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Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner

Nature Nanotechnology volume 7, pages 383–388 (2012)Cite this article

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Abstract

The blood vessels of cancerous tumours are leaky1,2,3 and poorly organized4,5,6,7. This can increase the interstitial fluid pressure inside tumours and reduce blood supply to them, which impairs drug delivery8,9. Anti-angiogenic therapies—which ‘normalize’ the abnormal blood vessels in tumours by making them less leaky—have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular weights10, but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here, we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor receptor-2, improves the delivery of smaller nanoparticles (diameter, 12 nm) while hindering the delivery of larger nanoparticles (diameter, 125 nm). Using a mathematical model, we show that reducing the sizes of pores in the walls of vessels through normalization decreases the interstitial fluid pressure in tumours, thus allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (∼12 nm) nanomedicines are ideal for cancer therapy due to their superior tumour penetration.

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Figure 1: Effects of vascular normalization on nanoparticle delivery in tumours.
Figure 2: Functional vascular normalization window for nanomedicine delivery.
Figure 3: Mathematical model predictions of how changes in vascular pore size distribution affect delivery for different sizes of drugs.
Figure 4: Dependence of transvascular pressure gradient and transport hindrance on pore size.
Figure 5: Improvement of cytotoxic nanomedicine effectiveness by vascular normalization.

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Acknowledgements

The authors thank J. Kahn and S. Roberge for technical assistance, J. Baish for assistance with the mathematical model and M. Ancukiewicz for assistance with statistical analysis. The authors acknowledge ImClone Systems for generously providing DC101, the National Institutes of Health (P01-CA080124, R01-CA126642, R01-CA115767, R01-CA096915, R01-CA085140, R01-CA098706, T32-CA073479), a DoD Breast Cancer Research Innovator award (W81XWH-10-1-0016) and an FP7 Marie-Curie IRG grant (PIRG08-GA-2010-276894).

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Author notes

  1. Vikash P. Chauhan and Triantafyllos Stylianopoulos: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, Massachusetts, USA

    Vikash P. Chauhan, Triantafyllos Stylianopoulos, John D. Martin, Walid S. Kamoun, Dai Fukumura & Rakesh K. Jain

  2. Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, 02138, Massachusetts, USA

    Vikash P. Chauhan

  3. Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, 1678, Cyprus

    Triantafyllos Stylianopoulos

  4. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    John D. Martin

  5. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Zoran Popović, Ou Chen & Moungi G. Bawendi

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Contributions

V.P.C. and R.K.J. conceived and designed the experiments. T.S. and R.K.J. designed and developed the mathematical model and its simulations. V.P.C., J.D.M. and O.C. performed the experiments. T.S. carried out the mathematical model simulations. V.P.C., T.S., J.D.M. and W.S.K. analysed the data. Z.P., O.C., W.S.K., M.G.B. and D.F. contributed materials/analysis tools. V.P.C., T.S. and R.K.J. co-wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Rakesh K. Jain.

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Competing interests

R.K.J. receives research support from Dyax, MedImmune and Roche, is a consultant for Dyax and Noxxon, is on the Scientific Advisory Board for Enlight and SynDevRx, is on the Board of Trustees for H&Q Capital Management and is a co-founder of Xtuit. The other authors declare no competing financial interests.

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Chauhan, V., Stylianopoulos, T., Martin, J. et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nature Nanotech 7, 383–388 (2012). https://doi.org/10.1038/nnano.2012.45

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