Modern Day Alchemy: Turning Silver to Gold

The Xia lab group members at Washington University in St. Louis are modern day alchemists, daily converting very small cubes of silver into hollow, porous boxes of gold, termed gold nanocages. Beyond conquering the age-old quest to turn base metals into precious gold, these scientists are going a step further, using gold nanocages as ‘magic bullets’ in the war against cancer.
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The Alchemy: Converting Silver Nanocubes to Gold Nanocages

Gold nanocages can be synthesized via a process known as galvanic replacement (Lu 2008), in which the difference of electrochemical potential between two different metals in solution is exploited to replace one solid metal surface with another, for example replacing silver (Ag) with gold (Au). The reaction proceeds as follows:

As a solution of dissolved gold salt is added drop-by-drop to a heated solution (90°C) of pre-made silver nanocubes (blue structure in the model below), the gold is stabilized as a solid crystal layer on the surface of the silver nanostructure, while at the same time silver is destabilized and dissolves into solution as silver chloride. Here we witness real-life alchemy, but without any magic wands, mysterious chants or smoke – the creation of hollow gold nanocages through the plating of solution-phase gold onto a sacrificial silver template. As the galvanic replacement reaction proceeds, silver gradually leaches out from the nascent gold-silver alloy nanocage, preferentially leaking out through unstable truncated corners of the cubic structure (see model below, teal structure). Subsequent steps of the galvanic replacement reaction involve a hollowing and dealloying of the once pure silver cube. Silver dissolves from inside the nanocages, leaving behind an intact and hollow gold ‘cage’, with holes at the truncated corners from whence the silver escaped from the inside (green structure in model below). The dealloying process gradually removes more silver from the gold-silver nanocage walls (gold structure in model below), which along with the hollowing process causes the color (i.e. wavelength) most strongly absorbed by the nanocage to shift from blue-green to yellow-red. This shifting of peak absorption to the red, or near-infrared, region of the color spectrum has a large impact on the application of gold nanocages as cancer-targeted imaging probes.

Imaging Cancer with Modern-Day Alchemy

Image from Xia et al 2011, Gold Nanocages: From Synthesis to Theranostic Applications

Xia’s gold nanocages have been investigated in previously published studies for their usefulness as imaging contrast agents, cancer diagnosis tools, transducers of photothermal therapy (killing tumor cells with the effects of light and heat), and targeted drug delivery vehicles, as which they can shuttle drugs trapped inside their hollow interiors to specific regions of disease in the human body, preventing harm to normal tissues. Nearly all of these applications rely on the special optical properties of very small, i.e. nanoscale, gold structures. These special optical properties, which affect the way the gold nanostructures absorb and scatter light at characteristic wavelengths (light wavelength is linked to its color), originate in a small-particle-phenomenon known as Localized Surface Plasmon Resonance (LSPR). At very small sizes, diameters less than 1000x smaller than the width of a single human hair, silver and gold metallic nanostructures begin to act as tiny harmonic oscillators, similar to a stretched spring or a vibrating violin string. However, unlike a stretched spring, which oscillates due to the physical structure of the spring and its resistance against a displacement force, surface plasmons_, which are oscillations of the free electron cloud around the ion core of the metal nanostructure, take place at the sub-atomic level. Electrons are displaced from their nuclei, the nuclei composing the ionic lattice of the gold nanocrystal, by an external electromagnetic wave, i.e. light. Because opposite charge attractions between the negative electrons and the heavier positive ions of the metal lattice pull back against the electrons, the electron cloud is forced to bounce back and forth like the free end of a fixed spring. animation.gif" width=“120” height=“50” class=“mt-image-right” style=“float: right; margin: 0 0 20px 20px;” /> This collective oscillation of electrons at the surface of the nanostructure is what gives gold nanocages their unique optical and electronic properties.

More information on Localized Surface Plasmon Resonance – link to article Big Physics for small Science Gold Nanocages and the Power of ‘Seeing’

Metallic nanostructures such as gold nanocages that display this LSPR effect will absorb and scatter light very strongly at a particular wavelength of light (the resonant wavelength) determined by the size, the shape, and the surface chemistry of the nanostructure. Thus, different sizes and shapes, for example spheres vs. cubes, of gold nanostructures will appear different colors in solution. The Xia lab’s gold nanocages, which are cubic and hollow, give off a deep blue color when suspended in a test-tube, due to the fact that the structures absorb light in the red to near-infrared (NIR) region, leaving mostly blue colors to be transmitted through the solution and seen by our eyes. Strong absorption of light in the NIR is exactly the characteristic of gold nanocages that suits these tiny entities so well for cancer imaging, diagnosis, and therapy applications. The near-infrared region of light, ranging from 700-900nm, is also the region of biological transparency. In other words, light in this region is not strongly absorbed by tissues and blood components (i.e. hemoglobin and water) of the human body, allowing NIR light to penetrate further into a tissue than lower wavelength blue or green light. For example, ultraviolet light (<400nm) can barely penetrate the innermost layer of our skin. The development of near-infrared imaging probes, such as the Xia group’s gold nanocages, is important if we want to ‘see’ and correctly diagnose a tumorous mass deep inside the body, for example a tumor in the liver or a small mass deeply embedded in breast tissue. Deep penetration imaging capability prevents having to perform surgery to get our medical imaging cameras close enough to the tumor site to get a clear picture of the disease.

Turning up the Heat on Cancer

The strong light absorption properties of gold nanocages at near-infrared wavelengths are instrumental in cancer therapies that employ heat to cause irreversible damage to targeted cancer cells and tumorous tissues. When a photon (the basic unit and elementary particle of electromagnetic energy, i.e. light) from an external source such as a near-infrared laser hits and is absorbed by the gold nanocage surface, the resultant energy of an excited gold electron must be dissipated by either a radiative (conversion back to light) or a non-radiative (conversion to vibrations and heat) process. In other words, the excited electron donates its energy to either another electron, a phonon, or to the emission of a secondary photon. The phonon is described as a quantum, i.e. basic unit, of vibrational energy within the gold crystal lattice. The electron-phonon process, which produces heat as a result of light energy conversion to atomic vibrations, is the basis of photothermal therapy as a cancer treatment. As energy is passed from the original near-infrared photon, to excited gold electron, to phonon in the gold nanocage lattice, local temperatures in and surrounding the nanocage can rise above threshold (42°C) for hyperthermia and cell death (Cobley 2010). When gold nanocages are targeted to cancer cells through targeting probes attached to the their surfaces, light irradiation directed to the tumor site can cause irreversible harm to tumor cells that contain relatively high concentrations of the gold nanocages as compared with healthy cells. Photothermal therapy with gold nanocages can be used as a cancer therapy with minimal adverse effects to healthy cells and normal tissues.

A particular advantage of gold nanocages over other types of gold nanostructures for photothermal therapy is the nanocages’ property of light absorption at near-IR wavelengths. The combination of deep tissue penetration of near-IR light, and the efficient heating of gold nanocages at red-shifted wavelengths, means that photothermal therapy with gold nanocages can be used in the treatment of deep-seated tumors in vivo. The Xia group has recently been in collaboration with experts in nuclear imaging (Chen 2010) to evaluate tumor metabolic activity before and after photothermal treatment with gold nanocages injected into the tail veins of tumor-bearing mice. Diode laser irradiation (output wavelength of ~800nm, within the window of biological transparency) of gold nanocage-treated mice effectively reduced tumor metabolic activity, as measured by a radioactive glucose analog, to near background levels. The Xia group’s gold nanocages are not only a feat in modern-day alchemy, but also promising ammunition in the battle against cancer. Left is to improve the targeting efficiency and therapeutic value of these ‘golden bullets’ through enhanced heating characteristics and/or addition of drug payloads to the inside of the hollow nanocages, while continuing to verify non-toxicity to healthy tissues at therapeutically significant concentrations.

References:

1. Lu et al. (2008) Galvanic replacement reaction: a simple and powerful route to hollow and porous metal nanostructures. Proc. IMechE Vol. 221 Part N: J. Nanoengineering and Nanosystems
2. Cobley et al. (2010) Targeting gold nanocages to cancer cells for photothermal destruction and drug delivery. Expert Opin. Drug Deliv. 7, 5: 577-587
3. Chen et al. (2010) Gold nanocages as photothermal transducer for cancer treatment. Small 6, 7: 811-817
4. Harmonic Oscillator animations from Wiki Commons

Xia Y, Li W, Cobley CM, Chen J, Xia X, Zhang Q, Yang M, Cho EC, & Brown PK (2011). Gold Nanocages: From Synthesis to Theranostic Applications. Accounts of chemical research PMID: 21528889

Cobley, C., Au, L., Chen, J., & Xia, Y. (2010). Targeting gold nanocages to cancer cells for photothermal destruction and drug delivery Expert Opinion on Drug Delivery, 7 (5), 577-587 DOI: 10.1517/17425240903571614

Chen J, Glaus C, Laforest R, Zhang Q, Yang M, Gidding M, Welch MJ, & Xia Y (2010). Gold nanocages as photothermal transducers for cancer treatment. Small (Weinheim an der Bergstrasse, Germany), 6 (7), 811-7 PMID: 20225187

Glossary:

Contrast Agent = a molecule or nanomaterial ‘used during medical imaging examinations to highlight specific parts of the body and make them easier to see’ – American Society of Radiologic Technologists

Crystal = ‘a substance in which the constituent atoms, molecules, or ions are packed in a regularly ordered, repeating three-dimensional pattern. Most crystals are solids.’ – Anne Marie Helmenstine, Ph.D., About.com Chemistry

Plasmon = quantum of plasma. ’Plasma is a distinct phase of matter, separate from the traditional solids, liquids, and gases. It is a collection of charged particles that respond strongly and collectively to electromagnetic fields, taking the form of gas-like clouds or ion beams. Since the particles in plasma are electrically charged (generally by being stripped of electrons), it is frequently described as an “ionized gas.” ’ – Andrew Zimmerman Jones, About.com Physics

Ion = ‘An atom or a group of atoms that has acquired a net electric charge by gaining or losing one or more electrons’ – Free Online Dictionary

Wavelength = ‘The distance between one peak or crest of a wave of light, heat, or other energy and the next corresponding peak or crest.’ – Free Online Dictionary

Radiative = ‘emitting or causing the emission of radiation – a radiative collision’ – Collins English Dictionary, Physics definition

Photon = ‘a quantum of electromagnetic radiation, regarded as a particle with zero rest mass and charge, unit spin, and energy equal to the product of the frequency of the radiation and the Planck constant’ – Collins English Dictionary, Physics definition

Electron = ‘a stable elementary particle present in all atoms, orbiting the nucleus in numbers equal to the atomic number of the element in the neutral atom’ – Collins English Dictionary, Physics definition

Photothermal = ‘Describing the production of heat by photoexcitation’ – Wiktionary

Nanostructure = ‘Something that has a physical dimension smaller than 100 nanometers, ranging from clusters of atoms to dimensional layers.’ – Answers.com, solid-state physics