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photothermal imaging as well as tumour treatment because of the impact

of small temperature changes on cell viability. Hyperthermia treatment

Cells are very sensitive to temperature variation and die above 42◦ C, the

normal value for human cells being 37◦ C. This fact can be exploited to

use localized hyperthermia to specifically kill tumour cells. To achieve this

objective, there are two prerequisites: particle accumulation in the tumour

cells and illumination of the nanoparticles with sufficient energy to induce

heating (Fig. 11.9). As discussed previously, in theory, AuNPs can target

cancer cells by encapsulating the particles with molecules which have a

high affinity for the proteins expressed only by the tumour. This leads to

particle accumulation in the tumour area due to their binding to the membrane with or without the ensuing internalization; in both cases, the consequence of the light absorption will be the same. As indicated previously, the

absorption resulting from plasmon resonance occurs at a wavelength which

varies according to the size,100 shape101 and structure102 of the particles: the

optimal parameters were found to be around 40 nm diameter for spherical

gold nanoparticles, between 20 and 70 nm length for nanorods and 50 to

100 nm total diameter for core-shell structures where the gold outer shell

Fig. 11.9. Treatment of a tumour by hyperthermia using AuNPs. AuNPs bearing a tumour specific

binding motif are injected; due to the increased permeability of the vessels surrounding the tumour,

AuNPs interact with abnormal cells. Laser illumination of the particles induces the production of thermal

energy sufficient to kill surrounding cells.



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has a thickness of 7–10 nm. In these cases, the maximum absorption is measured at 800 nm. In conclusion, by modifying the physical characteristics

of the nanoparticles, it is possible to modify the wavelength corresponding

to the maximum light energy absorption (see Chapter 3). This property is

very important because the main limitation of photothermal effects is the

light absorption by animal tissues: a very small fraction of the light energy

reaches the particles depending on the depth of the tumour. Tissue absorption

varies according to the wavelength and is minimal in the infrared spectrum

though, even in these conditions, the absorption remains fairly high. This

means that such treatment can only be achieved for tumours close to the

skin in the case of external illumination. For deep tumours, this technology

is difficult to apply even using IR wavelengths; we may, however, imagine

that in this case it would be possible to use intra-body laser illumination.

The penetration of particles into a tumour is often facilitated by the so-called

enhanced permeability and retention (EPR) effect observed in the vessels

around tumours, but this permeability varies from tumour to tumour.103 Drug delivery by photo-induced heating

The temperature increase induced by illumination of gold nanoparticles

can also be used to release drugs transported to the tumour area by AuNPs

(Fig. 11.10).

Firstly, this technique can be used to release both proteins and polynucleotides attached to particles. Kogan et al. have shown that aggregated

proteins at the particle surface may be solubilized by elevation of the

temperature.104 Several observations open new perspectives. For example,

Stehr and colleagues have shown that AuNPs can be used to rapidly increase

the temperature and liberate a polynucleotide;105 to date, this approach has

not yet been used for tumour treatment, but it has been shown, for example,

that small hairpin RNA (shRNA) delivered near a tumour may control its

proliferation.106 On the other hand, it is well known that double stranded

polynucleotide is dissociated by increasing the temperature; indeed, this

technique is used for polynucleotide amplification by PCR. We can imagine that the combination of these two strategies (link disruption by heating

and shRNA effect) may allow the delivery and release of polynucleotide by

AuNPs for the treatment of tumours.



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Fig. 11.10. Clinical use of hyperthermia induced by AuNPs. (a) Polynucleotide delivering in a specific

place: aunps bearing both a targeting motif (for example a RGD sequence) and a double stranded

polynucleotide are injected. The particles, which accumulate in the region of interest, are illuminated

by a laser. The hyperthermia in this case is sufficient to liberate the polynucleotide but too low to kill

the cells. (b) Drug delivery: drugs in containers bearing AuNPs with targeting motifs at their surface.

Illumination of AuNPs induces hyperthermia leading to the rupture of the container and the liberation

of the drug. (c) Cell killing: AuNPs bearing targeting motifs are injected. Their accumulation around

the cells may be followed by endocytosis or not; in both cases, light illumination induces the production

of heat energy; the number of laser pulses is determined to increase the temperature to a lethal level.

Second, the photo-induced heating can be used to liberate molecules

from containers: the principle being to confine the molecule of interest

in a container which is itself fixed to the AuNPs; the resulting hyperthermia induces the rupture of the wall of the container, and release of

the molecules.107 It can be performed outside or inside the cell after

internalization:108 a low number of laser pulses allows local heating of

the particles and rupture of the container without any toxic effect on the

cell, and cell apoptosis can be avoided: the thermal energy generated in

these conditions is too low to have an impact on cell viability. The consequences of such a release range from specific inhibition of molecules or cell

functions to cell labelling.109



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11.5 AuNPs in the Future

The number of techniques based on the use of gold nanoparticles for diagnosis and tumour treatment is considerable and continues to increase. Of

course, in some cases, gold could be replaced by other materials, however,

contrary to many other metals, AuNPs are easy to manufacture, the particles

are stable and most of the analysis shows that they are non-toxic. Because of

its optical properties, gold remains the metal with the largest potential; there

are many techniques based on the analysis of plasmon resonance modifications upon interaction of the particles with proteins, peptides or with other

gold nanoparticles. For these experiments, modification of particle size,

shape or structure induce changes in the optimum wavelength for plasmon

resonance and allows the optimization of their use in relation to the operating conditions. Because of the large surface of the particles compared to

their volume, there is a high number of binding sites for molecules of interest

(cellular targeting, cell treatment) and for molecules inducing the particle

stealth. The future of these technologies may be the use of particles as a

platform for multipurpose: cellular targeting, specific delivery of molecules,

hyperthermia, imagery, etc. Moreover, the structure of the particle may

evolve to combine the advantages of various metals Si/Gd or Fe/Gd. The

toxicity of such circulating complexes remains an important issue and needs

complete and detailed analysis; it has been recently proposed to decrease

the potential toxicity of nanoparticles by incorporation of proteins or peptides at their surface which may control the activation of the complement

system,110 for example, which may be a solution to reduce potential inflammation processes resulting from the injection of these materials.

All of these results indicate clearly that the use of AuNPs benefits from

the optical and chemical characteristics which are specific to this metal, and

we can assume that for both diagnosis and treatment, new applications will

be developed to increase the sensitivity, the selectivity and the efficiency of

these tools.


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Chapter 12

What About Toxicity

and Ecotoxicity of Gold


Marie Carrière

Laboratoire Lésions des Acides Nucléiques, Commissariat à l’Energie

Atomique (CEA), Université Joseph Fourier UMR_E3, 17 rue des

Martyrs, 38054 Grenoble cedex 9 France.

Email: marie.carriere@cen.fr

12.1 Introduction

While production and use of nanoparticles in commercial products increase

exponentially, the perception of risk also becomes more acute, as these new

substances may generate new adverse effects, both on human health and

on the environment. As mentioned in Chapters 10 and 11, gold nanoparticles (AuNPs) are promising tools for diagnostic and therapeutic purposes.

Before launching any medical protocol using AuNPs, their innocuousness

has to be proven. Gold colloids have been used for years for therapeutic purposes and this safe use suggests that AuNPs should also be safe. However

the properties of materials at the nanoscale, i.e. in the 1–100 nm size range,

are so different from the properties of the bulk material, that it is reasonable

to revisit their toxicological and ecotoxicological impact. During the last

decade several research groups have published valuable data proving that

AuNPs exert moderate toxic effects on eukaryotic cells, on animal models and on several organisms representing different levels of ecosystems.

These toxic effects greatly depend on AuNP size and surface coating, the

coating itself often being more harmful than AuNPs per se. Note also that



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most of the data collected to date have been obtained after exposure of the

organisms to very high concentrations of AuNPs, which do not reflect a

real exposure of humans or a real release in the environment. The present

chapter will survey these data and try to assess the risks generated by AuNP

known to date.

12.2 Impact of Gold Nanoparticles on Human Health

12.2.1 The toxicological approach, applied

to nanoparticles

Risk is commonly recognized as the product of hazard (H) and exposure

(E). If there is no exposure, then even if the substance is hazardous there

will be no risk. If exposure occurs, but the substance is safe, then there will

also be no risk. Risk assessment and management are thus only possible

if research data concerning these two elements are available. Hazard is an

inherent property of the considered substance, while the extent of exposure

is dependent of multiple variables and scenarios. There is an increasing

literature related to NP hazard assessment, while the extent of data related

to exposure is very low. Consequently, even if many advances have been

made in the field of NP toxicology in the last two decades, it is today not

possible to precisely answer the question of risk related to NP exposure.

Evaluating exposure to NPs is a challenging task. Several exposure scenarios can be ruled out: exposure of workers at their working place, accidental exposure of populations, and intentional exposure of patients for

medical purpose. The intentional exposure of patients, for medical purpose,

will probably concern AuNPs since they are seen as future therapeutic and

diagnostic agents. In this scenario, exposure might be controlled, since the

applied dose is known. However, depending on the route of application

(intravenous injection, instillation, inhalation, skin deposition, etc.), AuNPs

will have to cross different physiological barriers which have very different properties. The effective dose, reaching the target organ, will thus not

strictly be the applied dose. For example, dermal penetration of NPs has

been extensively studied, and it is now recognized that TiO2 NPs do not cross

an undamaged skin (whether this assumption is also true for AuNPs has not

been reported to date). Conversely TiO2 NPs have been shown to reach the



November 15, 2012


9in x 6in

Gold Nanoparticles for Physics, Biology and Chemistry

What About Toxicity and Ecotoxicity of Gold Nanoparticles?

brain when instilled in an animal’s nose. Moreover, when directly injected

intravenously, NPs diffuse through the whole body and reach various target organs. Each organ receives a particular quantity of NP, which depends

both on the organ morphology and physiology, and on NP physico-chemical

characteristics. Various degrees of toxic effects would then appear on all the

reached organs. Depending on the required therapy, NPs then sometimes

have to cross the cellular membrane to reach their final intracellular target.

Several routes are available for NPs to reach the intracellular environment,

from simple diffusion through cell membrane to cell uptake through specific

transporters, if the NP is complexed to a specific ligand. Finally NPs might

reach the intracellular compartment by endocytosis, which includes several

modes: macropinocytosis; clathrin- or caveolae-mediated endocytosis; and

clathrin/caveolae-independent endocytosis (for review, see Khalil et al.1 ).

Exposure extent thus varies depending on the route of application and on

the physico-chemical characteristics of applied NP.

Today, the question of hazard of chemical substances is regarded

intensely, through various legislations such as the European regulation

REACH which deals with Registration, Evaluation, Authorization and

restriction of Chemical substances. This regulation, implemented on 1 June

2007, aims at identifying the intrinsic properties of chemical substances.

Practically, manufacturers and importers must register their chemical substances, in a volume-triggered system: all substances produced and imported

at more than one ton per year have to be registered. For substances produced

or imported at more than ten ton per year, manufacturers and importers are

also required to gather physicochemical, toxicological and ecotoxicological information, that they have to provide together with a chemical safety

report. All this information is centralized on a database, run by the European Chemical Agency. Substances of “very high concern” are considered

separately. They have to be registered even if their production or importation is lower than one ton per year. But sufficient toxicological data are

needed to classify a substance as of “very high concern”. Progressive substitution of the most dangerous substances is demanded, when substitutes

are available. This regulation, in its present format, is partially applicable to

NPs, since they are, per se, a chemical substance. In the present format of

the regulation, AuNPs, if produced by more than one ton per year, will be

registered and evaluated as a chemical substance and not as a nanoscaled



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