Intrinsic Therapeutic Applications of Noble Metal Nanoparticles: Past, Present and Future
Overview
Biomedical nanotechnology is an evolving field having enormous potential to positively impact the health care system. Important biomedical applications of nanotechnology that may have potential clinical applications include targeted drug delivery, detection/diagnosis and imaging. Basic understanding of how nanomaterials, the building blocks of nanotechnology, interact with the cells and their biological consequences are beginning to evolve. Noble metal nanoparticles such as gold, silver and platinum are particularly interesting due to their size and shape dependent unique optoelectronic properties. These noble metal nanoparticles, particularly of gold, have elicited lots of interest for important biomedical applications because of their ease of synthesis, characterization and surface functionalization. Furthermore, recent investigations are demonstrating another promising applications of these nanomaterials as self-therapeutics. To realize the potential promise of these unique inorganic nanomaterials for future clinical translation, it is of utmost importance to understand few critical parameters; (i) how these nanomaterials interact with the cells at the molecular level; (ii) how their biodistribution and pharmacokinetics influenced by their surface and routes of administration; (iii) mechanism of their detoxification and clearance and (iv) finally their therapeutic efficacy in appropriate disease model. Thus in this review, we will discuss the various clinical applications of gold, silver and platinum nanoparticles with relevance to above parameters. We will also mention various routes of synthesis of these noble metal nanoparticles. However, before we discuss present research, we will also look into the past. We need to understand the discoveries made before us in order to further our knowledge and technological development.
I. Historical Perspective
Precious metals have a long and rich history of use harkening back to the Egyptian First Dynasty. Gold in particular was a much sought after metal and mined as early as 2900 BCE in the deserts of Ethiopia and Nubia1. In Egypt, mineralogists soon learned to purify this metal. Since then, there has been evidence of objects made from gold from the Early Dynastic period of Ur (2500 BCE) to Babylonia. Beni Hassan, a tomb dating in the same era, has representative inscriptions of the extraction process from quartz matrix and gold ores in addition to the weighing and melting processes2. 2000 years later, Darius, the king of Persia (558-486 BCE), was reported to have received unrefined gold and gold dust as gifts from the Ethiopians3. The early fascination with metals is further illustrated by the keen interest of early alchemy philosophers who believed in the spiritual connection between the seven metals: gold, silver, mercury, lead, tin and iron, with the seven heavenly bodies: the Sun, the Moon, Venus, Jupiter, Mercury, Saturn and Mars2. It was believed that Earth housed the seeds of metals and was under the influence of the heavenly bodies (Fig. 1).
For alchemists, gold was greatly treasured as evidenced by the common quest for the philosopher’s stone (lapis philosophorum), an agent that would make possible transmutation of base metals into gold4, 5. Furthermore, gold was considered to be indestructible and have immense medicinal value; hence early alchemists set out to produce potable gold, “the elixir of life”5. In 8th century CE, an alchemist in Arabia, Jabir ibn Hayyan, also known as “Geber” in Europe, succeeded in dissolving gold in aqua regia, a mixture of nitric and hydrochloric acid1. By the 7th century, gold chloride had become commonplace and in the early Renaissance, gold was recommended to purify blood and thought to have numerous medical virtues2. The first use of gold in modern medicine was in 1890 after the German bacteriologist Robert Koch discovered that low concentrations of potassium gold cyanide, K[Au(CN)2] had antibacterial properties against the tubercle bacillus6. In the 1920s gold therapy for tuberculosis was introduced6 and in 1935 Jacque Forestier reported the use of gold to treat rheumatoid arthritis7. Gold thiolates are still in use today to treat the disease. In the United States, gold sodium thiomalate and gold thioglucose are sold as Myochrysine and Solgonal respectively8. Auranofin (triethylphosphine(2,3,4,6-tetra-O-acetyl-β-1-D-thiopyranosato-S)gold(I) are some of the newer compounds in use as antiarthritic drugs (Fig 2. a–c). Other gold complexes have been implicated in treatment of cancer and malaria (Fig. 2d and e).
Structures of Gold complexes with antiarthritic, antitumor, and antimalarial activity. (a, b) antiarthritic drugs; (c) gold (III) antitumor agents; (d) antimalarial complex of chloroquine.
Silver has been valued throughout history as a precious metal and in ancient times it was considered to be more valuable than gold. Believing it to be feminine in nature with its white luster, silver was considered a symbol of purity. Evidence of the use of silver to make ornaments and decorations exists from as far back as 4000 BC9. Silver was oft referred to as white gold and was known to the Greeks and inhabitants of the region between the Indus and the Nile. A gold silver alloy was used to make coins by 800 BC2. Alchemists associated silver with the moon (oft referenced the element as luna), and hence used it to cure ailments related to the brain (hence the term lunatic). In Arabia, it was used to treat “falling-sickness” and vertigo2. Hippocrates proclaimed that silver contained medicinal properties and could cure multiple maladies10. Since silver was touted to have antiseptic properties, Phoenicians used silver vials for food storage to help prevent spoilage. Prior to the widespread use of antibiotics, silver compounds were used to help prevent infection during World War I11. In 1881, a physician named Crede used silver compounds to help prevent gonorrhea from being transmitted from the mother to new born babies12. Lunar caustic, silver nitrate amalgamated into sticks, was also used in antiquity to cauterize wounds. Silver nitrate also has a close relationship with photography. For silver, the history of the art form begins in 1727 when John Herman Schulze, a German professor first observed that silver salts turned black when exposed to light13. Silver salts were further investigated and even hundreds of years later continued to be the critical component of photographic film.
Another noble metal, platinum was discovered on the alluvial sands of the Pinto River in Columbia14. The first reported use was by Egyptians and South Americans ca. 2000 years ago14. Archeologists uncovered an ancient Egyptian box from ~720 B.C that contains hieroglyphic characters decorated with platinum bands 15. The Europeans did not know of platinum until the 16th century when the Spaniards came across the element following conquest of the lands of South America. When mining for gold in Columbia, they found lumps of platinum which they called platina del Pinto meaning “little silver of the Pinto river”14. Some of the samples were brought back to Europe in 1557 and studied by Italian-French scientist Julius Caesar Scaliger who concluded that the metal was not silver and in fact a new element, Platinum. Thus Julius Caesar Scaliger is widely reported to have discovered the metal. In 1735, a Spanish scientist Antonio de Ulloa rediscovered platinum in South America and in 1783 French chemist Francois Chabaneau successfully purified it thus initiating the use of the metal for decorative purposes. A famous object made from platinum in antiquity is a chalice made in 1788 for Pope Pius VI. The popularity of the metal rose in the following years and by the 19th century platinum was in high demand for use in jewelry and industrial purpose.
In 1965, Rosenberg et al. discovered that electrolysis using platinum electrodes inhibited division of Escherichia coli16. The group subsequently reported that platinum salts, [PtCl6]−2, generated via electrolysis, were responsible for the anti-proliferative action on the bacteria17. Thus began the resurgence of investigations with cisplatin, which had remained obscure since its first synthesis in 1845 by Michel Peyrone18. In 1893, Alfred Werner had already elucidated the structure of cisplatin but it wasn’t until Rosenberg that the antitumor activity of cisplatin was studied and so began the reign of the “Penicillin of cancer”. After successful studies in mice, the compound entered clinical trials in 1971. In 1977 cisplatin was licensed exclusively to Bristol-Myers Squibb and by 1978 it was approved for use in the US by the Food and Drug Administration18.
In contrast to metals, metallic nanoparticles (NPs) and their use may be considered a product of modern science since the potential of nanotechnology was only realized in recent years. Yet the synthesis and use of nanoparticles (NPs) dates back to ancient times. The first evidence of metallic nanoparticles is from 2000 years ago when gold NPs were a part of ancient ayurvedic medicine in India 19. 56 nm sized colloidal gold NPs, also called the swarna bhasmaI (gold ash) was mixed with honey or cow ghee and given orally to patients to treat a wide range of diseases including rheumatoid arthritis, bronchial asthma, diabetes mellitus and other diseases of the nervous system19, 20. The aesthetic property of gold NPs was later realized and exploited by the Romans. They used gold NPs to color glass; an exemplary case in point is the Lycurgus cup (Fig. 3). The colored glass and bronze cup is dated to the 4th century Roman Empire and shows a “dichroic” effect i.e the cup appears pea green in reflected light but in transmitted light it appears to be a deep wine red color19, 21. Studies conducted by the British Museum, which houses this work of art, report that the cup composite is an alloy of 70nm NPs containing 70% silver and 30% gold21. Although one can only speculate as to whether the use of NPs was purely accidental, artisans in other cultures have shown deliberate exploitation of the unique optical effect of NPs to create colorful church windows. Silver NPs were used to stain glass a yellow color22 while gold NPs were used to produce a ruby red hue. In 9thcentury Mesopotamia, silver and copper NPs were used to give pottery gold like iridescent, metallic luster23. The Muslim culture forbids the use of gold in artistic representation and so the artisans devised a method to employ other metallic NPs to produce a gold like result. Copper and silver salts and oxides were mixed with vinegar, clay, and ochre and then applied to glazed pottery. When “cooked” at high temperatures and a reducing environment, the metals ions would reduce and migrate to the outer layer of the glaze forming a NP coat, thus producing a brilliant gold-like end product.
The Lycurgus Cup 1958,1202.1 in reflected (a) and transmitted (b) light. Scene showing Lycurgus being enmeshed by Ambrosia, now transformed into a vine-shoot. Department of Prehistory and Europe, The British Museum. Height: 16.5 cm (with modern metal ...
But perhaps the first scientific study of metallic NPs in colloidal systems and the first observation of the unique optical properties of gold NPs was by English physicist and chemist Michael Faraday in 185724. Faraday was the first to study and report the size dependent optical properties of gold and silver colloids. Although it would be almost a century later when the field of nanotechnology would take off, Faraday’s observation that particles on the nanoscale behaved differently from its bulk was critical and fundamental discovery. In 1908 Gustav Mie studied the mathematic correlation of NP size and its optical manifestations25. In 1959, it was physicist Richard P. Feynman who, almost a century after Faraday, memorably championed the arrival of nanotechnology26. In that momentous lecture to the American Physical Society at Caltech, he said, “There’s plenty of room at the bottom—an invitation to enter a new field of physics” hinting at the potential for nanoscale design to influence a wide range of fields such as optics and electronics.
The use of metal NPs has expanded in recent years following significant developments in the synthesis process. Metals like platinum and silver have long been used as industrial catalysts. German chemist Johann Wolfgang Dobereiner, who is also known as the founder of the study of catalysis, was the first to discover the catalytic capability of finely divided platinum27. In 1820, Edmund Davy an English chemist had shown that chemically reduced platinum black could promote alcohol oxidation. Dobereiner repeated this experiment a year later and made the critical observation that at the end of the conversion of alcohol to acetic acid, platinum was unaltered and available to participate in another reaction. He later went on to develop the Dobereiner lamp, which is now appreciated as the first example to use a supported catalyst, which involves a jet of hydrogen from zinc and sulphuric acid that is spontaneously ignited in the presence of platinum27. The nanoscale size of particles was later known to enhance catalytic activity of a metal; thus metals in NP form have been keenly studied as a way to cut down costs and improve catalytic efficiency. It is interesting that gold was historically considered to be catalytically inactive. But in 1985, Graham Hutchings from the University of Cardiff, UK reported that the gold ions could catalyze the hydrochlorination reaction. Similarly, Masatake Haruta, from Tokyo Metropolitan University in Japan, later observed that in NP form gold could catalyze oxidation of carbon monoxide even at low temperatures of -76°C19. In recent years there has also been increasing interest in the use of silver NPs as antimicrobial agents. As mentioned earlier, this remarkable property of the metal was known since antiquity to Greeks who used the metal in their cooking and used it to for safe storage of water28. Modern application of nanoparticles extends even as far as restoring centuries old works of art29. Thus NPs has been involved in our life since time immemorial.
