Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mapping light distribution in tissue by using MRI-detectable photosensitive liposomes

Nature Biomedical Engineering volume 7, pages 313–322 (2023)Cite this article

Subjects

Abstract

Characterizing sources and targets of illumination in living tissue is challenging. Here we show that spatial distributions of light in tissue can be mapped by using magnetic resonance imaging (MRI) in the presence of photosensitive nanoparticle probes. Each probe consists of a reservoir of paramagnetic molecules enclosed by a liposomal membrane incorporating photosensitive lipids. Incident light causes the photoisomerization of the lipids and alters hydrodynamic exchange across the membrane, thereby affecting longitudinal relaxation-weighted contrast in MRI. We injected the nanoparticles into the brains of live rats and used MRI to map responses to illumination profiles characteristic of widely used applications of photostimulation, photometry and phototherapy. The responses deviated from simple photon propagation models and revealed signatures of light scattering and nonlinear responsiveness. Paramagnetic liposomal nanoparticles may enable MRI to map a broad range of optical phenomena in deep tissue and other opaque environments.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Principle of liposomal nanoparticle reporters.
Fig. 2: Formation and in vitro characterization of Light-LisNRs.
Fig. 3: Assessment of Light-LisNR performance in vivo.
Fig. 4: Light mapping using LisNRs.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw data generated in this study are available from the corresponding author on reasonable request. Source data for the figures are provided with this paper.

References

  1. Tu, C. & Louie, A. Y. Strategies for the development of gadolinium-based “q”-activatable MRI contrast agents. NMR Biomed. 26, 781–787 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Lux, J. & Sherry, A. D. Advances in gadolinium-based MRI contrast agent designs for monitoring biological processes in vivo. Curr. Opin. Chem. Biol. 45, 121–130 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wei, H., Frey, A. M. & Jasanoff, A. Molecular fMRI of neurochemical signaling. J. Neurosci. Methods 364, 109372 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Angelovski, G. What we can really do with bioresponsive MRI contrast agents. Angew. Chem. Int. Ed. Engl. 55, 7038–7046 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Boros, E., Gale, E. M. & Caravan, P. MR imaging probes: design and applications. Dalton Trans. 44, 4804–4818 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li, H. & Meade, T. J. Molecular magnetic resonance imaging with Gd(III)-based contrast agents: challenges and key advances. J. Am. Chem. Soc. 141, 17025–17041 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lauffer, R. B. Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chem. Rev. 87, 901–927 (1987).

    Article  CAS  Google Scholar 

  8. Wahsner, J., Gale, E. M., Rodriguez-Rodriguez, A. & Caravan, P. Chemistry of MRI contrast agents: current challenges and new frontiers. Chem. Rev. 119, 957–1057 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Venkataramani, S. et al. Magnetic bistability of molecules in homogeneous solution at room temperature. Science 331, 445–448 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Tu, C. & Louie, A. Y. Photochromically-controlled, reversibly-activated MRI and optical contrast agent. Chem. Commun. https://doi.org/10.1039/B616991K (2007).

  11. Gao, M. et al. Synthesis and comparative evaluation of photoswitchable magnetic resonance imaging contrast agents. ACS Omega 5, 14759–14766 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Reessing, F. et al. A light-responsive liposomal agent for MRI contrast enhancement and monitoring of cargo delivery. Chem. Commun. 55, 10784–10787 (2019).

    Article  CAS  Google Scholar 

  13. Reessing, F. et al. A photocleavable contrast agent for light-responsive MRI. Pharmaceuticals 13, 296 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Koenig, S. H. et al. Permeability of liposomal membranes to water: results from the magnetic field dependence of T1 of solvent protons in suspensions of vesicles with entrapped paramagnetic ions. Magn. Reson. Med. 23, 275–286 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Terreno, E. et al. Determination of water permeability of paramagnetic liposomes of interest in MRI field. J. Inorg. Biochem. 102, 1112–1119 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Morgan, C. G., Sandhu, S. S., Yianni, Y. P. & Dodd, N. J. The phase behaviour of dispersions of Bis-Azo PC: photoregulation of bilayer dynamics via lipid photochromism. Biochim. Biophys. Acta 903, 495–503 (1987).

    Article  CAS  PubMed  Google Scholar 

  17. Pernpeintner, C. et al. Light-controlled membrane mechanics and shape transitions of photoswitchable lipid vesicles. Langmuir 33, 4083–4089 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Morstein, J., Impastato, A. C. & Trauner, D. Photoswitchable lipids. ChemBioChem 22, 73–83 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Osborne, E. A., Jarrett, B. R., Tu, C. & Louie, A. Y. Modulation of T2 relaxation time by light-induced, reversible aggregation of magnetic nanoparticles. J. Am. Chem. Soc. 132, 5934–5935 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Kruttwig, K. et al. Reversible low-light induced photoswitching of crowned spiropyran-DO3A complexed with gadolinium(III) ions. Molecules 17, 6605–6624 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dommaschk, M. et al. Photoswitchable magnetic resonance imaging contrast by improved light-driven coordination-induced spin state switch. J. Am. Chem. Soc. 137, 7552–7555 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Dong, M., Babalhavaeji, A., Samanta, S., Beharry, A. A. & Woolley, G. A. Red-shifting azobenzene photoswitches for in vivo use. Acc. Chem. Res. 48, 2662–2670 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Chander, N. et al. Optimized photoactivatable lipid nanoparticles enable red light triggered drug release. Small 17, e2008198 (2021).

    Article  PubMed  Google Scholar 

  24. Thorne, R. G. & Nicholson, C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc. Natl Acad. Sci. USA 103, 5567–5572 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yona, G., Meitav, N., Kahn, I. & Shoham, S. Realistic numerical and analytical modeling of light scattering in brain tissue for optogenetic applications. eNeuro 3, ENEURO.0059-15.2015 (2016).

  26. Aravanis, A. M. et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J. Neural Eng. 4, S143–S156 (2007).

    Article  PubMed  Google Scholar 

  27. Acker, L., Pino, E. N., Boyden, E. S. & Desimone, R. FEF inactivation with improved optogenetic methods. Proc. Natl Acad. Sci. USA 113, E7297–E7306 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, L. V. & Wu, H.-I. Biomedical Optics: Principles and Imaging (Wiley, 2007).

  29. Canales, A., Park, S., Kilias, A. & Anikeeva, P. Multifunctional fibers as tools for neuroscience and neuroengineering. Acc. Chem. Res. 51, 829–838 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Ghosh, S., Harvey, P., Simon, J. C. & Jasanoff, A. Probing the brain with molecular fMRI. Curr. Opin. Neurobiol. 50, 201–210 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cabre, G. et al. Rationally designed azobenzene photoswitches for efficient two-photon neuronal excitation. Nat. Commun. 10, 907 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hai, A., Cai, L. X., Lee, T., Lelyveld, V. S. & Jasanoff, A. Molecular fMRI of serotonin transport. Neuron 92, 754–765 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was funded by NIH grants R21 DA044748 and R01 NS120592 and a grant from the G. Harold and Leila Y. Mathers Foundation to A.J. J.S. was supported by a Friends of the McGovern Fellowship from the McGovern Institute for Brain Research and by the MIT Neurobiological Engineering Training Program (NIH T32 EB019940). M.S. was the recipient of a Marie Curie Individual Fellowship from the European Commission. We thank G. Yona and S. Shoham for advice about light modelling and for sharing code for computing beam-spreading profiles.

Author information

Author notes

  1. These authors contributed equally: Jacob Simon, Miriam Schwalm.

Authors and Affiliations

  1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jacob Simon, Miriam Schwalm & Alan Jasanoff

  2. Department of Chemistry, New York University, New York, NY, USA

    Johannes Morstein & Dirk Trauner

  3. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    Alan Jasanoff

  4. Department of Nuclear Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Alan Jasanoff

Authors
  1. Jacob Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miriam Schwalm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johannes Morstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dirk Trauner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alan Jasanoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S. and A.J. developed the LisNR concept. J.S., M.S. and A.J. designed the research. J.S. performed and analysed the in vitro experiments. M.S. performed the in vivo experiments. M.S. and A.J. analysed the in vivo data. J.M. and D.T. synthesized and characterized AzoPC and advised on the in vitro light-response experiments. J.S., M.S. and A.J. wrote the paper.

Corresponding author

Correspondence to Alan Jasanoff.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Biomedical Engineering thanks Jeff Bulte and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Light-LisNR response as a function of stimulus duration.

a, MRI signal in response to UV irradiation of Light-LisNRs (orange) over varying durations: 0.5 min (left), 2 min (middle), and 6 min (right). Corresponding unilluminated control data shown in black. Shaded margins denote s.e.m. of n = 3 animals. b, Equivalent time course data for blue illumination. c, Signal differences observed following UV irradiation (orange) or control treatment (black) of LisNRs over the durations indicated. Error bars denote s.e.m. of n = 3 animals. d, Equivalent signal difference data for blue illumination.

Source data

Extended Data Fig. 2 Dissociation between light response rates and amplitudes.

a, Top: Light-LisNR response amplitudes to blue and UV light are highly correlated over a 25 ×25 voxel region around fibre optic tips in six animals (R = 0.89, p < 10−5). Bottom: in contrast, blue light response amplitudes and response rates are statistically independent over the same voxels (R = –0.013, p = 0.66), indicating that the LisNR response rates are not strongly affected by variations in probe concentration, which largely determine the signal change amplitude distribution. b, Response amplitudes and rates can also be dissociated from one another as a function of distance from the fibre tip: amplitudes decrease monotonically (top), while response rates peak and then diminish (bottom). Error bars denote SEM over 6 (top) or 3 to 6 (bottom) biological replicates. c, Histograms of blue light response amplitudes (top) and response rates (bottom) over three cycles of illumination (B1-B3), showing stability over time (n = 2 animals). d, Box plots corresponding to the distributions in panel c. Central line = median, box limits = first and third quartiles, whiskers = limiting values. Consistency of the distributions indicates that diffusion and convection over the ~1 hour experimental time period do not strongly affect the results.

Source data

Supplementary information

Source data

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Simon, J., Schwalm, M., Morstein, J. et al. Mapping light distribution in tissue by using MRI-detectable photosensitive liposomes. Nat. Biomed. Eng 7, 313–322 (2023). https://doi.org/10.1038/s41551-022-00982-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-022-00982-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing