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


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.


  1. Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).

    CAS  Article  Google Scholar 

  2. Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).

    CAS  Google Scholar 

  3. Li, Y. et al. Direct labeling and visualization of blood vessels with lipophilic carbocyanine dye DiI. Nature Protoc. 3, 1703–1708 (2008).

    CAS  Article  Google Scholar 

  4. Matsumoto, Y. et al. Direct and instantaneous observation of intravenously injected substances using intravital confocal micro-videography. Biomed. Opt. Express 1, 1209–1216 (2010).

    Article  Google Scholar 

  5. Nomoto, T. et al. In situ quantitative monitoring of polyplexes and polyplex micelles in the blood circulation using intravital real-time confocal laser scanning microscopy. J. Control. Release 151, 104–109 (2011).

    CAS  Article  Google Scholar 

  6. Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nature Nanotech. 6, 815–823 (2011).

    CAS  Article  Google Scholar 

  7. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).

    CAS  Article  Google Scholar 

  8. Lee, H., Fonge, H., Hoang, B., Reilly, R. M. & Allen, C. The effects of particle size and molecular targeting on the intratumoral and subcellular distribution of polymeric nanoparticles. Mol. Pharm. 7, 1195–1208 (2010).

    CAS  Article  Google Scholar 

  9. Matsumoto, K. et al. Study of normal and pathological blood vessel morphogenesis in Flt1-tdsRed BAC Tg mice. Genesis 50, 561–571 (2012).

    CAS  Article  Google Scholar 

  10. Dvorak, H. F., Nagy, J. A., Dvorak, J. T. & Dvorak, A. M. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am. J. Pathol. 133, 95–109 (1988).

    CAS  Google Scholar 

  11. Ruggeri, B. A., Camp, F. & Miknyoczki, S. Animal models of disease: pre-clinical animal models of cancer and their applications and utility in drug discovery. Biochem. Pharmacol. 87, 150–161 (2014).

    CAS  Article  Google Scholar 

  12. Tsuzuki, Y. et al. Pancreas microenvironment promotes VEGF expression and tumor growth: novel window models for pancreatic tumor angiogenesis and microcirculation. Lab. Invest. 81, 1439–1451 (2001).

    CAS  Article  Google Scholar 

  13. Stirland, D. L., Nichols, J. W., Miura, S. & Bae, Y. H. Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice. J. Control. Release 172, 1045–1064 (2013).

    CAS  Article  Google Scholar 

  14. Holback, H. & Yeo, Y. Intratumoral drug delivery with nanoparticulate carriers. Pharm Res 28, 1819–1830 (2011).

    CAS  Article  Google Scholar 

  15. Kumar, A. & Graham, M. D. Mechanism of margination in confined flows of blood and other multicomponent suspensions. Phys. Rev. Lett. 109, 108102 (2012).

    Article  Google Scholar 

  16. Lee, S. Y., Ferrari, M. & Decuzzi, P. Design of bio-mimetic particles with enhanced vascular interaction. J. Biomech. 42, 1885–1890 (2009).

    Article  Google Scholar 

  17. Lee, S. Y., Ferrari, M. & Decuzzi, P. Shaping nano-/micro-particles for enhanced vascular interaction in laminar flows. Nanotechnology 20, 495101 (2009).

    Article  Google Scholar 

  18. Mitragotri, S. & Lahann, J. Physical approaches to biomaterial design. Nature Mater. 8, 15–23 (2009).

    CAS  Article  Google Scholar 

  19. Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2011).

    CAS  Article  Google Scholar 

  20. Baron, V. T., Welsh, J., Abedinpour, P. & Borgstrom, P. Intravital microscopy in the mouse dorsal chamber model for the study of solid tumors. Am. J. Cancer Res. 1, 674–686 (2011).

    Google Scholar 

  21. Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nature Methods 9, 671–675 (2012).

    CAS  Article  Google Scholar 

  22. Weller, H. G. & Tabor, G. A tensorial approach to computational continuum mechanics using object-oriented techniques. Comput. Phys. 12, 620–631 (1998).

    Article  Google Scholar 

  23. Issa, R. I. Solution of the implicitly discretised fluid flow equations by operator-splitting. J. Comput. Phys. 62, 40–65 (1985).

    Article  Google Scholar 

  24. Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

    CAS  Article  Google Scholar 

  25. Boucher, Y. & Jain, R. K. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52, 5110–5114 (1992).

    CAS  Google Scholar 

  26. Levick, J. R. & Michel, C. C. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87, 198–210 (2010).

    CAS  Article  Google Scholar 

  27. Stohrer, M., Boucher, Y., Stangassinger, M. & Jain, R. K. Oncotic pressure in solid tumors is elevated. Cancer Res. 60, 4251–4255 (2000).

    CAS  Google Scholar 

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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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Authors and Affiliations



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.

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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).

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