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Contrast agents for molecular photoacoustic imaging

Nature Methods volume 13, pages 639–650 (2016)Cite this article

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Abstract

Photoacoustic imaging (PAI) is an emerging tool that bridges the traditional depth limits of ballistic optical imaging and the resolution limits of diffuse optical imaging. Using the acoustic waves generated in response to the absorption of pulsed laser light, it provides noninvasive images of absorbed optical energy density at depths of several centimeters with a resolution of ∼100 μm. This versatile and scalable imaging modality has now shown potential for molecular imaging, which enables visualization of biological processes with systemically introduced contrast agents. Understanding the relative merits of the vast range of contrast agents available, from small-molecule dyes to gold and carbon nanostructures to liposome encapsulations, is a considerable challenge. Here we critically review the physical, chemical and biochemical characteristics of the existing photoacoustic contrast agents, highlighting key applications and present challenges for molecular PAI.

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Figure 1: Photoacoustic imaging of endogenous chromophores.
Figure 2: Photoacoustic imaging of genetically encoded chromophores.
Figure 3: Assembly of molecular imaging contrast agents for PAI combining a signaling compound with a targeting ligand.
Figure 4: Reported extinction coefficients (ɛ) of a selection of signaling compounds used for PAI.
Figure 5: Optical properties of NIR small-molecule dyes and application for imaging the extravascular target EGFR in pancreatic cancer.
Figure 6: Optical properties of GNPs and application for imaging the intravascular target αvβ3 integrin in glioma.
Figure 7: Assembly and optical properties of SWNTs and CP NPs, with applications in molecular imaging.

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Acknowledgements

We thank J. Baumberg (Department of Physics, University of Cambridge) for helpful discussions on gold nanoparticle LSPR. This work was supported by CRUK (Career Establishment Award no. C47594/A16267 to J.W. and S.E.B., Core Funding C14303/A17197 to J.W. and S.E.B.), the European Commission (CIG FP7-PEOPLE-2013-CIG-630729 to J.W. and S.E.B.), the EPSRC-CRUK Cancer Imaging Centre in Cambridge and Manchester (C197/A16465 to J.W. and S.E.B.), King's College London and University College London Comprehensive Cancer Imaging Centre Cancer Research UK & Engineering and Physical Sciences Research Council, in association with the Medical Research Council and the Department of Health, UK (P.B.), and the European Union (project FAMOS FP7 ICT, contract 317744 to P.B.).

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Authors and Affiliations

  1. Department of Physics, University of Cambridge, Cambridge, UK

    Judith Weber & Sarah E Bohndiek

  2. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    Judith Weber & Sarah E Bohndiek

  3. Department of Medical Physics and Biomedical Engineering, University College London, London, UK

    Paul C Beard

Authors
  1. Judith Weber
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Correspondence to Paul C Beard or Sarah E Bohndiek.

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Integrated supplementary information

Supplementary Figure 1 Different photoacoustic tomography detection geometries using widefield excitation.

(a) 2D or 3D imaging using a linear or planar array respectively. (b) 3D imaging using hemi-spherical array. (c) 2D or 3D imaging using a circular or cylindrical array.

Supplementary Figure 2 Physiological barriers encountered during molecular imaging.

Design of contrast agents for molecular PAI must consider both circulatory and cellular barriers, as well as the active targeting of cell surface receptors, transporters, metabolic enzymes or biochemical processes to provide the molecular readout.

Supplementary Figure 3 Normalized absorption spectra of near-infrared dyes.

Methylene Blue, ATTO740, AlexaFluor750 (pH 7.2) and IRDye800CW (in PBS). Spectral data from http://www.spectra.arizona.edu/

Supplementary Figure 4 The origin of the optical properties of graphene and carbon nanodiamonds.

(a) Schematic honeycomb structure of a single layer graphene and grapheme oxide sheet. (b) Schematic illustration of the density of electronic states (DOS) with respect to energy for graphene (k = wavevector). (c) Absorption spectra of monolayer graphene and bilayer graphene.1 (d) Schematic illustration of the nanodiamond structure and its nitrogen-vacancies (NV). The NV centers are characterized by electrons (six or five) in dangling orbitals on the three carbon atoms and the nitrogen atom neighboring the vacancy and can be either negatively charged (six electrons) or neutral (five electrons). The combinations and transformation of these orbitals leads to different electronic states which allow strong optical absorption at higher wavelengths. The diamond surface is terminated by functional groups and sp2 carbons to stabilize the particle. (e) Schematic illustration of the energy levels and related absorptions of negatively charged and neutral NV centers (solid lines: electronic energy levels, dashed lines: vibrational energy levels).2 (f) Absorption spectrum of radiation-damaged nanodiamonds suspended in DI water (O.D. = optical density).3

References: 1. Sun, Z. et al. Growth of graphene from solid carbon sources. Nature 468, 549–552 (2010). 2. Manson, N. B. & Harrison, J. P. Photo-ionization of the nitrogen-vacancy center in diamond. Diam. Relat. Mater. 14, 1705–1710 (2005). 3. Zhang, T. et al. Photoacoustic contrast imaging of biological tissues with nanodiamonds fabricated for high near-infrared absorbance. J. Biomed. Opt. 18(2), 026018–1 – 026018–6 (2013).

Supplementary Figure 5 Absorption spectra of graphene oxide and single-walled carbon nanotubes modified with near-infrared dyes.

(a) Absorption spectra of unmodified graphene oxide (red line) and ICG-graphene oxide.1 (b) Absorption spectra of plain SWNT and with dyes (ICG and QSY) modified SWNT.2

References: 1. Wang, Y.-W. et al. Dye-enhanced graphene oxide for photothermal therapy and photoacoustic imaging. J. Mater. Chem. B 1, 5762 (2013). 2. De La Zerda, A. et al. Family of enhanced photoacoustic imaging agents for high-sensitivity and multiplexing studies in living mice. ACS Nano 6, 4694–4701 (2012).

Supplementary Figure 6 Optical properties of polymer nanoparticles.

(a) Schematic illustration of the components of polymer nanoparticles and the different methods of formulation. In green are the units that allow us to influence the optical properties of the polymer nanoparticles. (b) The effect of the conjugation length, attachment or incorporation of donor and acceptor units, metal complexation and aggregations during PNP formation on the optical properties. HOMO and LUMO stand for the highest occupied and lowest unoccupied molecule orbital. The extension of the conjugation length causes a bathochromic (red) shift. Not shown: sterically hindering substituents influence planarity of the backbone and thus decrease pi-overlap leading to blue shift.1,2 Donor/acceptor interaction leads to a decrease in the band gap yielding in a red shift (especially in close proximity they undergo (partial) intramolecular charge transfer upon excitation).1,3 The integration of a metal center to the porphyrin system influences the optical properties4 mainly due to the interactions of the d-orbitals of the metal with the molecular orbitals of the ligand. This enables ligand-to-metal transitions (LMCT), metal-to-ligand transitions (MLCT), metal-centered (MC) transitions and ligand-centered (LT) transitions. Electrostatic interactions between the conjugated cores lead to superstructures, known as more or less deformed H- or J-aggregates. In respect to the monomers, H-aggregation leads to a blue-shift (hypsochromic) and J-aggregation to a red-shift (bathochromic) of the pi-pi* transition.5

References: 1. Meier, H. Conjugated oligomers with terminal donor-acceptor substitution. Angew. Chemie - Int. Ed. 44, 2482–2506 (2005). 2. Ajayaghosh, A. Donor-acceptor type low band gap polymers: polysquaraines and related systems. Chem. Soc. Rev. 32, 181–191 (2003). 3. Slama-Schwok, a., Blanchard-Desce, M. & Lehn, J. M. Intramolecular charge transfer in donor-acceptor molecules. J. Phys. Chem. 94, 3894–3902 (1990). 4. Ho, I.-T., Sessler, J. L., Gambhir, S. S. & Jokerst, J. V. Parts per billion detection of uranium with a porphyrinoid-containing nanoparticle and in vivo photoacoustic imaging. Analyst 140, 3731–3737 (2015). 5. Pescitelli, G., Di Bari, L. & Berova, N. Application of electronic circular dichroism in the study of supramolecular systems. Chem. Soc. Rev. 43, 5211–33 (2014).

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Weber, J., Beard, P. & Bohndiek, S. Contrast agents for molecular photoacoustic imaging. Nat Methods 13, 639–650 (2016). https://doi.org/10.1038/nmeth.3929

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