Tag Archives: bioimaging

A ‘vascular running of the bulls’; nanoparticles in your bloodstream

An Oct. 5, 2016 news item on phys.org announces research into how nanoparticles behave in the bloodstream (Note: A link has been removed),

Researchers at the University of Connecticut have uncovered new information about how particles behave in our bloodstream, an important advancement that could help pharmaceutical scientists develop more effective cancer drugs.

Making sure cancer medications reach the leaky blood vessels surrounding most tumor sites is one of the critical aspects of treatment and drug delivery. While surface chemistry, molecular interactions, and other factors come into play once drug-carrying particles arrive at a tumor, therapeutic medication doesn’t do very much good if it never reaches its intended target.

Anson Ma, an assistant professor of chemical and biomolecular engineering at UConn, used a microfluidic channel device to observe, track, and measure how individual particles behaved in a simulated blood vessel.

The research team’s goal: to learn more about the physics influencing a particle’s behavior as it travels in our blood and to determine which particle size might be the most effective for delivering drugs to their targets. The team’s experimental findings mark the first time such quantitative data has been gathered. …

“Even before particles reach a target site, you have to worry about what is going to happen with them after they get injected into the bloodstream,” Ma says. “Are they going to clump together? How are they going to move around? Are they going to get swept away and flushed out of our bodies?”

Using a high-powered fluorescence microscope in UConn’s Complex Fluids Lab, Ma was able to observe particles being carried along in the simulated blood vessel in what could be described as a vascular Running of the Bulls [emphasis mine]. Red blood cells race through the middle of the channel as the particles – highlighted under the fluorescent light – get carried along in the rush, bumping and bouncing off the blood cells until they are pushed to open spaces – called the cell-free layer – along the vessel’s walls.

Nanocarrier particles injected into the bloodstream bounce off red and white blood cells and platelets, and are pushed toward the blood vessel walls. This physical interaction, measured and quantified for the first time by engineering professor Anson Ma’s lab, provides important information for drug developers. (Image courtesy of Anson Ma)

Nanocarrier particles injected into the bloodstream bounce off red and white blood cells and platelets, and are pushed toward the blood vessel walls. This physical interaction, measured and quantified for the first time by engineering professor Anson Ma’s lab, provides important information for drug developers. (Image courtesy of Anson Ma)

An Oct. 4, 2016 University of Connecticut news release, which originated the news item, provides more detail about the research,

What Ma found was that larger particles – the optimum size appeared to be about 2 microns – were most likely to get pushed to the cell-free layer, where their chances of carrying medication into a tumor site are greatest. The research team also determined that 2 microns was the largest size that should be used if particles are going to have any chance of going through the leaky blood vessel walls into the tumor site.

“When it comes to using particles for the delivery of cancer drugs, size matters,” Ma says. “When you have a bigger particle, the chance of it bumping into blood cells is much higher, there are a lot more collisions, and they tend to get pushed to the blood vessel walls.”

The results were somewhat surprising. In preparing their hypothesis, the research team estimated that smaller particles were probably the most effective since they would move the most in collisions with blood cells, much like what happens when a small ball bounces off a larger one. But just the opposite proved true. The smaller particles appeared to skirt through the mass of moving blood cells and were less likely to experience the “trampoline” effect and get bounced to the cell-free layer, says Ma.

Ma proposed the study after talking to a UConn pharmaceutical scientist about drug development at a campus event five years ago.

“We had a great conversation about how drugs are made and then I asked, ‘But how can you be sure where the particles go?’” Ma recalls, laughing. “I’m an engineer. That’s how we think. I was curious. This was an engineering question. So I said, ‘Let’s write a proposal!’”

The proposal was funded by the National Science Foundation’s Early-concept Grants for Exploratory Research or EAGER program, which supports exploratory work in its early stages on untested, but potentially transformative, research ideas or approaches.

Knowing how particles behave in our circulatory system should help improve targeted drug delivery, Ma says, which in turn will further reduce the toxic side effects caused by potent cancer drugs missing their target and impacting the body’s healthy tissue.

The findings were particularly meaningful for Ma, who lost two of his grandparents to cancer and who has long wanted to contribute to cancer research in a meaningful way as an engineer.

Measuring how particles of different sizes move in the bloodstream may also be beneficial in bioimaging, where scientists and doctors want to keep particles circulating in the bloodstream long enough for imaging to occur. In that case, smaller particles would be better, says Ma.

Moving forward, Ma would like to explore other aspects of particle flow in our circulatory system, such as how particles behave when they pass through a constricted area, such as from a blood vessel to a capillary. Capillaries are only about 7 microns in diameter. The average human hair is 100 microns.  Ma says he would like to know how that constricted space might impact particle flow or the ability of particles to accumulate near the vessel walls.

“We have all of this complex geometry in our bodies,” says Ma. “Most people just assume there is no impact when a particle moves from a bigger channel to a smaller channel because they haven’t quantified it. Our plan is to do some experiments to look at this more carefully, building on the work that we just published.”

Here’s a link to and a citation for the paper,

Direct Tracking of Particles and Quantification of Margination in Blood Flow by Erik J. Carbon, Brice H. Bognet, Grant M. Bouchillon, Andrea L. Kadilak, Leslie M. Shor, Michael D. Ward, Anson W.K. Ma. Biophysical Journal Volume 111, Issue 7, p1487–1495, 4 October 2016  DOI: http://dx.doi.org/10.1016/j.bpj.2016.08.026

This paper is behind a paywall.

Purple promises and bioimaging from Singapore’s A*STAR

A May 7, 2014 news item on Nanowerk describes a promising new approach to bioimaging,

Labeling biomolecules with light-emitting nanoparticles is a powerful technique for observing cell movement and signaling under realistic, in vivo conditions. The small size of these probes, however, often limits their optical capabilities. In particular, many nanoparticles have trouble producing high-energy light with wavelengths in the violet to ultraviolet range, which can trigger critical biological reactions.

Now, an international team led by Xiaogang Liu from the A*STAR Institute of Materials Research and Engineering and the National University of Singapore has discovered a novel class of rare-earth nanocrystals that preserve excited energy inside their atomic framework, resulting in unusually intense violet emissions …

A May 7, 2014 A*STAR (Agency for Science, Technology and Research) news release (h/t Imagist), which originated the news item, describes the problems with current bioimaging techniques and the new approach in more detail (Note: Links have been removed)

Nanocrystals selectively infused, or ‘doped’, with rare-earth ions have attracted the attention of researchers, because of their low toxicity and ability to convert low-energy laser light into violet-colored luminescence emissions — a process known as photon upconversion. Efforts to improve the intensity of these emissions have focused on ytterbium (Yb) rare-earth dopants, as they are easily excitable with standard lasers. Unfortunately, elevated amounts of Yb dopants can rapidly diminish, or ‘quench’, the generated light.

This quenching probably arises from the long-range migration of laser-excited energy states from Yb and toward defects in the nanocrystal. Most rare-earth nanocrystals have relatively uniform dopant distributions, but Liu and co-workers considered that a different crystal arrangement — clustering dopants into multi-atom arrays separated by large distances — could produce localized excited states that do not undergo migratory quenching.

The team screened numerous nanocrystals with different symmetries before discovering a material that met their criteria: a potassium fluoride crystal doped with Yb and europium rare earths (KYb2F7:Eu). Experiments revealed that the isolated Yb ‘energy clusters’ inside this pill-shaped nanocrystal (see image) enabled substantially higher dopant concentrations than usual — Yb accounted for up to 98 per cent of the crystal’s mass — and helped initiate multiphoton upconversion that yielded violet light with an intensity eight times higher than previously seen.

The researchers then explored the biological applications of their nanocrystals by using them to detect alkaline phosphatases, enzymes that frequently indicate bone and liver diseases. When the team brought the nanocrystals close to an alkaline phosphate-catalyzed reaction, they saw the violet emissions diminish in direct proportion to a chemical indicator produced by the enzyme. This approach enables swift and sensitive detection of this critical biomolecule at microscale concentration levels.

“We believe that the fundamental aspects of these findings — that crystal structures can greatly influence luminescence properties — could allow upconversion nanocrystals to eventually outperform conventional fluorescent biomarkers,” says Liu.

Here’s a link to and a citation for the paper,

Enhancing multiphoton upconversion through energy clustering at sublattice level by Juan Wang, Renren Deng, Mark A. MacDonald, Bolei Chen, Jikang Yuan, Feng Wang, Dongzhi Chi, Tzi Sum Andy Hor, Peng Zhang, Guokui Liu, Yu Han, & Xiaogang Liu. Nature Materials 13, 157–162 (2014) doi:10.1038/nmat3804 Published online 24 November 2013

This paper is behind a paywall but there is a free preview via ReadCube Access.