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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol. 2, 251–275 (2007).
Yuan, F. et al. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 54, 3352–3356 (1994).
Baish, J. W. et al. Scaling rules for diffusive drug delivery in tumor and normal tissues. Proc. Natl Acad. Sci. USA 108, 1799–1803 (2011).
Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).
Gazit, Y., Berk, D. A., Leunig, M., Baxter, L. T. & Jain, R. K. Scale-invariant behavior and vascular network formation in normal and tumor tissue. Phys. Rev. Lett. 75, 2428–2431 (1995).
Nagy, J. A., Chang, S. H., Dvorak, A. M. & Dvorak, H. F. Why are tumour blood vessels abnormal and why is it important to know? Br. J. Cancer 100, 865–869 (2009).
Chauhan, V. P., Stylianopoulos, T., Boucher, Y. & Jain, R. K. Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu. Rev. Chem. Biomol. Eng. 2, 281–298 (2011).
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).
Goel, S. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 91, 1071–1121 (2011).
Jain, R. K. & Baxter, L. T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48, 7022–7032 (1988).
Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004).
Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).
Nakahara, T., Norberg, S. M., Shalinsky, D. R., Hu-Lowe, D. D. & McDonald, D. M. Effect of inhibition of vascular endothelial growth factor signaling on distribution of extravasated antibodies in tumors. Cancer Res. 66, 1434–1445 (2006).
Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145–147 (2004).
Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).
Sorensen, A. G. et al. Increased survival of glioblastoma patients who respond to anti-angiogenic therapy with elevated blood perfusion. Cancer Res. 72, 402–407 (2012).
Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nature Rev. Clin. Oncol. 7, 653–664 (2010).
Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotech. 2, 751–760 (2007).
Popovic, Z. et al. A nanoparticle size series for in vivo fluorescence imaging. Angew. Chem. Int. Ed. 49, 8649–8652 (2010).
Chauhan, V. P. et al. Fluorescent nanorods and nanospheres for real-time in vivo probing of nanoparticle shape-dependent tumor penetration. Angew. Chem. Int. Ed. 50, 11417–11420 (2011).
Gazit, Y. et al. Fractal characteristics of tumor vascular architecture during tumor growth and regression. Microcirculation 4, 395–402 (1997).
Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).
Baish, J. W., Netti, P. A. & Jain, R. K. Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors. Microvasc. Res. 53, 128–141 (1997).
Pozrikidis, C. & Farrow, D. A. A model of fluid flow in solid tumors. Ann. Biomed. Eng. 31, 181–194 (2003).
Bungay, P. M. & Brenner, H. The motion of a closely-fitting sphere in a fluid-filled tube. Int. J. Multiphase Flow 1, 25–56 (1973).
Deen, W. M. Hindered transport of large molecules in liquid-filled pores. AIChE J. 33, 1409–1425 (1987).
Sarin, H. Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J. Angiogenes. Res. 2, 14 (2010).
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).
Ruoslahti, E., Bhatia, S. N. & Sailor, M. J. Targeting of drugs and nanoparticles to tumors. J. Cell Biol. 188, 759–768 (2010).
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).
Author information
Authors and Affiliations
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
Ethics declarations
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.
Supplementary information
Supplementary information
Supplementary information (PDF 1107 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nnano.2012.45
This article is cited by
-
Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours
Nature Nanotechnology (2024)
-
Anti-lymphangiogenesis for boosting drug accumulation in tumors
Signal Transduction and Targeted Therapy (2024)
-
An in silico model of the capturing of magnetic nanoparticles in tumour spheroids in the presence of flow
Biomedical Microdevices (2024)
-
The impact of tumor microenvironment: unraveling the role of physical cues in breast cancer progression
Cancer and Metastasis Reviews (2024)
-
The role of HIF in angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers
Molecular Biology Reports (2024)