Optical Methods

  • Christoph Bremer
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 185/2)


Molecular imaging requires the highest possible signal-to-noise ratios (SNRs) at the target of interest. In order to maximize the SNR for optical imaging techniques, various strategies have been developed to design fluorescent probes that can be activated, for example, by proteolytic degradation. Generally speaking, these probes are quenched in their native state—e.g., by fluorescence resonance energy transfer (FRET)—and dequenched after cleavage or hybridization, which is associated with a strong fluorescence signal increase.

Different strategies of fluorescence signal amplification ranging from large and small protease-sensing molecules to oligonucleotide-sensing and nanoparticle-based probes are presented in this chapter.


Fluorescence Resonance Energy Transfer Optical Probe Cerebral Venous Sinus Thrombosis NIRF Image Molecular Contrast Agent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aparicio T, Kermorgant S, Dessirier V, Lewin MJ, Lehy T (1999) Matrix metalloproteinase inhibition prevents colon cancer peritoneal carcinomatosis development and prolongs survival in rats. Carcinogenesis 20:1445–1451PubMedCrossRefGoogle Scholar
  2. Bremer C, Ntziachristos V, Weissleder R (2003) Optical-based molecular imaging: contrast agents and potential medical applications. Eur Radiol 13:231–243PubMedGoogle Scholar
  3. Bremer C, Ntziachristos V, Weitkamp B, Theilmeier G, Heindel W, Weissleder R (2005) Optical imaging of spontaneous breast tumors using protease sensing ‘smart’ optical probes. Invest Radiol 40:321–327PubMedCrossRefGoogle Scholar
  4. Bremer C, Tung CH, Bogdanov A Jr, Weissleder R (2002) Imaging of differential protease expression in breast cancers for detection of aggressive tumor phenotypes. Radiology 222:814–818PubMedCrossRefGoogle Scholar
  5. Bremer C, Tung CH, Weissleder R (2002) Molecular imaging of MMP expression and therapeutic MMP inhibition. Acad Radiol 9(Suppl 2):S314–S315PubMedCrossRefGoogle Scholar
  6. Bullok K, Piwnica-Worms D (2005) Synthesis and characterization of a small, membrane-permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis. J Med Chem 48:5404–5407PubMedCrossRefGoogle Scholar
  7. Chen J, Tung CH, Mahmood U, Ntziachristos V, Gyurko R, Fishman MC, Huang PL, Weissleder R (2002) In vivo imaging of proteolytic activity in atherosclerosis. Circulation 105:2766–2771PubMedCrossRefGoogle Scholar
  8. Dubertret B, Calame M, Libchaber AJ (2001) Single-mismatch detection using gold-quenched fluorescent oligonucleotides. Nat Biotechnol 19:365–370PubMedCrossRefGoogle Scholar
  9. Edwards DR, Murphy G (1998) Cancer. Proteases–invasion and more. Nature 394:527–528PubMedCrossRefGoogle Scholar
  10. Fang J, Shing Y, Wiederschain D, Yan L, Butterfield C, Jackson G, Harper J, Tamvakopoulos G, Moses MA (2000) Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci USA 97:3884–3889PubMedCrossRefGoogle Scholar
  11. Folkman J (1999) Angiogenic zip code. Nat Biotechnol 17:749PubMedCrossRefGoogle Scholar
  12. Herszenyi L, Plebani M, Carraro P, De Paoli M, Roveroni G, Cardin R, Tulassay Z, Naccarato R, Farinati F (1999) The role of cysteine and serine proteases in colorectal carcinoma. Cancer 86:1135–1142PubMedCrossRefGoogle Scholar
  13. Jaffer FA, Tung CH, Wykrzykowska JJ, Ho NH, Houng AK, Reed GL, Weissleder R (2004) Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi. Circulation 110:170–176PubMedCrossRefGoogle Scholar
  14. Jiang T, Olson ES, Nguyen QT, Roy M, Jennings PA, Tsien RY (2004) Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci USA 101:17867–17872PubMedCrossRefGoogle Scholar
  15. Josephson L, Kircher MF, Mahmood U, Tang Y, Weissleder R (2002) Near-infrared fluorescent nanoparticles as combined MR/optical imaging probes. Bioconjug Chem 13:554–560PubMedCrossRefGoogle Scholar
  16. Kim DE, Schellingerhout D, Jaffer FA, Weissleder R, Tung CH (2005) Near-infrared fluorescent imaging of cerebral thrombi and blood-brain barrier disruption in a mouse model of cerebral venous sinus thrombosis. J Cereb Blood Flow Metab 25:226–233PubMedCrossRefGoogle Scholar
  17. Kircher MF, Mahmood U, King RS, Weissleder R, Josephson L (2003) A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. Cancer Res 63:8122–8125PubMedGoogle Scholar
  18. Koblinski JE, Ahram M, Sloane BF (2000) Unraveling the role of proteases in cancer. Clin Chim Acta 291:113–135PubMedCrossRefGoogle Scholar
  19. Law B, Weissleder R, Tung CH (2005) Mechanism-based fluorescent reporter for protein kinase A detection. Chembiochem 6:1361–1367PubMedCrossRefGoogle Scholar
  20. Messerli SM, Prabhakar S, Tang Y, Shah K, Cortes ML, Murthy V, Weissleder R, Breakefield XO, Tung CH (2004) A novel method for imaging apoptosis using a caspase-1 near-infrared fluorescent probe. Neoplasia 6:95–105PubMedCrossRefGoogle Scholar
  21. Metelev V, Weissleder R, Bogdanov A, Jr. (2004) Synthesis and properties of fluorescent NF-kappa B-recognizing hairpin oligodeoxyribonucleotide decoys. Bioconjug Chem 15:1481–1487PubMedCrossRefGoogle Scholar
  22. Pham W, Choi Y, Weissleder R, Tung CH (2004) Developing a peptide-based near-infrared molecular probe for protease sensing. Bioconjug Chem 15:1403–1407PubMedCrossRefGoogle Scholar
  23. Pham W, Weissleder R, Tung CH (2002) An azulene dimer as a near-infrared quencher. Angew Chem Int Ed Engl 41:3659–3662, 3519Google Scholar
  24. Schellenberger EA, Sosnovik D, Weissleder R, Josephson L (2004) Magneto/optical annexin V, a multimodal protein. Bioconjug Chem 15:1062–1067PubMedCrossRefGoogle Scholar
  25. Tung CH, Mahmood U, Bredow S, Weissleder R (2000) In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. Cancer Res 60:4953–4958PubMedGoogle Scholar
  26. Tung CH, Zeng Q, Shah K, Kim DE, Schellingerhout D, Weissleder R (2004) In vivo imaging of beta-galactosidase activity using far red fluorescent switch. Cancer Res 64:1579–1583PubMedCrossRefGoogle Scholar
  27. Tyagi S, Marras SA, Kramer FR (2000) Wavelength-shifting molecular beacons. Nat Biotechnol 18:1191–1196PubMedCrossRefGoogle Scholar
  28. Weissleder R, Tung CH, Mahmood U, Bogdanov A Jr. (1999) In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat Biotechnol 17:375–378PubMedCrossRefGoogle Scholar
  29. Wunder A, Tung CH, Muller-Ladner U, Weissleder R, Mahmood U (2004) In vivo imaging of protease activity in arthritis: a novel approach for monitoring treatment response. Arthritis Rheum 50:2459–2465PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Christoph Bremer
    • 1
    • 2
  1. 1.Department of Clinical RadiologyUniversity of Münster, University HospitalMünsterGermany
  2. 2.Interdisciplinary Center for Clinical Research (IZKF Münster, FG3)University of MünsterMünsterGermany

Personalised recommendations