May 3, 2004 A UCLA-led team of chemists has developed a unique new coating for inorganic particles at the nanoscale that may be able to disguise the particles as proteins -- a process that allows particles to function as probes that can penetrate the cell and light up individual proteins inside, and create the potential for application in a wide range of drug development, diagnostic tools and medications.
The findings will be published in the May 19 edition of the Journal of the American Chemical Society.
The organic coatings -- short chains of stringed amino acids (peptides) -- can be used to disguise particles called "quantum dots," "quantum rods" and "quantum "wires" so effectively that the cells mistake them for proteins, even when the coatings are used on particles that are inorganic and possibly even toxic.
"These peptide coatings serve as 'Halloween costumes' for the particles, and trick the live cell into thinking that the nanoparticles are benign, protein-like entities," said Shimon Weiss, UCLA professor of chemistry and a member of the university's California NanoSystems Institute. "As a result, we can use these coated particles to track the proteins in a live cell and conduct a range of studies at the molecular level, which is a major step toward using nanotechnology to create practical applications for biology and medicine."
Particles made of semiconductors at the nanoscale (one-billionth of a meter, or about one-thousandth the thickness of a human hair) have long found applications in the electronic and information technology industries. For example, the active part of a single transistor on a Pentium silicon chip is a few tenths of a nanometer in size. The semiconductor laser used to read digital information on a CD or DVD has an active layer of similar dimensions.
"Creating the ability to import such electronic functions into the cell and meshing them with biological functions could open tremendous new possibilities, both for basic biological sciences and for medical and therapeutic applications," Weiss said.
One of these electronic functions is the emission of light called fluorescence. Using the new coatings, Weiss' team has been able to solubilize and introduce into the cell different color quantum dots that can all be excited by a single blue light source.
The color encoding method is similar to the encoding of information that is sent down an optical fiber, called "wavelength division multiplexing," or WDM. The peptide coating technology could, in principle, color encode biology itself, by "painting" different proteins in the cell with different-color quantum dots.
The research team includes Weiss -- the principal investigator -- and graduate student Fabien Pinaud, along with UC Berkeley assistant research biochemist David S. King and Hsiao-Ping Moore, professor of molecular and cell biology.
Weiss and Pinaud are developing methods to attach quantum dots of specific colors to the different proteins on cells' surface and inside cells.
"Humans have close to 40,000 genes," Weiss said. "A large group of these genes operates at every moment, in every single cell of our body, in very complicated ways. By painting a subset of proteins in the cell with different color quantum dots, we can follow the molecular circuitry, the dynamic rearrangement of circuit nodes and the molecular interactions -- or, in short, observe the 'molecular dance' that defines life itself."
In addition to the capacity to paint and observe many different proteins with separate colors, quantum dots can be used for the ultimate detection sensitivity: observing a single molecule. Until now, tracking and following a single protein in the cell has been extremely challenging and was the equivalent of searching for the proverbial needle in a haystack.
By using the new methods developed at UCLA, and observing with a fluorescence microscope and high-sensitivity imaging cameras, researchers can track a single protein tagged with a fluorescent quantum dot inside a living cell in three dimensions and within a few nanometers of accuracy.
"This process is, in some ways, the molecular equivalent of using the global positioning system to track a single person anywhere on earth," Pinaud said. "We can use optical methods to track several different proteins tagged with different-color quantum dots, measure the distances between them and use those findings to better understand the molecular interactions inside the cell."
Particles disguised with the peptide coatings developed by the Weiss team can enter a cell without affecting its basic functioning -- creating a water-soluble and biocompatible thin layer for the particles that can be targeted to bind to individual proteins in the live cell.
"Since the peptide-coated quantum dots are small, they have easy and rapid entry through the cell membrane," Pinaud said. "In addition, since multiple peptides of various lengths and functions could be deposited on the same single quantum dot, we can easily envision the creation of 'smart' probes with multiple functions."
The Weiss teamwork on coatings was inspired by nature. Some plants and bacteria cells evolved unique capabilities to block toxic heavy-metal ions as a strategy to clean up the toxic environment in which they grow. These organisms synthesize peptides, called phytochelatins, that reduce the amount of toxic-free ions by strongly binding to inorganic nanoparticles made of the sequestered toxic salts and other products.
"Our peptide coating bridges the inorganic chemistry world with the organic world on the nanometer scale," Weiss said. "Ideally, these coatings will be used to provide electrical contact between nanoscale inorganic electronic devices and functional proteins, which would lead to the evolution of novel and powerful 'smart drugs,' 'smart enzymes,' 'smart catalysts,' 'protein switches' and many other functional hybrids of inorganic-organic substances.
"The possibilities are endless," Weiss said. "For example, just imagine the potential for this process in cancer treatment, if a hybrid nanoparticle could be created that was specifically targeted to identify and destroy cancer cells in the body."
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