Combining Nanoparticles with Proteins for Energy Conversion, Drug Delivery, and Medical Imaging

In groundbreaking research, scientists have demonstrated the ability to strategically attach gold nanoparticles--particles on the order of billionths of a meter--to proteins so as to form sheets of protein-gold arrays. The nanoparticles and methods to create nanoparticle-protein complexes can be utilized to help decode protein structures, to identify functional components of proteins, and to adhere together new protein complexes. Applications foreseen by the researchers include catalysts for converting biomass to energy and precision vehicles for targeted drug delivery.

The study, which was conducted at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory (Upton, NY, USA), was published in the July 2, 2007, issue of the journal Angewandte Chemie.

"Our study demonstrates that nanoparticles are appealing templates for assembling functional biomolecules with extensive potential impact across the fields of energy conversion, structural biology, drug delivery, and medical imaging,” said lead author Dr. Minghui Hu, a postdoctoral student working with Drs. James Hainfeld, Raymond Brinas, Luping Qian, and Elena Lymar in the biology department at Brookhaven Lab.

In the field of energy conversion, scientists have been looking for effective ways to convert organic fuels such as ethanol into electricity using catalytic electrodes. But making single layers of densely packed enzymes, the functional part of such catalytic electrodes, has been a challenge. This new study demonstrates that precisely engineered gold nanoparticles can be used to fasten enzymes together to form oriented and ordered single layers, and that these monolayers are mechanically stable enough to be transferred onto a solid surface such as an electrode.

For this research, the scientists attached gold nanoparticles to an enzyme complex that helps drug-resistant tuberculosis (TB) bacteria survive, which has been examined by Brookhaven Lab biologist Dr. Huilin Li. The researchers suggested that gold nanoparticles might also be engineered to inactivate this enzyme complex, thereby thwarting drug-resistant TB--a research prospect they may further examine in future studies.

In another area of the study, the investigators used proteins found on the surface of the adenovirus, a virus that causes the common cold. Earlier research by Broookhaven's Dr. Paul Freimuth have characterized how this virus binds to the human cells it infects, and have suggested that modified forms of adenovirus could be used as vehicles to deliver drugs to specific target cells, such as those that comprise tumors.

One goal of this approach would be to enhance strong binding to the target cells. To achieve this, Drs. Hu and Hainfeld's team attached multiple viral proteins to the gold nanoparticles. Such constructs should have increased binding affinity for target cells and their larger size should extend blood residence time for improved drug delivery.

In another application, this new research showed that gold nanoparticles can enhance scientists' ability to decipher the structures and functionally significant regions of protein molecules--the workhorses that carry out every function of living cells and whose dysfunction often leads to disease. With added nanoparticles, the signal-to-noise ratio and resolution of an imaging technique, known as cryo-electron microscopy, were considerably increased. This technique might enable analysis of small biologic macromolecules and complexes that are currently difficult to study by cryo-electron microscopy or x-ray crystallography.

Throughout this research, the biggest hurdle was to synthesize size-controllable nanoparticles coated with organic molecules created to react with specific protein sites. Dr. Hu explained the steps: "First, we design the specific interactions between gold nanoparticles and the proteins by coating the gold nanoparticles with functional organic molecules using a biocompatible linker. Then we add a genetically engineered sequence of peptides, called a tag, to the protein molecule, which acts as the binding site for the gold nanoparticles. Finally, we incubate the nanoparticles with the protein solution to allow the nanoparticles and proteins to bind, transfer the solution onto a transmission electron microscopy grid, and analyze the complexes using state-of-the-art electron microscopes.”


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Brookhaven National Laboratory