26 Feb 2016
Nanoparticles form in a 3-D-printed microfluidic channel. Each droplet shown here is about 250 micrometers in diameter, and contains billions of platinum nanoparticles. Credit: Richard Brutchey and Noah Malmstadt/USC
Nanoparticles – tiny particles 100,000 times smaller than the width of a strand of hair – can be found in everything from drug delivery formulations to pollution controls on cars to HD TV sets. With special properties derived from their tiny size and subsequently increased surface area, they’re critical to industry and scientific research.
They’re also expensive and tricky to make.
Now, researchers at USC have created a new way to manufacture nanoparticles that will transform the process from a painstaking, batch-by-batch drudgery into a large-scale, automated assembly line.
The method, developed by a team led by Noah Malmstadt of the USC Viterbi School of Engineering and Richard Brutchey of the USC Dornsife College of Letters, Arts and Sciences, was published in Nature Communications on Feb. 23.
Consider, for example, gold nanoparticles. They have been shown to be able to easily penetrate cell membranes without causing any damage – an unusual feat, given that most penetrations of cell membranes by foreign objects can damage or kill the cell. Their ability to slip through the cell’s membrane makes gold nanoparticles ideal delivery devices for medications to healthy cells, or fatal doses of radiation to cancer cells.
However, a single milligram of gold nanoparticles currently costs about $80 (depending on the size of the nanoparticles). That places the price of gold nanoparticles at $80,000 per gram – while a gram of pure, raw gold goes for about $50.
“It’s not the gold that’s making it expensive,” Malmstadt said. “We can make them, but it’s not like we can cheaply make a 50 gallon drum full of them.”
Right now, the process of manufacturing a nanoparticle typically involves a technician in a chemistry lab mixing up a batch of chemicals by hand in traditional lab flasks and beakers.
Brutchey and Malmstadt’s new technique instead relies on microfluidics – technology that manipulates tiny droplets of fluid in narrow channels.
“In order to go large scale, we have to go small,” Brutchey said. Really small.
The team 3D printed tubes about 250 micrometers in diameter – which they believe to be the smallest, fully enclosed 3D printed tubes anywhere. For reference, your average-sized speck of dust is 50 micrometers wide.
They then built a parallel network of four of these tubes, side-by-side, and ran a combination of two non-mixing fluids (like oil and water) through them. As the two fluids fought to get out through the openings, they squeezed off tiny droplets. Each of these droplets acted as a micro-scale chemical reactor in which materials were mixed and nanoparticles were generated. Each microfluidic tube can create millions of identical droplets that perform the same reaction.
This sort of system has been envisioned in the past, but its hasn’t been able to be scaled up because the parallel structure meant that if one tube got jammed, it would cause a ripple effect of changing pressures along its neighbors, knocking out the entire system. Think of it like losing a single Christmas light in one of the old-style strands – lose one, and you lose them all.
Brutchey and Malmstadt bypassed this problem by altering the geometry of the tubes themselves, shaping the junction between the tubes such that the particles come out a uniform size and the system is immune to pressure changes.
Malmstadt and Brutchy collaborated with Malancha Gupta of USC Viterbi and USC graduate students Carson Riche and Emily Roberts.
More information: Carson T. Riche et al. Flow invariant droplet formation for stable parallel microreactors, Nature Communications (2016). DOI: 10.1038/ncomms10780
In one of the first efforts to date to apply nanotechnology to targeted cancer therapeutics, researchers have created a nanoparticle formulation of a cancer drug that is both effective and nontoxic — qualities harder to achieve with the free drug. Their nanoparticle creation releases the potent but toxic targeted cancer drug directly to tumors, while sparing healthy tissue.
The findings in rodents with human tumors have helped launch clinical trials of the nanoparticle-encapsulated version of the drug, which are currently underway. Aurora kinase inhibitors are molecularly targeted agents that disrupt cancer’s cell cycle.
While effective, the inhibitors have proven highly toxic to patients and have stalled in late-stage trials. Development of several other targeted cancer drugs has been abandoned because of unacceptable toxicity. To improve drug safety and efficacy, Susan Ashton and colleagues designed polymeric nanoparticles called Accurins to deliver an Aurora kinase B inhibitor currently in clinical trials.
The nanoparticle formulation used ion pairing to efficiently encapsulate and control the release of the drug. In colorectal tumor-bearing rats and mice with diffuse large B cell lymphoma, the nanoparticles accumulated specifically in tumors, where they slowly released the drug to cancer cells. Compared to the free drug, the nanoparticle-encapsulated inhibitor blocked tumor growth more effectively at one half the drug dose and caused fewer side effects in the rodents.
A related Focus by David Bearss offers more insights on how Accurin nanoparticles may help enhance the safety and antitumor activity of Aurora kinase inhibitors and other molecularly targeted drugs.
The above post is reprinted from materials provided by American Association for the Advancement of Science. Note: Materials may be edited for content and length.
- Susan Ashton, Young Ho Song, Jim Nolan, Elaine Cadogan, Jim Murray, Rajesh Odedra, John Foster, Peter A. Hall, Susan Low, Paula Taylor, Rebecca Ellston, Urszula M. Polanska, Joanne Wilson, Colin Howes, Aaron Smith, Richard J. A. Goodwin, John G. Swales, Nicole Strittmatter, Zoltán Takáts, Anna Nilsson, Per Andren, Dawn Trueman, Mike Walker, Corinne L. Reimer, Greg Troiano, Donald Parsons, David De Witt, Marianne Ashford, Jeff Hrkach, Stephen Zale, Philip J. Jewsbury, and Simon T. Barry. Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo. Science Translational Medicine, 2016 DOI: 10.1126/scitranslmed.aad2355
Gold nanoparticles have unusual optical, electronic and chemical properties, which scientists are seeking to put to use in a range of new technologies, from nanoelectronics to cancer treatments.
Some of the most interesting properties of nanoparticles emerge when they are brought close together — either in clusters of just a few particles or in crystals made up of millions of them. Yet particles that are just millionths of an inch in size are too small to be manipulated by conventional lab tools, so a major challenge has been finding ways to assemble these bits of gold while controlling the three-dimensional shape of their arrangement.
One approach that researchers have developed has been to use tiny structures made from synthetic strands of DNA to help organize nanoparticles. Since DNA strands are programmed to pair with other strands in certain patterns, scientists have attached individual strands of DNA to gold particle surfaces to create a variety of assemblies. But these hybrid gold-DNA nanostructures are intricate and expensive to generate, limiting their potential for use in practical materials. The process is similar, in a sense, to producing books by hand.
Enter the nanoparticle equivalent of the printing press. It’s efficient, re-usable and carries more information than previously possible. In results reported online in Nature Chemistry, researchers from McGill’s Department of Chemistry outline a procedure for making a DNA structure with a specific pattern of strands coming out of it; at the end of each strand is a chemical “sticky patch.” When a gold nanoparticle is brought into contact to the DNA nanostructure, it sticks to the patches. The scientists then dissolve the assembly in distilled water, separating the DNA nanostructure into its component strands and leaving behind the DNA imprint on the gold nanoparticle.
“These encoded gold nanoparticles are unprecedented in their information content,” says senior author Hanadi Sleiman, who holds the Canada Research Chair in DNA Nanoscience. “The DNA nanostructures, for their part, can be re-used, much like stamps in an old printing press.”
From stained glass to optoelectronics
Some of the properties of gold nanoparticles have been recognized for centuries. Medieval artisans added gold chloride to molten glass to create the ruby-red colour in stained-glass windows — the result, as chemists figured out much later, of the light-scattering properties of tiny gold particles.
Now, the McGill researchers hope their new production technique will help pave the way for use of DNA-encoded nanoparticles in a range of cutting-edge technologies. First author Thomas Edwardson says the next step for the lab will be to investigate the properties of structures made from these new building blocks. “In much the same way that atoms combine to form complex molecules, patterned DNA gold particles can connect to neighbouring particles to form well-defined nanoparticle assemblies.”
These could be put to use in areas including optoelectronic nanodevices and biomedical sciences, the researchers say. The patterns of DNA strands could, for example, be engineered to target specific proteins on cancer cells, and thus serve to detect cancer or to selectively destroy cancer cells.
Financial support for the research was provided by the Natural Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation, the Centre for Self-Assembled Chemical Structures, the Canada Research Chairs Program and the Canadian Institutes of Health Research.
- Thomas G. W. Edwardson, Kai Lin Lau, Danny Bousmail, Christopher J. Serpell, Hanadi F. Sleiman. Transfer of molecular recognition information from DNA nanostructures to gold nanoparticles. Nature Chemistry, 2016; DOI: 10.1038/nchem.2420