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A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

Nature Nanotechnology volume 11, pages 378–387 (2016)Cite this article

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Abstract

Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.

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Figure 1: Concepts of spatiotemporal-synchronized combination therapy using PMILs.
Figure 2: Synthesis and characterization of a benzoporphyrin–XL184 PMIL.
Figure 3: Structural imaging of NP[XL184] encapsulation and XL184 photorelease from PMILs.
Figure 4: MET inhibition enhancement of PDT-induced cancer cell death in vitro using PMILs.
Figure 5: Prolonged tumour reduction in vivo with a single cycle of PMIL-treatment.
Figure 6: Antivascular and antimetastatic effects using a single PMIL-treatment cycle in vivo.

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Acknowledgements

We thank N. Watson (W. M. Kreck Microscopy Facility at the Whitehead Institute, Massachusetts Institute of Technology) for providing ionized carbon coated grids; E. Oliva (Department of Pathology at Massachusetts General Hospital) for expert histopathologic review of tissue sections; G. Orbaid for a critical reading; and, A. Villanueva for assistance in preparing a 3D render of a PMIL cryo-EM tomogram. This work was supported by National Institutes of Health Grants R01 CA156177 (to T.H.), R01-CA160998 (to T.H.), and P01-CA084203 (to B.W.P., S.P.P. and T.H.) and F32-CA144210 (to B.Q.S.).

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Author notes

  1. Bryan Q. Spring, R. Bryan Sears and Lei Zak Zheng: These authors contributed equally to this work

Authors and Affiliations

  1. Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, Massachusetts, USA

    Bryan Q. Spring, R. Bryan Sears, Lei Zak Zheng, Zhiming Mai, Margaret E. Sherwood & Tayyaba Hasan

  2. Department of Physics, Northeastern University, Boston, 02115, Massachusetts, USA

    Bryan Q. Spring

  3. Department of Chemistry, Emmanuel College, Boston, 02115, Massachusetts, USA

    R. Bryan Sears

  4. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, 92093, California, USA

    Reika Watanabe & Elizabeth Villa

  5. Massachusetts General Hospital and Harvard University, Biostatistics Unit, Boston, 02114, Massachusetts, USA

    David A. Schoenfeld

  6. Thayer School of Engineering, Dartmouth College, Hanover, 03755, New Hampshire, USA

    Brian W. Pogue

  7. UCL Institute for Liver and Digestive Health, University College London, Royal Free Hospital Campus, London, NW3 2QG, UK

    Stephen P. Pereira

  8. Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Tayyaba Hasan

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Contributions

B.Q.S., R.B.S., L.Z.Z., and T.H. conceived and designed experiments. B.Q.S., R.B.S., L.Z.Z., Z.M., R.W., M.E.S., and E.V. performed experiments. R.B.S. synthesized the nanomaterials. B.Q.S., R.B.S. and E.V. developed methodology and performed data analysis. D.A.S. contributed to statistical analysis of the data. B.Q.S., R.B.S., L.Z.Z., and T.H. prepared the manuscript. B.W.P., S.P.P. and E.V. contributed to experimental design and manuscript preparation. All authors contributed to editing the final manuscript.

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Correspondence to Tayyaba Hasan.

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Spring, B., Bryan Sears, R., Zheng, L. et al. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways. Nature Nanotech 11, 378–387 (2016). https://doi.org/10.1038/nnano.2015.311

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