Shining a Light on Cancer Research

NCI Alliance for Nanotechnology in Cancer Monthly Feature January/February 2005 tiple biochemical and genetic pathways that are involved in cancer. But that is just one of the many developing uses for tunable Shining a Light on nanoscale beacons. “From their initial use as easily-tracked markers, these nanoscale beacons are proving to be quite versatile in what we can do with them,” says Shuming Nie, associate professor of biomedical engineering Cancer Research at Emory University School of Medicine and director of nanotechnology at the Winship Quantum dots and nanoshells are driving Cancer Institute. development of novel analytical and therapeutic Nie, for example, is heading a multi-institu- tional consortium that is attempting to approaches for cancer develop second-generation quantum dots for use as tumor detection agents, and perhaps delivery vehicles for anticancer therapeutic In the early 1980s, researchers at Bell opment of new technologies that are chang- agents. Recent recipients of a $7.1 million Laboratories in the United States and at the ing the way that cancer researchers, among grant from the National Cancer Institute, Yoffe Institute in Russia made an unexpected others, are observing the fundamental molec- Nie’s team has modified the original cadmi- observation: as semiconductor crystals grew ular events that occur in and around cells. um selenide (CdSe) quantum dot with a ever smaller, their optical properties began to Using nanoscale semiconductor quantum coating of polymer that has two functions: change in what, at the time, seemed a myste- dots and gold nanoshells of various diame- the impermeable coating prevents highly rious fashion. Depending on their size, the ters, and thus different colors, biomedical toxic cadmium from leaching out of the crystals fluoresced at different wavelengths researchers are able to tag multiple different quantum dots and it provides a means of even though the chemical composition of the biological molecules with brightly colored chemically attaching tumor-targeting mole- crystals stayed the same. Eventually, the beacons that they can easily track in vivo cules and drug-delivery functionality to the researchers came to understand that the using a variety of imaging technologies, such molecular beacon.3 His team plans on using unusual behavior of these “quantum dots” as fluorescence microscopy. these quantum dots to identify tumor markers resulted from their nanoscale size, which from an extensive collection of archived tumor changed the electronic properties of the semi- As an example of this type of approach, a biopsies taken from hundreds of patients. conductor materials in a fundamental manner. team from Quantum Dot Corp., a company based in Hayward, CA, and Genentech, a In the future, targeted quantum dots could Fast forward to the mid-1990s, when pharmaceutical company in South San also serve as in vivo imaging agents if Nie researchers at Rice University made a similar Francisco, CA, used quantum dots to simul- and others, such as John Frangioni, assistant discovery about another class of materials. taneously label and visualize Her-2 on the professor at Harvard Medical School, and Working with gold-coated silica nanoshells, surface of live cancer cells and nuclear anti- Massachusetts Institute of Technology chem- Naomi Halas, professor of chemistry and gens inside the cell.1 More recently, investiga- istry professor Moungi Bawendi, are success- electrical and computer engineering at Rice tors at Quantum Dot have used quantum ful in their on-going efforts to extend the University in Houston, determined that by dots that fluoresce at different colors to wavelength at which these nanoparticles emit varying the thickness of the gold coating rel- simultaneously label and track mammalian light above 900 nanometers, the current ative to the diameter of the silica core, it was cells in culture using either standard fluores- upper limit. Nie explains that since there are possible to tune the optical behavior of the cence microscopy or a commercial cell sorter. no biomolecules that fluoresce above 1000 resulting nanoshells. But instead of emitting To get the quantum dots into cells, the nanometers, quantum dots capable of fluo- light of defined wavelength, i.e. color, as do group used a ferrying peptide known as Pep- rescing in that range would provide an quantum dots, the nanoshells absorbed or 1 to carry the quantum dots through the cell unambiguous signal when used in imaging scattered light at well-defined frequencies. membrane. The researchers estimate that applications. He adds that computer calcula- Two different materials, two different mecha- they can tag and image over 100 different tions predict that fluorescence above 1000 nisms explaining a color change, and both cells simultaneously using this method.2 nanometers should be capable of passing relying on fundamental differences in the through more tissue and be detectable at far way matter behaves at the nanoscale. The ability to keep track of multiple mole- lower levels, which would boost the sensitivi- cules and cells will undoubtedly be a boon ty of any test using such materials. As a Today, those initial discoveries and the for molecular and cell biologists who are try- corollary to this work, the Emory team is research they fostered have led to the devel- ing to understand the interplay among mul- NCI Alliance for Nanotechnology in Cancer1 Monthly Feature January/February 2005 NCI Alliance for Nanotechnology in Cancer Monthly Feature January/February 2005 also developing a new imaging camera that light falls on a semiconductor, electrons are mechanics allows scientists to predict the will be sensitive to emissions at 1000 excited from what chemists call the valence properties of complex molecules, the work nanometers. band – where they are tightly bound to their performed by the Rice team shows how the parent atom – into the so-called conduction properties of plasmons in complex metallic Proof that imaging with quantum dots is not band, where they can move and contribute nanostructures can be predicted in a simple just a goal but a reality comes from recent to current flow. Each electron leaves a posi- manner. As a result of this advance in work out of Harvard Medical School, where tive hole in the valence band, and the elec- understanding plasmons, Halas explains a team led by Frangioni and assistant profes- tron stays close to this hole in a bound system that, “we can design nanoscale materials in sor Tomislav Mihaljevic, also of Harvard called an exciton. Electrons emit their excess advance on the computer and then create Medical School, used coated, water-soluble energy as light when they recombine with them with the predicted optical properties quantum dots to detect so-called sentinel positive holes, and this means that excitons in the laboratory.” lymph nodes – the first lymph nodes to accumulate metastatic cells shed by nearby Figure 1: Comparing Nanoshells to Quantum Dots tumors – in animals as large as a 35 kilogram Courtesy of Naomi Halas, Rice University pig. These coated semiconductor nanoparticles, developed by Massachusetts Institute of Technology chemistry professor Moungi Bawendi, are readily visible in lymph nodes up to one centimeter beneath the skin4 and five centimeters in lung tissue.5 Photo by Corey Radlof Meanwhile, Halas and Rice University colleagues Jennifer West and Rebekah Drezek, Photo by Colleen Nehl (Hafner Group) both professors of biomedical engineering, 50 nm have used gold nanoshells to image tumors in mice using an imaging approach that can Nanoshells Quantum Dots work as deep as 10 centimeters within an Tunable plasmonic nanoparticles Tunable excitonic nanoparticles ~ 10-300 nm diameter ~ 1-10 nm diameter(uncoated) animal’s body.6 Halas and West have also pio- neered nanoshells as miniature “thermal Quantum efficiencies ~10-4 Quantum efficiencies ~0.1-0.5 Spectral range (extinction): 500(Ag)-9000 nm Spectral range (emission): 400-2000 nm scalpels” that can literally cook cancer cells to Cross sections: ~10-13 m2 Cross sections: ~10-19 m2 death. The operating principle here is that these nanoshells will become hot when irra- diated with relatively low-intensity near- are the source of light in semiconductors. infrared laser light, and tests in laboratory In contrast, gold nanoshells owe their opti- Given the way that science works, it should animals have shown that the nanoshells can cal properties to plasmons, ripples of waves not be surprising that the research communi- transfer this thermal energy to tumor cells in the ocean of electrons flowing across the ty is not content with having two different, and kill them.7 Thus, if the nanoshells are surface of metallic nanostructures. The type versatile nanoscale tagging systems at their targeted to tumor cells, they may enable of plasmon that exists on a surface of a command. Among the up-and-coming physicians to first image the tumors and then nanoscale object is directly related to its nanoscale beacons are those developed by kill them by turning up the light intensity. geometric structure – the precise curvature Weihong Tan, professor of chemistry at the Nanospectra Biosciences, based in Houston, of a nanoscale gold sphere or a nano-sized University of Florida. He and his colleagues TX, is currently conducting further animal pore in metallic foil, for example. When have worked out methods for incorporating a tests and is hoping to begin human clinical light of a specific frequency strikes a plas- wide range of organic fluorescent dyes into trials with these nanoshells early in 2006. mon that oscillates at a compatible frequen- the core of silica nanoparticles.9 Florida col- Halas and her team are trying to better cy, the energy from the light is harvested by league Shouguang Jin, associate professor of understand how these particles turn light the plasmon, converted into electrical ener- molecular genetics and microbiology, and his into heat in order to better predict what type gy that propagates through the nanostruc- team recently used these nanobeacons to of gold nanoshell is best suited as a thermal ture and eventually converted back to light.

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