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Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery

Abstract

Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions1,2. This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps3. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy4,5 we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named ‘eruptions’) into the tumour interstitial space. We propose that ‘dynamic vents’ form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug6,7.

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Figure 1: Analysis of IVCLSM images for 30 and 70 nm nanoparticles.
Figure 2: Exploring the causes of eruptions.
Figure 3: Computer simulation of eruption of nanoparticles through a blood vessel pore into bulk tumour tissue.
Figure 4: Clinical implications of dynamic vents.

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Acknowledgements

We would like to thank D. Stirland for providing the code used to perform distance to GFP analysis. This work was supported by the Core Research Program for Evolutional Science and Technology (CREST) and Center of Innovation (COI) Program from the Japan Science and Technology Corporation (JST), the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from the Japan Society for the Promotion of Science (JSPS), KAKENHI Grant Numbers 2379004 (Y.M.), 15K06871 (K.T.), 25750172 (H.C.), 24659584 (Y.M.), and 25000006 (K.K.) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, the Research Foundation for Pharmaceutical Sciences (Y.M.), the Photographic Research Fund of the Konica Minolta Imaging Science Foundation (Y.M.), and Grants from the Initiative for Accelerating Regulatory Science in Innovative Drug, Medical Device, and Regenerative Medicine of the Ministry of Health, Labour and Welfare (MHLW) of Japan. Funding for this work from J.N. and Y.H.B. was provided in part by NIH CA122356.

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Y.M. conceived, designed, and performed IVCLSM experiments, analysed the data, and wrote the paper. J.N. designed and performed computer simulation experiments, analysed the data, and wrote the paper. Y. Matsumoto and J.N. contributed equally to this work. K.T. and T.N. assisted with IVCLSM experiments. H.C., Y. Miura, and N.Y. synthesized the fluorescent nanoparticles. T.O. customized the microscope and maintained it in excellent condition. All authors discussed the results and commented on the manuscript. H.C., N.N., Y.H.B. and K.K. edited the manuscript. Y.H.B. and K.K. supervised the whole project.

Corresponding authors

Correspondence to You Han Bae or Kazunori Kataoka.

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Competing interests

T.O. is an employee of Nikon Instech Co., Ltd., Japan. All other authors declare no competing financial interest.

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Matsumoto, Y., Nichols, J., Toh, K. et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nature Nanotech 11, 533–538 (2016). https://doi.org/10.1038/nnano.2015.342

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