Feature Article

By: David Williams

Gold is a noble metal, often described as a precious metal. It lends its name to a number of phrases that imply stability, for example, the “Gold Standard.” When other things in life seem unstable such as stock markets, many people turn to gold as the best guarantee of safety. But how stable and inert is it? Can it be displaced as the premier option? After all, the real Gold Standard, which was a commitment by participating countries worldwide to fix the prices of their domestic currencies in terms of a specified amount of gold, foundered at times of war in the twentieth century and was eventually abandoned in the 1970s when a better system of establishing exchange rates was established. Similarly, “gold standard” diagnostic and therapeutic techniques, which for many years are considered as the standard of care, will change as new and better methods are developed.

 

Gold has never been a strong candidate as a biomaterial. Its expense eliminates its use for most applications. Its high density does not help either, although that is an advantage when it is used for implantation in the upper eyelid to assist in its closure in conditions such as lagaphthalmos, which result from facial palsy. As a pure metal, gold is also weak and soft, but special alloying techniques involving copper can produce good mechanical properties, which is the reason why it is an excellent aesthetic casting alloy for visible dental restorations.

 

Yet, gold has always been an enigma from a medical point of view. We know that the metal is highly inert, but some of its salts can be effective drugs. This is particularly the case in the treatment of rheumatoid arthritis, where oral and injectable forms such as auranofin can be used to decrease the inflammation of the lining of articular joints. Interestingly, the precise mode of action of these drugs is still unknown, even though they have been approved for use by the United States Food and Drug Administration since the mid 1980s. Because of this uncertainty about mechanisms, they form part of a group of agents that are known as Disease Modifying Anti-Rheumatic Drugs. More recently, some gold compounds have attracted interest as anti-cancer agents. Of course, this is not the only situation where a noble metal finds therapeutic use as a drug. Platinum, used as a biomaterial for electrodes in view of its electrical conductivity and inertness, is a highly potent chemotherapeutic agent in the form of cisplatin or cis-diamminedichloridoplatinum(II). However, ruthenium based drugs are also used, usually with fewer side effects than platinum. Silver has an extensive history as an antimicrobial agent and is used in many medical devices and pharmaceutical preparations, although the balance between achieving the required effects on bacteria without incurring adverse effects on the patient is still a matter of debate.

 

There is now a major increase in interest in these noble metals and their compounds for medicine and biotechnology. The new possibilities are based on the same types of mechanisms by which these metals have interacted with the body in established therapies, but there is a greater degree of understanding. The real issue is that gold, like silver and the others, has a considerable attraction for certain proteins. As with many cases where potentially therapeutic or potentially toxic substances interact with the body through specific protein interactions, a great deal depends on precisely how that interaction takes place. An antibacterial effect may be achieved through direct interaction with, and disablement of, a specific structural protein of the bacterial membrane. An anticancer effect may be achieved through direct interaction and interference with a protein that enables cancer cells to multiply. An inadvertent cytotoxic effect may be seen when metal ions interact with, and inhibit, certain crucial intracellular enzymes on which those cells depend for their metabolism. Gold is particularly attracted to thiol groups, that is, groups in organic molecules that contain sulphur, and has a special affinity for the sulphur containing groups of proteins and peptides, for example, the free thiol group on the cysteine-34 section of human serum albumin.

 

Once the specificity of gold–protein interactions becomes clarified it opens up possible routes to the therapeutic or diagnostic use of those reactions. Of crucial importance here has been the development of the technology of gold nanoparticles and the exploitation of this technology in several parallel directions. The first of these directions involves the potential use of gold nanoparticles in some areas of drug therapy, especially, although not limited to chemotherapy. In particular it has been shown that gold nanoparticles of approximately 5 nm can bind specifically to certain growth factors such as vascular endothelial growth factor (VEGF), produced by reaction with the cysteine residues on the heparin binding domain of VEGF. This has the effect of inhibiting angiogenesis, which is the process of neo-vascularisation that tumours depend on for their growth. It is, of course, necessary to target these gold nanoparticles precisely to the site of the tumour. The chemical structure of gold allows the surface to be functionalised by certain molecules, including monoclonal antibodies to the HER2 receptor in certain breast cancer cells, which offer powerful options for the treatment of these cancers. In addition, it appears that gold nanoparticles of a certain size range are highly interactive with DNA and when targeted to, and internalised within cancer cells, they have a high degree of toxicity.

 

The second direction this nanotechnology pathway takes us involves the quantum physics of the nanoscale. We should remember that there are two important aspects of nanoscience that make the nanoscale so attractive: one is the high surface area to volume ratio seen with nanoparticles, which allows us to take advantage of chemical functionality; the second is that quantum effects may be seen when the entities are 10 nm or less. Gold nanoparticles scatter light intensely; they are much brighter than normal chemical fluorophores and retain this property under many conditions. Moreover, this light scattering can be tuned by controlling the shape and size of the nanoparticles, which makes them attractive for a variety of imaging and diagnostic techniques. In addition, gold is amenable to the preparation of core-shell nanoparticles, where the inner core is made of a different material to the outer shell, which allows for multifunctionality. For example, the core can be a 50-nm diameter mass of a dielectric material such as silica, with an outer 5-nm layer of the conducting material gold, which allows for functionality in different imaging modes. These structures offer considerable promise in photodynamic therapy where intra-tumoral injection can result in rapid, powerful local toxicity on excitement with near-infrared radiation.

 

These examples, and there are several others, show just how the world of biomaterials is changing. From inert pieces of gold, platinum and silver, we now have collections of chemically, biologically and physically interactive nanoparticles that offer powerful new modes of therapy and diagnosis. I am writing this column whilst in South Africa, whose past has obviously been heavily dependent on gold. It will be interesting to see where this new gold rush and the new therapeutic gold standards lead us. 

Morgan & Masterson, Avenue de la Forêt 103, Brussels 1000, Belgium, tel. +32 4 7597 0556, e-mail: peggy@morgan-masterson.com,

Professor David Williams DSc, FREng