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The dose threshold for nanoparticle tumour delivery

Abstract

Nanoparticle delivery to solid tumours over the past ten years has stagnated at a median of 0.7% of the injected dose. Varying nanoparticle designs and strategies have yielded only minor improvements. Here we discovered a dose threshold for improving nanoparticle tumour delivery: 1 trillion nanoparticles in mice. Doses above this threshold overwhelmed Kupffer cell uptake rates, nonlinearly decreased liver clearance, prolonged circulation and increased nanoparticle tumour delivery. This enabled up to 12% tumour delivery efficiency and delivery to 93% of cells in tumours, and also improved the therapeutic efficacy of Caelyx/Doxil. This threshold was robust across different nanoparticle types, tumour models and studies across ten years of the literature. Our results have implications for human translation and highlight a simple, but powerful, principle for designing nanoparticle cancer treatments.

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Fig. 1: The liver clearance threshold.
Fig. 2: The dose threshold is determined by uptake rate.
Fig. 3: The dose threshold for tumour delivery.
Fig. 4: Tumour penetration and cell delivery above the threshold.
Fig. 5: Therapeutic efficacy of Caelyx above the threshold.
Fig. 6: Identifying a dose threshold in publications from 2005–2015.

Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information files. The raw data that support the findings of this study are available from the corresponding author on reasonable request. Additional data from the meta-analysis of literature are available from the Cancer Nanomedicine Repository at http://inbs.med.utoronto.ca/cnr/.

Code availability

All code (used to run the simulation data in Supplementary Figs. 12 and 13) is available via GitHub at https://github.com/beeno/trillionParticlesODEs. All code for 3D image analysis is available via GitHub at https://github.com/BenKingston/nanoparticle_vessel_analysis.

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Acknowledgements

We thank W. Jiang, W. Hou and T. Komal for help with experiments involving radioactivity, S. Lheureux for Caelyx and M. Ganguly, V. Bradaschia and K. Duffin in Pathology at The Centre for Phenogenomics for histology and blood biochemistry. We thank M. Egeblad for the c-fms-EGFP BALB/c breeder mice, and S. Grinstein for RAW264.7 cells. We thank L. Dunning and the Division of Comparative Medicine for animal husbandry. We thank J. Rothschild, C. E. Shin, S. Wilhelm, S. MacParland, J. Jonkman, S. Grinstein and K. Kataoka for discussions. We thank A. Malekjahani, B. Udugama, S. MacParland, M. Rajora, J. Ngai and S. Wilhelm for discussions with the manuscript revisions. We thank the Toronto Nanomedicine Fabrication Centre for use of the ICP-MS, the Nanoscale Biomedical Imaging Facility for use of the TEM and the Advanced Optical Microscopy Facility for guidance and use of the intravital microscope. This work was supported by the Canadian Cancer Society (grant numbers 502200 and 706286), the Canadian Institutes of Health Research (grant numbers PJT-148848 and FDN-159932), the Natural Sciences and Engineering Research Council of Canada (grant number 2015–06397), the Canada Research Chair Program (grant numbers 950–223924 and 950–232468), the Canada Foundation for Innovation (grant number 21765) and the Princess Margaret Cancer Foundation. B.O. thanks the Vanier Canada Graduate Scholarship, CIHR and the McLaughlin Centre for MD/PhD studentships, and the Ontario Graduate Scholarships, the Institute of Biomaterials and Biomedical Engineering, the University of Toronto School of Graduate Studies, the Donnelly Centre, the Frank Fletcher Memorial Fund, C. Yip and J. J. Ruffo for graduate fellowships. W.P. thanks the CIHR and OGS for graduate scholarships, and acknowledges fellowship support from C. Yip, B. and F. Milligan and the University of Toronto Faculty of Applied Science and Engineering. Y.-N.Z. thanks the NSERC, Wildcat Foundation, Ontario Graduate Scholarship, and Paul and Sally Wang fellowships. B.R.K. thanks NSERC, the Donnelly Centre, the Wildcat Fellows Program, the Royal Bank of Canada and Borealis AI for student fellowships and scholarships. A.J.T. thanks CIHR for the provision of a postdoctoral fellowship. M.S.V. thanks the Department of Defense Ovarian Cancer Research Program and the Terry Fox Research Institute for funding. J.C.-S. thanks the University of Toronto Faculty of Medicine for funding. P.M. thanks the Walter C. Sumner foundation for the fellowship.

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B.O., W.P., Y.-N.Z. and W.C.W.C. conceptualized the project. B.O., W.P., Y.-N.Z., Z.P.L., B.R.K., A.M.S., A.J.T., P.M. and J.C.-S. designed and performed the nanoparticle synthesis and biodistribution experiments. J.C., M.S.V. and B.O. designed and performed the radioactive liposome validation biodistribution experiments. B.O., W.P., Y.-N.Z. and Z.P.L. designed and performed the delivery enhancer experiments. B.R.K., A.M.S. and P.M. designed and performed the 3D tissue microscopy experiments. Y.Z. designed and performed the protein corona analysis experiments. G.Z. and W.C.W.C. acquired funding for this project. B.O. and W.C.W.C. wrote the initial manuscript draft. All authors contributed to reviewing and editing the manuscript.

Corresponding author

Correspondence to Warren C. W. Chan.

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B.O., W.P., Y.-N.Z., Z.P.L. and W.C.W.C. declare patents pending on the delivery enhancer technique in the United States (63/017,322) and Canada (3,079,765).

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Supplementary information

Supplementary Information

Supplementary Figs. 1–41, Tables 1–3, video captions, methods and references.

Reporting Summary

Supplementary Video 1

Live intravital imaging of Cy3 gold nanoparticle uptake in Kupffer cells in a mouse administered with a low dose.

Supplementary Video 2

Live intravital imaging of Cy3 gold nanoparticle uptake in Kupffer cells in a mouse administered with a high dose.

Supplementary Video 3

Live intravital imaging of Cy5 gold nanoparticle uptake in Kupffer cells in a mouse administered with a high dose.

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Ouyang, B., Poon, W., Zhang, YN. et al. The dose threshold for nanoparticle tumour delivery. Nat. Mater. 19, 1362–1371 (2020). https://doi.org/10.1038/s41563-020-0755-z

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