Elsevier

Biomaterials

Volume 29, Issue 12, April 2008, Pages 1912-1919
Biomaterials

Particle size-dependent organ distribution of gold nanoparticles after intravenous administration

https://doi.org/10.1016/j.biomaterials.2007.12.037Get rights and content

Abstract

A kinetic study was performed to determine the influence of particle size on the in vivo tissue distribution of spherical-shaped gold nanoparticles in the rat. Gold nanoparticles were chosen as model substances as they are used in several medical applications. In addition, the detection of the presence of gold is feasible with no background levels in the body in the normal situation. Rats were intravenously injected in the tail vein with gold nanoparticles with a diameter of 10, 50, 100 and 250 nm, respectively. After 24 h, the rats were sacrificed and blood and various organs were collected for gold determination. The presence of gold was measured quantitatively with inductively coupled plasma mass spectrometry (ICP-MS).

For all gold nanoparticle sizes the majority of the gold was demonstrated to be present in liver and spleen. A clear difference was observed between the distribution of the 10 nm particles and the larger particles. The 10 nm particles were present in various organ systems including blood, liver, spleen, kidney, testis, thymus, heart, lung and brain, whereas the larger particles were only detected in blood, liver and spleen. The results demonstrate that tissue distribution of gold nanoparticles is size-dependent with the smallest 10 nm nanoparticles showing the most widespread organ distribution.

Introduction

Nanoscience can be defined as the study of phenomena and manipulation of materials at atomic, molecular and macromolecular scales where physico-chemical properties may differ significantly from those at a larger particulate scale. Nanotechnology is then the design, characterization, production and application of structures, devices and systems by controlling the shape and size at the nanometer scale [1]. The fast growing number of applications of engineered nanoparticles in drug delivery systems, medical devices, food products, consumer products and the subsequent disposal of engineered nanoparticles in the environment imply that human exposure to engineered nanoparticles is expected to increase greatly. Engineered nanoparticles show remarkable structural diversity, each structure exhibiting their own individual characteristics, such as tubes, dots, wires, fibres and capsules [2], [3], [4]. The size at which the different structures change their properties is not a generally applicable limit value, but it probably differs from compound to compound. Although no scientifically accepted definition exists, in general the nanoscale applies to the structures having at least one dimension at a size in the order of 100 nm or less. However, for regulatory purposes the 100 nm threshold is of limited value, as there is no reason to assume that 100 nm would be an absolute threshold for changes in the physico-chemical properties of nanoparticles.

The specific physico-chemical properties at the nanoscale are expected to result in increased reactivity with biological systems. So, in addition to their beneficial effects, engineered nanoparticles of different types may also represent a potential hazard to human health. Several studies indeed suggest that these nanoparticles have a different toxicity profile compared with larger particles [5], [6].

Kinetic properties are considered to be an important descriptor for potential human toxicity and thus for human health risk. It is important to know the amount of the total external exposure that will be absorbed by the body and result in an internal exposure. In addition, the distribution of absorbed nanoparticles inside the body over the various organ systems and within the organs needs to be determined. After the initial absorption of nanoparticles the systemic circulation can distribute the particles towards all organs and tissues in the body. Several studies have shown distribution of particles to multiple organs including liver, spleen, heart and brain [7], [8], [9], [10].

As a model particle for nanotechnology research, metallic colloidal gold nanoparticles are widely used. They can be synthesized in different forms (rods, dots), are commercially available in various size ranges and can be detected at low concentrations. It has been reported that human cells can take up gold nanoparticles without cytotoxic effects [11]. In particular for biomedical applications, they can be considered relevant models, since they are used as potential carriers for drug delivery, imaging molecules and even genes [12], and for the development of novel cancer therapy products [13], [14], [15], [16], [17]. In addition, they have a history as label for tracking protein distribution in vivo in which proteins are coupled to small colloidal gold beads at nanoscale dimensions [18].

Hillyer and Albrecht [7] showed that after oral administration of metallic colloidal gold nanoparticles of decreasing size (58, 28, 10 and 4 nm) to mice an increased distribution to other organs was observed. The smallest particle (4 nm) administered orally resulted in an increased presence of gold particles in kidney, liver, spleen, lungs and even the brain. The biggest particle (58 nm) tested was detected almost solely inside the gastrointestinal tract. For 13 nm sized colloidal gold beads the highest amount of gold was observed in liver and spleen after intraperitoneal administration [18]. In another study, intravenously injected gold nanorods (length 65 ± 5 nm; width 11 ± 1 nm) revealed that within 30 min these particles accumulated predominantly in the liver. The PEGylation (coating with polyethylene glycol) of these gold nanorods resulted in a prolonged circulation [19].

The aim of our study was to determine the influence of particle size on the in vivo tissue distribution of gold nanoparticles in the rat. To circumvent the absorption process, rats were intravenously injected with solutions containing various sized metallic colloidal gold nanoparticles (10, 50, 100 and 250 nm).

Section snippets

Animals

Male WU Wistar-derived rats, 6–8 weeks of age were obtained from the animal facility of the Institute (RIVM, Bilthoven, The Netherlands). Animals were bred under SPF conditions and barrier maintained during the experiment. Drinking water and conventional feed were provided ad libitum. Husbandry conditions were maintained according to all applicable provisions of the national laws, Experiments on Animals Decree and Experiments on Animals Act. The experiment was approved by an independent ethical

Gold nanoparticles characteristics and general quality control aspects

The total amount of elemental gold injected was determined with ICP-MS. The gold concentration as determined by calculation using the information of the manufacturer and the dilution factor was compared with the gold concentration measured by ICP-MS. There was a maximum of 20% deviation of the claimed concentration. Table 1 shows the characteristics of the different sized nanoparticles in the injection solution per volume. The results of the quality control aspects of ICP-MS are given in Table 3

Discussion

In this study, we compared the tissue distribution of various sized gold nanoparticles in the rat. Although the study was designed with specific relevance for intravenously administered nanoparticles in medical applications, the results can also be considered useful for other routes of exposure. After absorption of nanoparticles following, e.g. inhalation, oral or dermal exposure, further distribution in the body then occurs via the blood circulation. The distribution of gold nanoparticles

Conclusion

We have demonstrated that the distribution of gold nanoparticles is size-dependent, the smallest particles showing the most widespread organ distribution including blood, heart, lungs, liver, spleen, kidney, thymus, brain, and reproductive organs. With the obtained results no reliable prediction about the distribution pattern can be made outside the tested size range. Therefore further kinetic and toxicokinetic studies are required to extend the existing knowledge on particle behavior in vivo.

Acknowledgements

We thank Dr. J. Sabine Becker, Research Centre Jülich, Jülich, Germany, for her support and the scientific discussions about ICP-MS. We also acknowledge the excellent technical assistance of Mrs. Trudy Riool – Nesselaar, Mrs. Liset De La Fonteyne and Mr. Henny Verharen.

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    Current address: MiPlaza Materials Analysis, Philips Research, High Tech Campus 12, 5656 AE Eindhoven, The Netherlands.

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