-2772
• 69 Zamecnik P C, Stephenson M L. Inhibition of Rous sarcoma by virus replication and cell transformation by a specific oligodeoxynucleotide.  Proc Natl Acad Sci USA. 1978;  75 280-284
• 70 Orr R M. Technology evaluation: fomivirsen, Isis Pharmaceuticals Inc/CIBA vision.  Curr Opin Mol Ther. 2001;  3 (3) 288-294
• 71 Shi N, Boado R J, Pardridge W M. Antisense imaging of gene expression in the brain in vivo.  Proc Natl Acad Sci USA. 2000;  97 14709-14714
• 72 Sato N, Kobayashi H, Saga T, Nakamoto Y, Ishimori T, Togashi K, Fujibayashi Y, Konishi J, Brechbiel M W. Tumor targeting and imaging of intraperitoneal tumors by use of antisense oligo-DNA complexed with dendrimers and/or avidin in mice.  Clin Cancer Res. 2001;  7 3606-3612
• 73 Zhang Y M, Rusckowski M, Liu N, Liu C, Hnatowich D J. Cationic liposomes enhance cellular/nuclear localization of 99mTc-antisense oligonucleotides in target tumor cells.  Cancer Biother Radiopharm. 2001;  5 411-419
• 74 Tavitian B, Terrazzino S, Kuhnast B, Marzabal S, Stettler O, Dolle F, Deverre J R, Jobert A, Hinnen F, Bendriem B, Crouzel C, Di Giamberardino L. In vivo imaging of oligonucleotides with positron emisssion tomography.  Nat Med. 1998;  4 467-471
• 75 Kühnast B, Dolle F, Terrazzino S, Rousseau B, Loc'h C, Vaufrey F, Hinnen F, Doignon I, Pillon F, David C, Crouzel C, Tavitian B. General method to label antisense oligonucleotides with radioactive halogens for pharmacological and imaging studies.  Bioconjug Chem. 2000;  5 627-636
• 76 Kobori N, Imahori Y, Mineura K, Ueda S, Fujii R. Visualization of mRNA expression in CNS using 11C-labeled phosphorotidoate oligodeoxynucleotide.  Neuroreport. 1999;  10 (14) 2971-2974
• 77 Nielsen P E, Egholm M, Berg R H, Buchardt O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide.  Science. 1991;  254 1497-1500
• 78 Hyrup B, Nielsen P E. Peptide nucleic acids (PNA): Synthesis, properties and potential applications.  Bioorg Med Chem. 1996;  4 (1) 5-23
• 79 Braun K, Peschke P, Pipkorn R, Lampel S, Wachsmuth M, Waldeck W, Debus J. A biological transporter for the delivery of peptide nucleic acids (PNAs) to the nuclear compartment of living cells.  J Mol Biol. 2002;  318 237-243
• 80 Heckl S, Debus J, Jenne J, Pipkorn R, Rastert R, Waldeck W, van Kaick G, Braun K. Novel Transporter for Gadolinium enables fast and specific cellular uptake into tumor cells.  Mol Imag. 2002;  1 (2) 125