Elements which have a high atomic number, in the form of "nanoparticles have been shown as potential radiation dose enhancing agents for the treatment of cancer." (Hainfeld et al., 2004) If such elements could be preferentially delivered to tumour sites, then the dose and the damage to healthy tissues could be reduced whilst enhancing the destructive effects of radiation on cancer cells.
This approach, which primarily depends on the nanoparticle concentration in cancerous regions and the firm interaction with the active cancer killing agents, has the potential to contribute to limiting some of the current and frequent challenges encountered by current cancer therapies. The challenges "include non-specific systemic distribution of anti-tumour agents and radiation, inadequate drug or radiation concentrations reaching the tumour site, intolerable cytotoxicity, limited ability to monitor therapeutic responses and development of multiple drug resistance." (Das,. et al. 2009) This obviously has extremely exciting ramifications for the future of radiotherapy as well as other forms of cancer therapy.
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Currently there is ongoing Intensive research into Gold nanoparticles, (AuNPs) to enhance the effectiveness of radiotherapy. Gold is seen as a prime candidate as a nanoparticle constituent as it has a high atomic number (Z = 79), is effective in it's to absorption of radiation (notably x-rays), it is easily available and utilised because of its ease of conjugation and compatibility with bio-molecules, it is inert and it is also believed to be non-toxic to the human body. Also, the "AuNPs themselves have anti-angiogenic properties." (Mukherjee et al,. 2005)
However, "despite the great excitement about the potential uses of AuNPs 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" (Murphy et al., 2008) as "the effects at the nanoparticle level cannot be automatically extrapolated from their bulk counterparts." (Soto et al 2007, Chithrani et al 2006) Yu Pan states that there is much "conflicting data regarding the cytotoxicity of gold nanoparticles" (Yu Pan., 2007) In fact, "there are extensive reports showing that Au nanoparticles have very high chemical activity due to their small sizes and surface defects." (Wang and Ro 2006, Chiang et al 2007). Therefore we need to ask the fundamental question of whether there is any toxicological impact of AuNPs on living cells.
It has been documented that many studies on AuNPs cytotoxicity are inconsistent so far, and at the current time it is not possible to give a generalised statement about the toxicity of AuNPs. "Systematic studies are under way, but they require a huge research effort owing to the large number of different control parameters playing a critical role in the complex interplay between nanoparticles and cells." (Murphy et al. 2008). The "size and the shape of the particles as well as the nature of the ligand shell, the binding strength of the ligand to the gold surface and the functionalities in the outer sphere seem to play a critical role in the cellular uptake and in possible intracellular modifications and thus on cytotoxicity." (Jahnen-Dechent & Simon 2008). However, once these questions related to toxicity are answered, the path to utilising AuNPs in increasing the efficacy of radiotherapy (AuNPs selectively interacting with cancerous cellular subunits) along with many other exciting applications in biomedicine will become clearer.
"Commonly, particles greater than 10nm are referred to as 'non-toxic', mostly independent of the specific ligand molecules." (Homburger & Simon., 2009) However, it has been reported that cetyltrimethylammonium bromide (CTAB)-stabilized gold nanorods (around 65 Ã- 11 nm) are toxic to HeLa cells." (Niidome et al. 2006) "Nevertheless, the toxic effect within these particles probably refers more to the toxicity of the stabilizing ligand itself, as the gold nanorods are stabilized by a non-covalently adsorbed bi-layer of CTAB, which may be desorbed upon entering the cells." (Connor et al. 2005). This fact indicates that the toxic properties of the AUNP rely on the binding strength of the ligand to the Au surface as well as the toxicity of the nanoparticle itself. This fact also has to be considered when looking for possible adverse effects in the application of AuNPs in biomedicine.
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In previous studies smaller AuNPs of sizes below 2nm have showed surprisingly high cytotoxicities in different cell lines. For example, "systematic investigations of water-soluble AuNPs in the size range of 0.8-15nm in four major functional cell types with barrier and phagocyte function revealed that the small gold particles of size 1.4nm show high toxicity comparable to that of the cytostatic drug cisplatinum." (Pan et al. 2007). "In the same set of measurements, the gold particles of 15nm and Tauredon (gold thiomalate) were shown to be non-toxic at up to 60-fold and 100-fold higher concentrations, respectively." (Homburger & Simon., 2009) Furthermore, these investigations revealed that AuNPs of size 1.4nm caused rapid cell death by necrosis within a twelve hour period and AuNPs of size 1.2nm caused primarily programmed cell death by apoptosis.
In further studies by Homburger & Simon in 2009, who focused on the major cell death pathways, it was found that the "cytotoxicity of 1.4nm AuNPs was accompanied by oxidative stress, which causes mitochondrial permeability transition and triggers cell death by necrosis," (Homburger & Simon in 2009) and "that this effect critically depends on the ligand chemistry." (Pan et al. 2009) Oxidative stress can be defined as the "pathogenic outcome of the over production of reative oxygen species (ROS) that overwhelms the cellular antioxidant capacity. ROS are normally cleared from the cell by the action of superoxide dismutase (SOD), catalase, or glutathione (GSH) peroxidise" (Hellawell and Gutteridge 1999), but "over production damages cells by the alteration of macromolecules such as polyunsaturated fatty acids in membrane lipids, protein denaturation, and ultimately DNA." (Garza et al., 2008) Researchers are currently questioning whether the induced oxidative stress effect results from ROS deriving directly from AuNPs or whether ROS production occurred secondary to AuNP cell inclusion and interaction with intracellular target molecules.
To answer this question Homburger & Simon ran a series of tests on HeLa cells applying anti-oxidising compounds, either in a treatment before addition of the toxic triphenylphosphinemonosulphonate (TPPMS)-stabilized 1.4nm AuNPs or by treating the cells with a combination of both AuNPs and anti-oxidising species. Their results suggested, along with other conclusions, that the creation of ROS directly evolving from the original reactivity of the AuNP causes the observed cell toxicities.
Interactions between Au clusters and intracellularly present biological species such as DNA have also been studied. "The treatment of natural B-DNA with Au55 clusters resulted in cluster 'decorated' DNA fragments" (Liu et al. 2003) which were visible by Atomic Force Microscopy (AFM). It is understood that this 'decoration' is due to NPs binding firmly to major troughs of DNA as the size of the major troughs fit well with the NP's size, and the surface charge of the NP's result in strong electrostatic interactions with the negatively charged phosphates of the DNA and the particle's surface. This means that a percentage of the AuNPs taken up by the cells will be finally bound to DNA and inhibit the DNA transcription and replication processes which may have severe detrimental effects to the cell. Finally, NPs can stimulate the clustering of low affinity ligands on nanoparticle scaffolds and therefore enhance biological signalling (Jiang et al. 2008) which may also negatively effect the cell.
In conclusion, the applications of AuNPs have extremely exciting ramifications in the field of radiotherapy and similar treatments where they may offer the chance to deliver a concentrated dose to the cancerous tissue whilst limiting the dose exposed to healthy tissues and therefore minimising the often severe side affects associated with such procedures. However these benefits of the application of AuNPs maybe clouded by the fact that many studies on AuNPs cytotoxicity are inconsistent. Therefore more studies on the effects of cellular AuNPs internalisation are both warranted and necessary, especially on the molecular level changes of the cells to monitor the biocompatibility and potential cytotoxicity of AuNPs. However, it will be extremely difficult to establish a generalised statement about the cytotoxicity because of the large range of parameters that have to be considered when thinking of an in-vivo application of AuNPs such as size, shape, ligand binding strength and the interaction with intracellular components which may all affect AuNP cytotoxicity. So, once these parameters are fully understood and are controllable, then the full potential of the use of AuNPs in radiotherapy and other treatments can be realised.
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