Abstract
Purpose
Several established optical imaging approaches have been applied, usually in isolation, to preclinical studies; however, truly useful in vivo imaging may require a simultaneous combination of imaging modalities to examine dynamic characteristics of cells and tissues. We developed a new multimode optical imaging system designed to be application-versatile, yielding high sensitivity, and specificity molecular imaging.
Procedures
We integrated several optical imaging technologies, including fluorescence intensity, spectral, lifetime, intravital confocal, two-photon excitation, and bioluminescence, into a single system that enables functional multiscale imaging in animal models.
Results
The approach offers a comprehensive imaging platform for kinetic, quantitative, and environmental analysis of highly relevant information, with micro-to-macroscopic resolution. Applied to small animals in vivo, this provides superior monitoring of processes of interest, represented here by chemo-/nanoconstruct therapy assessment.
Conclusions
This new system is versatile and can be optimized for various applications, of which cancer detection and targeted treatment are emphasized here.
Similar content being viewed by others
References
Weissleder R (2002) Scaling down imaging: molecular mapping of cancer in mice. Nat Rev Cancer 2:11–18
Contag CH (2007) In vivo pathology: seeing with molecular specificity and cellular resolution in the living body. Annu Rev Pathol 2:277–305
Rice BW, Cable MD, Nelson MB (2001) In vivo imaging of light-emitting probes. J Biomed Opt 6:432–440
Deniset-Besseau A, Leveque-Fort S, Fontaine-Aupart MP et al (2007) Three-dimensional time-resolved fluorescence imaging by multifocal multiphoton microscopy for a photosensitizer study in living cells. Appl Opt 46:8045–8051
Zacharakis G, Ripoll J, Weissleder R et al (2005) Fluorescent protein tomography scanner for small animal imaging. IEEE Trans Med Imaging 24:878–885
Hoffman RM (2002) In vivo imaging of metastatic cancer with fluorescent proteins. Cell Death Differ 9:786–789
Paulmurugan R, Massoud TF, Huang J et al (2004) Molecular imaging of drug-modulated protein-protein interactions in living subjects. Cancer Res 64:2113–2119
Yamauchi K, Yang M, Jiang P et al (2005) Real-time in vivo dual-color imaging of intracapillary cancer cell and nucleus deformation and migration. Cancer Res 65:4246–4252
Hwang JY, Agadjanian H, Medina-Kauwe LK et al (2008) Large field of view scanning fluorescence lifetime imaging system for multimode optical imaging of small animals. Proceeding of SPIE 6859:68590G–68598G
Contag CH, Bachmann MH (2002) Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng 4:235–260
Levenson RM, Lynch DT, Kobayashi H et al (2008) Multiplexing with multispectral imaging: from mice to microscopy. ILAR J 49:78–88
Chung A, Karlan S, Lindsley E et al (2006) In vivo cytometry: a spectrum of possibilities. Cytometry A 69:142–146
Hanson KM, Behne MJ, Barry NP et al (2002) Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient. Biophys J 83:1682–1690
Feng Y, Huang SH (2007) The analysis of sinusoidal modulated method used for measuring fluorescence lifetime. Guang Pu Xue Yu Guang Pu Fen Xi 27:2523–2526
Lin HJ, Herman P, Lakowicz JR (2003) Fluorescence lifetime-resolved pH imaging of living cells. Cytometry A 52:77–89
Esposito A, Gerritsen HC, Oggier T et al (2006) Innovating lifetime microscopy: a compact and simple tool for life sciences, screening, and diagnostics. J Biomed Opt 11:34016
Lin HJ, Szmacinski H, Lakowicz JR (1999) Lifetime-based pH sensors: indicators for acidic environments. Anal Biochem 269:162–167
Cubeddu R, Canti G, Taroni P et al (1993) Time-gated fluorescence imaging for the diagnosis of tumors in a murine model. Photochem Photobiol 57:480–485
Cubeddu R, Canti G, Pifferi A et al (1997) Fluorescence lifetime imaging of experimental tumors in hematoporphyrin derivative-sensitized mice. Photochem Photobiol 66:229–236
Denk W, Strickler JH, Webb WW (1990) Two-photon laser scanning fluorescence microscopy. Science (New York) 248:73–76
Patterson GH, Piston DW (2000) Photobleaching in two-photon excitation microscopy. Biophys J 78:2159–2162
Chirico G, Cannone F, Baldini G et al (2003) Two-photon thermal bleaching of single fluorescent molecules. Biophys J 84:588–598
Falati S, Gross P, Merrill-Skoloff G et al (2002) Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat Med 8:1175–1181
Laemmel E, Genet M, Le Goualher G et al (2004) Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy. J Vasc Res 41:400–411
St Croix CM, Leelavanichkul K, Watkins SC (2006) Intravital fluorescence microscopy in pulmonary research. Adv Drug Deliv Rev 58:834–840
Bhaumik S, Lewis XZ, Gambhir SS (2004) Optical imaging of Renilla luciferase, synthetic Renilla luciferase, and firefly luciferase reporter gene expression in living mice. J Biomed Opt 9:578–586
Lee BS, Fujita M, Khazenzon NM et al (2006) Polycefin, a new prototype of a multifunctional nanoconjugate based on poly(beta-l-malic acid) for drug delivery. Bioconjugate chem 17:317–326
Hwang JY, Moffatt-Blue C, Equils O et al (2007) Multimode optical imaging of small animals: development and applications. Prog Biomed Optics Imaging 8:1–10
Agadjanian H, Weaver JJ, Mahammed A et al (2006) Specific delivery of corroles to cells via noncovalent conjugates with viral proteins. Pharm Res 23:367–377
Agadjanian H, Ma J, Rentsendorj A et al (2009) Tumor detection and elimination by a targeted gallium corrole. Proc Natl Acad Sci U S A 106:6105–6110
Gammon ST, Leevy WM, Gross S et al (2006) Spectral unmixing of multicolored bioluminescence emitted from heterogeneous biological sources. Anal Chem 78:1520–1527
Wachsmann-Hogiu S, Hwang JY, Lindsley E et al (2007) Wide-field two-photon microscopy: features and advantages for biomedical applications. Prog Biomed Optics Imaging 8:1–8
Fujimoto JG, Farkas DL (2009) Biomedical optical imaging. Oxford University, Oxford
Frykman PK, Lindsley EH, Gaon M et al (2008) Spectral imaging for precise surgical intervention in Hirschsprung’s disease. J Biophotonics 1:97–103
Hwang JY, Wachsmann-Hogiu S, Ramanujan VK et al (2011) Multimodal wide-field two-photon excitation imaging: characterization of the technique for in vivo applications. Biomed Opt Express 2:356–364
Hwang JY, Gross Z, Gray HB et al (2011) Ratiometric spectral imaging for fast tumor detection and chemotherapy monitoring in vivo. J Biomed Opt 16:066007
Kocisova E, Praus P, Rosenberg I et al (2004) Intracellular uptake of modified oligonucleotide studied by two fluorescence techniques. Biopolymers 74:110–114
Farkas DL, Baxter G, DeBiasio RL et al (1993) Multimode light microscopy and the dynamics of molecules, cells, and tissues. Annu Rev Physiol 55:785–817
Soubret A, Ntziachristos V (2006) Fluorescence molecular tomography in the presence of background fluorescence. Phys Med Biol 51:3983–4001
Evans JA, Nishioka NS (2005) Endoscopic confocal microscopy. Curr Opin Gastroenterol 21:578–584
Takehana S, Kaneko M, Mizuno H (1999) Endoscopic diagnostic system using autofluorescence. Diagn ther endosc 5:59–63
Ikeda N, Honda H, Katsumi T et al (1999) Early detection of bronchial lesions using lung imaging fluorescence endoscope. Diagn ther endosc 5:85–90
Acknowledgements
We thank Dr. Mark Gaon for help developing and testing the gated anesthesia instrument. Some of this work was done in partial fulfillment of Ph.D. thesis research requirements by Dr. J.Y. Hwang, at the University of Southern California. Work at the California Institute of Technology was supported by the Arnold and Mabel Beckman Foundation. Z.G. thanks Johnson & Johnson for research support. We are grateful for the following federal support of our research: NIH (5R01CA123495-03 and 1U01CA151815-0) to JYL; NIH (1R01 CA140995 and 1R01 CA129822) and DOD W81XWH-06-1-0549 to LKMK; and US Navy Bureau of Medicine and Surgery (1435-04-04-GT-41387 and -43096), NIH (N01-CO-07119), and NSF (BESOO 79483) to DLF.
Conflict of Interest. The authors declare they have no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hwang, J.Y., Wachsmann-Hogiu, S., Ramanujan, V.K. et al. A Multimode Optical Imaging System for Preclinical Applications In Vivo: Technology Development, Multiscale Imaging, and Chemotherapy Assessment. Mol Imaging Biol 14, 431–442 (2012). https://doi.org/10.1007/s11307-011-0517-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11307-011-0517-z