Imagine a scenario where a routine blood test shows markers indicating a tumor. The type, size, and location of the main tumor are not known with great precision (except for palpitating by the doctor in suspected areas) nor is there any knowledge of potential metastases.
Now, imagine an injection of smart gold nanoparticles into the patient’s bloodstream. Innocuous to the body, these particles accumulate in various locations where there may be malignancies, binding to even very small tumors with new vasculature.
Next, a full body scan reveals the exact location and dimensions of the tumors based on increased contrast—also built into these particles. Localized scans allow the particle to reveal malignancies based on reactions on the particles’ surface, which increase their visibility or release a marker identifying the tumor type.
A laser is then used with a fiber optic delivery system to illuminate these precise locations. The laser and nanoparticles heat the tumor from within and destroy it while surrounding tissue is left unharmed. Later, dead cells and nanoparticles are resorbed and removed by the body’s natural defense systems.
The day when new optical imaging technologies can offer hope for more accurate diagnoses and treatment of cancer is coming, and plasmonic gold nanoparticles will form a foundation for the full realization of these goals.
The excitation of electrons on the surface of metal nanoparticles with specific wavelengths of light can lead to localized heat generation sufficient to rupture a cell membrane and destroy malignancies.
Gold makes a particularly interesting and relevant material for building nanoparticles for medical devices due to its long standing in medicine as being inherently inert. Even at nanoscale dimensions, gold is relatively innocuous to cells and the human body. The plasmon resonance of spherical solid gold nanoparticles (gold colloid) makes them appear red in suspension (peak absorption of energy at ~ 500-530 nm wavelength)—similar to hemoglobin of blood. The main components of tissue, water, and hemoglobin have minimal interaction with light of wavelengths between 650-950 nm. These near infrared (NIR) wavelengths are relatively unimpeded by tissue components, so this is an ideal region for selectively creating plasmonic-based therapies.
The latest classes of gold nanoparticles, which can be tuned to produce plasmon resonance in the NIR range, are of various shapes and sizes. They include spherical nanoshells, elliptical nanorice, elliptical solid gold nanorods, and cubic nanocages.
Spherical nanoshells, developed at Naomi Halas’ lab at Rice University, were first used for cellular ablation and successful in vivo treatment of cancer tumors by Rice’s Jennifer West. Nanoshells are probably the furthest along in development into a therapeutic product, which will have a broad impact on cancer treatment in a minimally invasive procedure.
Nanoshells are composites consisting of a gold layer (shell) on the surface of a solid dielectric core of silica. For therapeutic applications, nanoshells can be easily fabricated to dimensions that allow both scattering of NIR light as well as absorption, properties that allow detection and treatment, respectively.
Nanoshells with a targeting molecule can specifically bind and allow photothermal ablation of prostate tumor cells. The figure shows cells that were incubated with targeting nanoshells and subsequently treated with a NIR laser for 5 minutes. By using fluorescent stains, live cells appear green and dead cells appear red. The image shows confinement of death to just the cells in the spot of the laser beam. A scale bar (500 microns) is shown for size comparison.
The gold surface of nanoshells actually makes it easy to attach other molecules, which can confer targeting and stealth ability to the particles. In vitro targeting to malignant human breast cancer cells, medulloblastoma, gliomas and prostate tumor lines have been successful in demonstrating preferential binding and cellular ablation of targeted cells, with no effect to normal cell lines in close proximity.
Nanospectra Biosciences in Texas, exclusive licensee to Nanoshells, is developing these particles into therapies and beginning human clinical trials of patients with recurrent head and neck tumors in 2008.
Nanorods are solid cylindrical particles of gold that have strong, predictable, tunable plasmon resonance depending on the length to diameter (L/D) ratios. At an L/D of approximately 4, there is a strong NIR resonance at 800 nm, making these suitable for work in biological systems similar to gold nanoshells. However, the fabrication process for nanorods growth involves the use of a surfactant considered cytotoxic. This complicates the process slightly, although these nanoparticles can and have been processed to the point where they can be used in vivo.
Another composite NIR plasmonic nanoparticle is the “nanorice” also out of Halas’ lab at Rice. These have a core shell structure like nanoshells. However, their elongated geometry imparts higher intensity local fields in the particle as a result of the plasmon resonance of the electron in the shells. As with spherical nanoshells, the peak resonances of nanorice can be shifted to different wavelengths by adjusting shell thicknesses.
The spectral profiles of these particles display the dominant resonance at longer wavelength due to the longitudinal resonance within the particle and a smaller peak due to transverse resonance, similar to nanorods. Nanorice is made with a core of hematite: iron oxide, Fe2O3. The tunability of these particles and higher intensity fields could be useful in enhancing spectroscopic techniques for characterization of large molecules such as DNA and proteins.
Nanoshells with a gold sulfide core are also being developed and studied. They are two to three times smaller than gold/silica nanoshells and have higher absorbing efficiencies. These have the potential for treatment of a wider variety of tumor types and for use in smart drug delivery systems.
Nanocages are an even newer class of nanoparticles. These are cubic and made through a silver precipitation process with sodium sulfide. These particles exhibit strong NIR resonances with side walls around 45nm in length and can be synthesized to have a gold-silver alloy with up to 25% silver, allowing the particles to have some of the surface characteristics of gold nanoshells and nanorods.
A close-up of a single prostate tumor cell from the experiment shown in the first figure. The tumor cell is covered with nanoshells that were specifically designed to bind to receptors overexpressed on this cell type. Each point of light represents a single nanoshell. Scale bar = 10 microns.
These gold-silver nanocages can be conjugated with antibodies, and in vitro these can photo-thermally ablate cells upon exposure to NIR laser. These nanocages exhibit large absorbing cross-sectional areas similar to that of nanoshells. With easy manufacturing processes, they may prove useful in therapeutic applications in the future.
NIR-absorbing gold nanoparticles have utility in many aspects of biomedical therapies, not just cancer therapy. Nanoshells have been used to demonstrate heating and bonding of tissue using a technique where tissue is “welded” together with NIR-absorbing nanoshells suspended in a protein “glue.” Nanoshells have also been used to create extremely sensitive detection systems based on shifts in the resonance of the particles as specific molecules of interest bind to them, causing aggregation of the particles.
The ability to create NIR-resonant nanoparticles with different core materials means that we will have particles that can increase MRI imaging contrast in the future, allowing us to locate small tumors situated deep within the body. The high resolution of optical systems combined with these nanoparticles can allow information to be obtained to determine malignancies’ location and dimensions with greater accuracy.
Conjugation of targeting molecules and cleavable peptide sequences to the nanoparticles can enable tuning of the behavior of these nanoparticles to provide information at a cellular level.
All of these developments are in the pipeline and are leading to an exciting future where a smart golden bullet with unprecedented accuracy seeks out even the smallest tumors and allows their destruction with light.
Cancer is a devastating disease that extracts a tremendous cost on individuals, families and our society. The number of deaths and treatment costs are staggering. It is the second leading killer in the United States, with approximately one in four deaths due to cancer. Treatment costs are estimated at well over $200 billion.
With new technologies being developed in optical imaging and detection, the sensitivity and accuracy of diagnoses are increasing, leading to more lives saved. Nanomaterials with plasmonic properties (SPIE Professional, July 2007) offer new hope for treatment and detection of cancer.
Shuming Nie and his research collaborators at Georgia Tech and Emory University published the results of their studies injecting mice tumors with gold nanoparticles in the January issue of Nature Biotechnology
André M. Gobin
André M. Gobin is assistant professor of bioengineering at the University of Lousiville where he directs the Nanotherapeutics Laboratory. His Ph.D. in bioengineering is from Rice University and he received his B.S. in chemical engineering at Cornell University.