Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery
Source abstract
Abstract
Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions. 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 gaps. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy 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 drug.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: Nanoparticle-Based Drug Delivery · 3D Printing in Biomedical Research · Erythrocyte Function and Pathophysiology
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (27)
Show source-provided references
1. Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).10.1016/S0002-9440(10)65006-7 ↗
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).
3. Li, Y. et al. Direct labeling and visualization of blood vessels with lipophilic carbocyanine dye DiI. Nature Protoc. 3, 1703–1708 (2008).10.1038/nprot.2008.172 ↗
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).10.1364/BOE.1.001209 ↗
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).10.1016/j.jconrel.2011.02.011 ↗
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).10.1038/nnano.2011.166 ↗
7. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).10.1038/nrclinonc.2010.139 ↗
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).10.1021/mp100038h ↗
9. Matsumoto, K. et al. Study of normal and pathological blood vessel morphogenesis in Flt1-tdsRed BAC Tg mice. Genesis 50, 561–571 (2012).10.1002/dvg.22031 ↗
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).
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).10.1016/j.bcp.2013.06.020 ↗
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).10.1038/labinvest.3780357 ↗
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).10.1016/j.jconrel.2013.09.026 ↗
14. Holback, H. & Yeo, Y. Intratumoral drug delivery with nanoparticulate carriers. Pharm Res 28, 1819–1830 (2011).10.1007/s11095-010-0360-y ↗
15. Kumar, A. & Graham, M. D. Mechanism of margination in confined flows of blood and other multicomponent suspensions. Phys. Rev. Lett. 109, 108102 (2012).10.1103/PhysRevLett.109.108102 ↗
16. Lee, S. Y., Ferrari, M. & Decuzzi, P. Design of bio-mimetic particles with enhanced vascular interaction. J. Biomech. 42, 1885–1890 (2009).10.1016/j.jbiomech.2009.05.012 ↗
17. Lee, S. Y., Ferrari, M. & Decuzzi, P. Shaping nano-/micro-particles for enhanced vascular interaction in laminar flows. Nanotechnology 20, 495101 (2009).10.1088/0957-4484/20/49/495101 ↗
18. Mitragotri, S. & Lahann, J. Physical approaches to biomaterial design. Nature Mater. 8, 15–23 (2009).10.1038/nmat2344 ↗
19. Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2011).10.1073/pnas.1018382108 ↗
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).
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).10.1038/nmeth.2089 ↗
22. Weller, H. G. & Tabor, G. A tensorial approach to computational continuum mechanics using object-oriented techniques. Comput. Phys. 12, 620–631 (1998).10.1063/1.168744 ↗
23. Issa, R. I. Solution of the implicitly discretised fluid flow equations by operator-splitting. J. Comput. Phys. 62, 40–65 (1985).10.1016/0021-9991(86)90099-9 ↗
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).10.1073/pnas.95.8.4607 ↗
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).
26. Levick, J. R. & Michel, C. C. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87, 198–210 (2010).10.1093/cvr/cvq062 ↗
27. Stohrer, M., Boucher, Y., Stangassinger, M. & Jain, R. K. Oncotic pressure in solid tumors is elevated. Cancer Res. 60, 4251–4255 (2000).