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Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy

Nature Materials volume 18, pages 1376–1383 (2019)Cite this article

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Abstract

Among the strategies used for enhancement of tumour retention of imaging agents or anticancer drugs is the rational design of probes that undergo a tumour-specific enzymatic reaction preventing them from being pumped out of the cell. Here, the anticancer agent olsalazine (Olsa) was conjugated to the cell-penetrating peptide RVRR. Taking advantage of a biologically compatible condensation reaction, single Olsa-RVRR molecules were self-assembled into large intracellular nanoparticles by the tumour-associated enzyme furin. Both Olsa-RVRR and Olsa nanoparticles were readily detected with chemical exchange saturation transfer magnetic resonance imaging by virtue of exchangeable Olsa hydroxyl protons. In vivo studies using HCT116 and LoVo murine xenografts showed that the OlsaCEST signal and anti-tumour therapeutic effect were 6.5- and 5.2-fold increased, respectively, compared to Olsa without RVRR, with an excellent ‘theranostic correlation’ (R2 = 0.97) between the imaging signal and therapeutic response (normalized tumour size). This furin-targeted, magnetic resonance imaging-detectable platform has potential for imaging tumour aggressiveness, drug accumulation and therapeutic response.

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Fig. 1: Schematic illustration for the formation of Olsa-NPs by furin-mediated intracellular reduction and condensation of Olsa-RVRR, resulting in enhanced CEST signal and tumour treatment efficacy.
Fig. 2: Physicochemical characterization of Olsa-RVRR and Olsa-NPs in solution.
Fig. 3: In vitro cell studies.
Fig. 4: In vivo theranostic studies.

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Data availability

The experimental data supporting the findings of this study are available in the main text or in the supplementary materials. Additional data are available from the corresponding author upon reasonable request.

Code availability

Custom-written MATLAB scripts, including codes for correcting B0 inhomogeneity and image post-processing, are available at our website http://godzilla.kennedykrieger.org/CEST/.

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Acknowledgements

We thank J. Xu, Z. Han, C. Wang and S. Bo for experimental assistance. This project was supported by the Pearl and Yueh-Heng Yang Foundation and NIH (grant no. P41 EB024495).

Author information

Authors and Affiliations

  1. The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yue Yuan, Jia Zhang, Xiaoliang Qi, Guanshu Liu, Ishan Barman, Xiaolei Song, Michael T. McMahon & Jeff W. M. Bulte

  2. Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yue Yuan, Xiaoliang Qi, Xiaolei Song & Jeff W. M. Bulte

  3. Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Shuoguo Li

  4. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA

    Guanshu Liu, Michael T. McMahon & Jeff W. M. Bulte

  5. Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, MD, USA

    Soumik Siddhanta & Ishan Barman

  6. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ishan Barman & Jeff W. M. Bulte

  7. Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Jeff W. M. Bulte

  8. Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA

    Jeff W. M. Bulte

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  1. Yue Yuan
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Contributions

Y.Y. and J.W.M.B. conceived the project, designed the experiments and wrote the manuscript with input from all authors. Y.Y. performed all experiments. J.Z. assisted with animal studies and MRI. X.Q. assisted with compound synthesis. S.L. performed 3D-SIM imaging. G.L. assisted with image post-processing. S.S. and I.B. performed the Raman imaging experiments. X.S. and M.T.M. provided expertise on CEST MRI.

Corresponding author

Correspondence to Jeff W. M. Bulte.

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Supplementary information

Supplementary Information

Supplementary methods and Figs. 1–36,

Reporting Summary

Supplementary Video 1

3D-SIM super-resolution fluorescence imaging of HCT116 cells incubated with 8 μM Alexa-RVRR.

Supplementary Video 2

3D-SIM super-resolution fluorescence imaging of LoVo cells incubated with 8 μM Alexa-RVRR.

Supplementary Video 3

3D-SIM super-resolution fluorescence imaging of HCT116 cells incubated with 8 μM Alexa 488.

Supplementary Movie 4

3D-SIM super-resolution fluorescence imaging of LoVo cells incubated with 8 μM Alexa 488.

Supplementary Video 5

3D-SIM super-resolution fluorescence imaging of HCT116 tumours after intravenous injection of 50 nmol Alexa-RVRR.

Supplementary Video 6

3D-SIM super-resolution fluorescence imaging of LoVo tumours after intravenous injection of 50 nmol Alexa-RVRR.

Supplementary Video 7

3D-SIM super-resolution fluorescence imaging of HCT116 tumours after intravenous injection of 50 nmol Alexa 488.

Supplementary Video 8

3D-SIM super-resolution fluorescence imaging of LoVo tumours after intravenous injection of 50 nmol Alexa 488.

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Yuan, Y., Zhang, J., Qi, X. et al. Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy. Nat. Mater. 18, 1376–1383 (2019). https://doi.org/10.1038/s41563-019-0503-4

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