Spontaneous penetration of gold nanoparticles through the blood brain barrier (BBB)

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Abstract

Background

The blood brain barrier (BBB) controls the brain microenvironment and limits penetration of the central nervous system (CNS) by chemicals, thus creating an obstacle to many medical imaging and treatment procedures. Research efforts to identify viable routes of BBB penetration have focused on structures such as micelles, polymeric nanoparticles and liposomes as drug carriers, however, many of them failed to provide unequivocal proof of BBB penetration. Here we proved that gold nanoparticles (AuNPs) penetrate the BBB in rats to reach brain regions.

Results

Injection of AuNPs to the abdominal cavity of rats resulted in levels of gold found in blood, urine, brain regions and body organs. After perfusion the concentration of gold in brain regions diminished dramatically indicating that most of the gold was in venous blood and not in the brain tissues. Injection of Na, K or Ca ion channel blockers reduced BBB penetration by half. A biological half-life of 12.9 ± 4.9 h was found for the gold nanoparticles. Possible mechanisms for the transport of AuNPs through the BBB are discussed.

Conclusions

BBB penetration by AuNPs is spontaneous without the application of an external field. A major amount of gold resides in blood vessels therefore perfusion required. Ion channel blockers can be used to control the transport of AuNPs.

Electronic supplementary material

The online version of this article (doi:10.1186/s12951-015-0133-1) contains supplementary material, which is available to authorized users.

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Most cited references 28

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Gold nanoparticles in biology: beyond toxicity to cellular imaging.

Catherine J Murphy, Anand M. Gole, John W Stone … (2008)

Gold, enigmatically represented by the target-like design of its ancient alchemical symbol, has been considered a mystical material of great value for centuries. Nanoscale particles of gold now command a great deal of attention for biomedical applications. Depending on their size, shape, degree of aggregation, and local environment, gold nanoparticles can appear red, blue, or other colors. These visible colors reflect the underlying coherent oscillations of conduction-band electrons ("plasmons") upon irradiation with light of appropriate wavelengths. These plasmons underlie the intense absorption and elastic scattering of light, which in turn forms the basis for many biological sensing and imaging applications of gold nanoparticles. The brilliant elastic light-scattering properties of gold nanoparticles are sufficient to detect individual nanoparticles in a visible light microscope with approximately 10(2) nm spatial resolution. Despite the great excitement about the potential uses of gold nanoparticles for medical diagnostics, as tracers, and for other biological applications, researchers are increasingly aware that potential nanoparticle toxicity must be investigated before any in vivo applications of gold nanoparticles can move forward. In this Account, we illustrate the importance of surface chemistry and cell type for interpretation of nanoparticle cytotoxicity studies. We also describe a relatively unusual live cell application with gold nanorods. The light-scattering properties of gold nanoparticles, as imaged in dark-field optical microscopy, can be used to infer their positions in a living cell construct. Using this positional information, we can quantitatively measure the deformational mechanical fields associated with living cells as they push and pull on their local environment. The local mechanical environment experienced by cells is part of a complex feedback loop that influences cell metabolism, gene expression, and migration.

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Mechanisms of Cellular Uptake of Cell-Penetrating Peptides

Fatemeh Madani, Staffan Lindberg, Ülo Langel … (2011)

Recently, much attention has been given to the problem of drug delivery through the cell-membrane in order to treat and manage several diseases. The discovery of cell penetrating peptides (CPPs) represents a major breakthrough for the transport of large-cargo molecules that may be useful in clinical applications. CPPs are rich in basic amino acids such as arginine and lysine and are able to translocate over membranes and gain access to the cell interior. They can deliver large-cargo molecules, such as oligonucleotides, into cells. Endocytosis and direct penetration have been suggested as the two major uptake mechanisms, a subject still under debate. Unresolved questions include the detailed molecular uptake mechanism(s), reasons for cell toxicity, and the delivery efficiency of CPPs for different cargoes. Here, we give a review focused on uptake mechanisms used by CPPs for membrane translocation and certain experimental factors that affect the mechanism(s).

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Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles.

Ayush Verma, Oktay Uzun, Yuhua Hu … (2008)

Nanoscale objects are typically internalized by cells into membrane-bounded endosomes and fail to access the cytosolic cell machinery. Whereas some biomacromolecules may penetrate or fuse with cell membranes without overt membrane disruption, no synthetic material of comparable size has shown this property yet. Cationic nano-objects pass through cell membranes by generating transient holes, a process associated with cytotoxicity. Studies aimed at generating cell-penetrating nanomaterials have focused on the effect of size, shape and composition. Here, we compare membrane penetration by two nanoparticle 'isomers' with similar composition (same hydrophobic content), one coated with subnanometre striations of alternating anionic and hydrophobic groups, and the other coated with the same moieties but in a random distribution. We show that the former particles penetrate the plasma membrane without bilayer disruption, whereas the latter are mostly trapped in endosomes. Our results offer a paradigm for analysing the fundamental problem of cell-membrane-penetrating bio- and macro-molecules.

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Author and article information

Contributors

Hagit Sela: hagitsel@post.bgu.ac.il

Hagit Cohen: hagitc@bgu.ac.il

Paz Elia: pazel@post.bgu.ac.il

Raya Zach: raya970@gmail.com

Zeev Karpas: zeevkar44@gmail.com

Yehuda Zeiri:

ORCID: http://orcid.org/0000-0002-5488-5823

+972-8-6479611 , yehuda.zeiri@gmail.com , yehuda@bgu.ac.il

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 21 October 2015

Publication date PMC-release: 21 October 2015

Publication date Collection: 2015

Volume: 13

Electronic Location Identifier: 71

Affiliations

[ ]Department of Biomedical Engineering, Ben-Gurion University of the Negev, Beer-Sheva, 8410501 Israel

[ ]Department of Chemistry, NRCN, P.O. Box 9001, Beer-Sheva, 8419001 Israel

[ ]The State of Israel Ministry of Health, Anxiety and Stress Research Unit, Faculty of Health Sciences, Beer-Sheva Mental Health Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Author information

Yehuda Zeiri http://orcid.org/0000-0002-5488-5823

Article

Publisher ID: 133

DOI: 10.1186/s12951-015-0133-1

PMC ID: 4618365

PubMed ID: 26489846

SO-VID: e2e01ec4-11e3-47cb-af78-5afdbe6498a8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 June 2015

Date accepted : 6 October 2015

Custom metadata

ScienceOpen disciplines: Biotechnology

Keywords: gold nanoparticles,rat,biokinetics,penetration,blood-brain barrier,icp-ms,la-icp-ms

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ScienceOpen disciplines: Biotechnology

Keywords: gold nanoparticles, rat, biokinetics, penetration, blood-brain barrier, icp-ms, la-icp-ms

Spontaneous penetration of gold nanoparticles through the blood brain barrier (BBB)

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Abstract

Background

Results

Conclusions

Electronic supplementary material

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Nanoparticles to cross the blood-brain barrier (BBB)

Most cited references 28

Gold nanoparticles in biology: beyond toxicity to cellular imaging.

Mechanisms of Cellular Uptake of Cell-Penetrating Peptides

Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles.

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