Gold nanoparticles are emerging as promising agents for cancer therapy and are being investigated as drug carriers, photothermal agents, contrast agents and radiosensitisers. This article introduces the field of nanotechnology with a focus on recent gold nanoparticle research which has led to early-phase clinical trials. In particular, the pre-clinical evidence for gold nanoparticles as sensitisers with ionising radiation in vitro and in vivo at kilovoltage and megavoltage energies is discussed.
Nanotechnologies can be defined as the design, characterisation, production and application of structures, devices and systems by controlling shape and size at a nanometre scale.
In medicine, most interest is in the use of nanoparticles to enhance drug delivery with interest also in in vitro diagnostics, novel biomaterial design, bioimaging, therapies and active implants. The most studied nanoparticles are carbon nanotubes, gold nanoparticles (GNPs) and cadmium selenide quantum dots.
Common oxidation states of gold include +1 (Au [I] or aurous compounds) and +3 (Au [III] or auric compounds). GNPs, however, exist in a non-oxidised state. GNPs are not new, in the 19th century, Michael Faraday published the first scientific paper on GNP synthesis, describing the production of colloidal gold by the reduction of aurochloric acid by phosphorous. In the late 20th century, techniques including transmission electron microscopy (TEM) and atomic force microscopy (AFM) enabled direct imaging of GNPs, and control of properties such as size and surface coating was refined.Common methods of GNP production include citrate reduction of Au [III] derivatives such as aurochloric acid (HAuCl4) in water to Au (0) and the Brust–Schiffrin method, which uses two-phase synthesis and stabilisation by thiols. In recent years there has been a phenomenal growth in GNP research, with a rapid increase in GNP publications in diverse fields including imaging, bioengineering and molecular biology.
GNPs show unique physicochemical properties including surface plasmon resonance and the ability to bind amine and thiol groups, allowing surface modification and use in biomedical applications.
There has been considerable debate about the mode of entry of GNPs into cells, with the most likely mechanism being non-specific receptor mediated endocytosis. In vivo, even in the absence of functionalisation, nanoparticles passively accumulate at tumour sites that have leaky, immature vasculature with wider openings than normal mature blood vessels. This is known as the enhanced permeability and retention (EPR) effect.
There is a super interest in modifying existing drugs to improve pharmacokinetics, thereby reducing non-specific side effects and enabling higher dose delivery to target tissues. An important demonstration of the potential of multifunctional GNPs for drug delivery was the use of 5-nm GNPs as a delivery vehicle, covalently bound to cetuximab, as an active targeting agent and gemcitabine as a therapeutic payload in pancreatic cancer. The epidermal growth factor receptor (EGFR) is overexpressed in up to 60% of pancreatic cancers and the combination of cetuximab and gemcitabine has been investigated in Phase II trials of this disease . Patra et al demonstrated that high intratumoural gold concentrations (4500 ?g g?1) could be achieved using this approach compared with 600 ?g g?1 with untargeted GNPs with minimal accumulation in the liver or kidney. The GNP–cetuximab–gemcitabine nanocomplex was superior to any of the agents alone or in combination in vitro and in vivo. Low doses of complex gemcitabine (2 mg
kg?1) led to >80% tumour growth inhibition in an orthotopic pancreatic cancer model compared with 30% inhibition using the non-conjugated agents in combination.
While GNP radiosensitisation has been observed in many studies, much work has been phenomenological and the mechanisms by which sensitisation occurs remain unclear. Most researchers have attributed GNP radiosensitisation to increased photoelectric photon absorption by high-Z materials at kilovoltage photon energies. However, if sensitisation occurs by this physical mechanism, effects would not be predicted to occur at clinically relevant megavoltage energies where Compton interactions are dominant. For clinical translation and optimisation of effect, it would be beneficial to know the importance of GNP size, concentration, surface coating and distance from target material such as DNA on GNP-mediated radiosensitisation. Knowledge of the range and type of secondary energies released from the nanoparticle, such as short-range low-energy electrons, Auger electrons, photoelectrons or characteristic X-rays, and in turn how they vary with primary photon energies would also enable the development of more rationally designed GNPs for use with radiation. Some of the studies attempting to address these complex issues are discussed below. The concept of high-Z radiation dose enhancement has been known for many years. This is a physical concept which makes use of the much greater photoelectric photon absorption in high-Z materials compared with soft tissue, particularly at kilovoltage photon energies, as demonstrated in Figure 4. Increased radiation side effects have been observed at the interface with high-Z materials owing to greater absorption of photons and deposition of energy in surrounding tissue from photoelectrons, Auger electrons and characteristic X-rays. In therapeutic terms, if a high-Z material is present at higher concentrations in the tumour than in normal tissue, an improvement in the therapeutic index should be realised. Much work has been carried out with iodine (Z=53), a commonly used contrast agent; Matsudaira et al demonstrated increased cell killing in an in vitro cell model with iodine added to growth medium. Santos Mello achieved an intratumoural concentration of 5 mg ml–1 iodine and demonstrated reduced tumour growth delay in a rabbit model. These results led to a Phase I feasibility trial in which 8 patients received 3–5 weekly 5-Gy boosts with 140-kVp X-rays to intracranial metastases while undergoing whole brain radiotherapy with 40 Gy in 20 fractions over 4 weeks with 6-MV photons. IV iodine contrast medium was administered prior to radiation and 140-kVp X-rays were delivered in 360o rotations in three planes to minimise skull dose. Brain metastases were measured on weekly CTs prior to and during treatment. Of eight patients treated, there was one complete response and four partial responses to therapy with no increase in early or late radiation side effects.
Hope for treatment of Cervical Cancer:
Researchers from Ferdowsi University of Mashhad in association with their colleagues from Mashhad University of Medical Sciences used gold nanoparticles as perfect carrier to deliver the hydrophobic protoporphyrin molecule to cancerous cells ("Protoporphyrin IX–gold nanoparticle conjugates as an efficient photosensitizer in cervical cancer therapy").
In this research, results showed that the coupled nanoparticles can be considered effective candidate in the treatment of cancer in general, and as a sample in the treatment of cervical cancer.
Gold nanoparticles were designed and synthesized in the present study, and their application was studied in the treatment of cancer. The aim of the study was to investigate the effect of photodynamic therapy in the presence of gold nanoparticles coupled with protoporiphyin on the life of cervical cancer cells.
Results of the research showed that the synthesized coupled gold nanoparticles can be used as a very effective carrier to take photosensitizer into the cells to treat cervical cancer cells. In addition, results obtained from verification test showed that the synthesized coupled nanoparticles are a very effective parameter in photodynamic treatment of cervical cancer cells.
Morphologic images of the cells depict that cellular death has happened in a large number of the cancerous cells. The cores of the majority of the cells were divided into some individual colorful parts. Moreover, the thickness of the color in the core was stronger than the color in the living cells, which proved that apoptosis has happened.
Gold nanoparticles coupled with porphyrin photosensitizers can be widely used in medical industry in the treatment of diseases due to their curing specifications and importance.