Skip to main content
Biophysical Journal logoLink to Biophysical Journal
. 2001 Jan;80(1):542–548. doi: 10.1016/S0006-3495(01)76036-5

Poly[N-(2-hydroxypropyl)methacrylamide] polymers diffuse in brain extracellular space with same tortuosity as small molecules.

S Prokopová-Kubinová 1, L Vargová 1, L Tao 1, K Ulbrich 1, V Subr 1, E Syková 1, C Nicholson 1
PMCID: PMC1301255  PMID: 11159424

Abstract

Integrative optical imaging was used to show that long-chain synthetic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) polymers in a range of molecular weights from 7.8 to 1057 kDa were able to diffuse through the extracellular space in rat neocortical slices. Tortuosity (square root of ratio of diffusion coefficient in aqueous medium to that in brain) measured with such polymers averaged 1.57, a value similar to that obtained previously with tetramethylammonium, a small cation. When PHPMA was conjugated with bovine serum albumin (BSA) to make a bulky polymer with molecular weight 176 kDa, the tortuosity rose to 2.27, a value similar to that obtained previously with BSA alone and with 70-kDa dextran. The method of image analysis was justified with diffusion models involving spherical and nonspherical initial distributions of the molecules.

Full Text

The Full Text of this article is available as a PDF (258.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blum J. J., Lawler G., Reed M., Shin I. Effect of cytoskeletal geometry on intracellular diffusion. Biophys J. 1989 Nov;56(5):995–1005. doi: 10.1016/S0006-3495(89)82744-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chen K. C., Nicholson C. Changes in brain cell shape create residual extracellular space volume and explain tortuosity behavior during osmotic challenge. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8306–8311. doi: 10.1073/pnas.150338197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Haller M. F., Saltzman W. M. Localized delivery of proteins in the brain: can transport be customized? Pharm Res. 1998 Mar;15(3):377–385. doi: 10.1023/a:1011911912174. [DOI] [PubMed] [Google Scholar]
  4. Mazel T., Simonová Z., Syková E. Diffusion heterogeneity and anisotropy in rat hippocampus. Neuroreport. 1998 May 11;9(7):1299–1304. doi: 10.1097/00001756-199805110-00008. [DOI] [PubMed] [Google Scholar]
  5. Nicholson C. Diffusion from an injected volume of a substance in brain tissue with arbitrary volume fraction and tortuosity. Brain Res. 1985 May 6;333(2):325–329. doi: 10.1016/0006-8993(85)91586-0. [DOI] [PubMed] [Google Scholar]
  6. Nicholson C., Phillips J. M. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol. 1981 Dec;321:225–257. doi: 10.1113/jphysiol.1981.sp013981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Nicholson C. Quantitative analysis of extracellular space using the method of TMA+ iontophoresis and the issue of TMA+ uptake. Can J Physiol Pharmacol. 1992;70 (Suppl):S314–S322. doi: 10.1139/y92-278. [DOI] [PubMed] [Google Scholar]
  8. Nicholson C., Syková E. Extracellular space structure revealed by diffusion analysis. Trends Neurosci. 1998 May;21(5):207–215. doi: 10.1016/s0166-2236(98)01261-2. [DOI] [PubMed] [Google Scholar]
  9. Nicholson C., Tao L. Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophys J. 1993 Dec;65(6):2277–2290. doi: 10.1016/S0006-3495(93)81324-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Noguchi Y., Wu J., Duncan R., Strohalm J., Ulbrich K., Akaike T., Maeda H. Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues. Jpn J Cancer Res. 1998 Mar;89(3):307–314. doi: 10.1111/j.1349-7006.1998.tb00563.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. OGSTON A. G., WOODS E. F. Molecular configuration of dextrans in aqueous solution. Nature. 1953 Jan 31;171(4344):221–222. doi: 10.1038/171221a0. [DOI] [PubMed] [Google Scholar]
  12. Pluen A., Netti P. A., Jain R. K., Berk D. A. Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys J. 1999 Jul;77(1):542–552. doi: 10.1016/S0006-3495(99)76911-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pérez-Pinzón M. A., Tao L., Nicholson C. Extracellular potassium, volume fraction, and tortuosity in rat hippocampal CA1, CA3, and cortical slices during ischemia. J Neurophysiol. 1995 Aug;74(2):565–573. doi: 10.1152/jn.1995.74.2.565. [DOI] [PubMed] [Google Scholar]
  14. Rice M. E., Nicholson C. Diffusion characteristics and extracellular volume fraction during normoxia and hypoxia in slices of rat neostriatum. J Neurophysiol. 1991 Feb;65(2):264–272. doi: 10.1152/jn.1991.65.2.264. [DOI] [PubMed] [Google Scholar]
  15. Rice M. E., Okada Y. C., Nicholson C. Anisotropic and heterogeneous diffusion in the turtle cerebellum: implications for volume transmission. J Neurophysiol. 1993 Nov;70(5):2035–2044. doi: 10.1152/jn.1993.70.5.2035. [DOI] [PubMed] [Google Scholar]
  16. Rosen A. S., Andrew R. D. Osmotic effects upon excitability in rat neocortical slices. Neuroscience. 1990;38(3):579–590. doi: 10.1016/0306-4522(90)90052-6. [DOI] [PubMed] [Google Scholar]
  17. Rusakov D. A., Kullmann D. M. Geometric and viscous components of the tortuosity of the extracellular space in the brain. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8975–8980. doi: 10.1073/pnas.95.15.8975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Tao L. Effects of osmotic stress on dextran diffusion in rat neocortex studied with integrative optical imaging. J Neurophysiol. 1999 May;81(5):2501–2507. doi: 10.1152/jn.1999.81.5.2501. [DOI] [PubMed] [Google Scholar]
  19. Tao L., Nicholson C. Diffusion of albumins in rat cortical slices and relevance to volume transmission. Neuroscience. 1996 Dec;75(3):839–847. doi: 10.1016/0306-4522(96)00303-x. [DOI] [PubMed] [Google Scholar]
  20. Tao L., Nicholson C. The three-dimensional point spread functions of a microscope objective in image and object space. J Microsc. 1995 Jun;178(Pt 3):267–271. doi: 10.1111/j.1365-2818.1995.tb03604.x. [DOI] [PubMed] [Google Scholar]
  21. Ulbrich K., Pechar M., Strohalm J., Subr V., Ríhová B. Synthesis of biodegradable polymers for controlled drug release. Ann N Y Acad Sci. 1997 Dec 31;831:47–56. doi: 10.1111/j.1749-6632.1997.tb52183.x. [DOI] [PubMed] [Google Scholar]
  22. Wright A. K., Thompson M. R. Hydrodynamic structure of bovine serum albumin determined by transient electric birefringence. Biophys J. 1975 Feb;15(2 Pt 1):137–141. doi: 10.1016/s0006-3495(75)85797-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Zoli M., Jansson A., Syková E., Agnati L. F., Fuxe K. Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol Sci. 1999 Apr;20(4):142–150. doi: 10.1016/s0165-6147(99)01343-7. [DOI] [PubMed] [Google Scholar]
  24. el-Kareh A. W., Braunstein S. L., Secomb T. W. Effect of cell arrangement and interstitial volume fraction on the diffusivity of monoclonal antibodies in tissue. Biophys J. 1993 May;64(5):1638–1646. doi: 10.1016/S0006-3495(93)81532-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES