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Edited by Alexander M. Klibanov, Massachusetts Institute of Technology, Cambridge, MA, and approved November 29, 2006 (received for review September 28, 2006)
Abstract
Nanoparticles larger than the reported mesh-pore size range (10–200 nm) in mucus have been thought to be much too large to undergo rapid diffusional transport through mucus barriers. However, large nanoparticles are preferred for higher drug encapsulation efficiency and the ability to provide sustained delivery of a wider array of drugs. We used high-speed multiple-particle tracking to quantify transport rates of individual polymeric particles of various sizes and surface chemistries in samples of fresh human cervicovaginal mucus. Both the mucin concentration and viscoelastic properties of these cervicovaginal samples are similar to those in many other human mucus secretions. Unexpectedly, we found that large nanoparticles, 500 and 200 nm in diameter, if coated with polyethylene glycol, diffused through mucus with an effective diffusion coefficient (D eff) only 4- and 6-fold lower than that for the same particles in water (at time scale τ = 1 s). In contrast, for smaller but otherwise identical 100-nm coated particles, D eff was 200-fold lower in mucus than in water. For uncoated particles 100–500 nm in diameter, D eff was 2,400- to 40,000-fold lower in mucus than in water. Much larger fractions of the 100-nm particles were immobilized or otherwise hindered by mucus than the large 200- to 500-nm particles. Thus, in contrast to the prevailing belief, these results demonstrate that large nanoparticles, if properly coated, can rapidly penetrate physiological human mucus, and they offer the prospect that large nanoparticles can be used for mucosal drug delivery.
Footnotes
- ‖To whom correspondence should be addressed. E-mail: hanes{at}jhu.edu
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Author contributions: S.K.L., R.C., and J.H. designed research; S.K.L., D.E.O., S.H., S.T.M., and Y.-Y.W. performed research; S.K.L., D.E.O., S.H., S.T.M., and Y.-Y.W. analyzed data; and S.K.L., R.C., and J.H. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS direct submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0608611104/DC1.
- Abbreviations:
- COOH-PS,
- COOH-modified particles;
- CV,
- cervicovaginal;
- Deff,
- effective diffusivity;
- MSD,
- mean-squared displacements;
- PEG-PS,
- PEGylated particles;
- RC,
- relative change.
- © 2007 by The National Academy of Sciences of the USA
Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus
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