Tag Archives: caterpillar

Nanoparticle ‘caterpillars’ and immune system ‘crows’

This University of Colorado work fits in nicely with other efforts to ensure that nanoparticle medical delivery systems get to their destinations. From a Dec. 19, 2016 news item on phys.org,

In the lab, doctors can attach chemotherapy to nanoparticles that target tumors, and can use nanoparticles to enhance imaging with MRI, PET and CT scans. Unfortunately, nanoparticles look a lot like pathogens – introducing nanoparticles to the human body can lead to immune system activation in which, at best, nanoparticles are cleared before accomplishing their purpose, and at worst, the onset of dangerous allergic reaction. A University of Colorado Cancer Center paper published today [Dec. 19, 2016] in the journal Nature Nanotechnology details how the immune system recognizes nanoparticles, potentially paving the way to counteract or avoid this detection.

Specifically, the study worked with dextran-coated iron oxide nanoparticles, a promising and versatile class of particles used as drug-delivery vehicles and MRI contrast enhancers in many studies. As their name implies, the particles are tiny flecks of iron oxide encrusted with sugar chains.

“We used several sophisticated microscopy approaches to understand that the particles basically look like caterpillars,” says Dmitri Simberg, PhD, investigator at the CU Cancer Center and assistant professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences, the paper’s senior author.

The comparison is striking: the iron oxide particle is the caterpillar’s body, which is surrounded by fine hairs of dextran.

Caption: University of Colorado Cancer Study shows how nanoparticles activate the complement system, potentially paving the way for expanded use of these technologies.
Credit: University of Colorado Cancer Center

A Dec. 19, 2016 University of Colorado news release on EurekAlert, which originated the news item, describes the work in more detail,

If Simberg’s dextran-coated iron oxide nanoparticles are caterpillars, then the immune system is a fat crow that would eat them – that is, if it can find them. In fact, the immune system has evolved for exactly this purpose – to find and “eat” foreign particles – and rather than one homogenous entity is actually composed of a handful of interrelated systems, each specialized to counteract a specific form of invading particle.

Simberg’s previous work shows that it is the immune subcomponent called the complement system that most challenges nanoparticles. Basically, the complement system is a group of just over 30 proteins that circulate through the blood and attach to invading particles and pathogens. In humans, complement system activation requires that three proteins come together on a particle -C3b, Bb and properdin – which form a stable complex called C3-convertase.

“The whole complement system activation starts with the assembly of C3-convertase,” Simberg says. “In this paper, we ask the question of how the complement proteins actually recognize the nanoparticle surface. How is this whole reaction triggered?”

First, it was clear that the dextran coating that was supposed to protect the nanoparticles from human complement attack was not doing its job. Simberg and colleagues could see complement proteins literally invade the barrier of dextran hairs.

“Electron microscopy images show protein getting inside the particle to touch the iron oxide core,” Simberg says.

In fact, as long as the nanoparticle coating allowed the nanoparticle to absorb proteins from blood, the C3 convertase was assembled and activated on these proteins. The composition of the coating was irrelevant – if any blood protein was able to bind to nanoparticles, it always led to complement activation. Moreover, Simberg and colleagues also showed that complement system activation is a dynamic and ongoing process – blood proteins and C3 convertase constantly dissociate from nanoparticles, and new proteins and C3 convertases bind to the particles, continuing the cascade of immune system activation. The group also demonstrated that this dynamic assembly of complement proteins occurs not only in the test tubes but also in living organisms as particles circulate in blood.

Simberg suggests that the work points to challenges and three possible strategies to avoid complement system activation by nanoparticles: “First, we could try to change the nanoparticle coating so that it can’t absorb proteins, which is a difficult task; second, we could better understand the composition of proteins absorbed from blood on the particle surface that allow it to bind complement proteins; and third, there are natural inhibitors of complement activation – for example blood Factor H – but in the context of nanoparticles, it’s not strong enough to stop complement activation. Perhaps we could get nanoparticles to attract more Factor H to decrease this activation.”

At one point, the concept of nanomedicine seemed as if it would be simple – engineers and chemists would make a nanoparticle with affinity for tumor tissue and then attach a drug molecule to it. Or they would inject nanoparticles into patients that would improve the resolution of diagnostic imaging. When the realities associated with the use of nanoparticles in the landscape of the human immune system proved more challenging, many researchers realized the need to step back from possible clinical use to better understand the mechanisms that challenge nanoparticle use.

“This basic groundwork is absolutely necessary,” says Seyed Moein Moghimi, PhD, nanotechnologist at Durham University, UK, and the coauthor of the Simberg paper. “It’s essential that we learn to control the process of immune recognition so that we can bridge between the promise that nanoparticles demonstrate in the lab and their use with real patients in the real world.”

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

Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo by Fangfang Chen, Guankui Wang, James I. Griffin, Barbara Brenneman, Nirmal K. Banda, V. Michael Holers, Donald S. Backos, LinPing Wu, Seyed Moein Moghimi, & Dmitri Simberg. Nature Nanotechnology  (2016) doi:10.1038/nnano.2016.269 19 December 2016

This paper is behind a paywall.

I have a few previous postings about nanoparticles as drug delivery systems which have yet to fulfill their promise. There’s the April 27, 2016 posting (How many nanoparticle-based drugs does it take to kill a cancer tumour? More than 1%) and the Sept. 9, 2016 posting (Discovering how the liver prevents nanoparticles from reaching cancer cells).

Quantum dots cycling through the food chain

Rice University (Texas, US) researchers have published a study which follows quantum dot nanoparticles as they enter the water supply and are taken up by plant roots and leaves and eaten by caterpillars. From a Dec. 16, 2014 news item on ScienceDaily,

In one of the most comprehensive laboratory studies of its kind, Rice University scientists traced the uptake and accumulation of quantum dot nanoparticles from water to plant roots, plant leaves and leaf-eating caterpillars.

The study, one of the first to examine how nanoparticles move through human-relevant food chains, found that nanoparticle accumulation in both plants and animals varied significantly depending upon the type of surface coating applied to the particles. The research is available online in the American Chemical Society’s journal Environmental Science & Technology.

A Dec. 16, 2014 Rice University news release (also on EurekAlert), which originated the news item, provides insight into some of the issues being addressed with this research (Note: Links have been removed),

“With industrial use of nanoparticles on the rise, there are increasing questions about how they move through the environment and whether they may accumulate in high levels in plants and animals that people eat,” said study co-author Janet Braam, professor and chair of the Department of BioSciences at Rice.

Braam and colleagues studied the uptake of fluorescent quantum dots by Arabidopsis thaliana, an oft-studied plant species that is a relative of mustard, broccoli and kale. In particular, the team looked at how various surface coatings affected how quantum dots moved from roots to leaves as well as how the particles accumulated in leaves. The team also studied how quantum dots behaved when caterpillars called cabbage loopers (Trichoplusia ni) fed upon plant leaves containing quantum dots.

“The impact of nanoparticle uptake on plants themselves and on the herbivores that feed upon them is an open question,” said study first author Yeonjong Koo, a postdoctoral research associate in Braam’s lab. “Very little work has been done in this area, especially in terrestrial plants, which are the cornerstone of human food webs.”

Some toxins, like mercury and DDT, tend to accumulate in higher concentrations as they move up the food chain from plants to animals. It is unknown whether nanoparticles may also be subject to this process, known as biomagnification.

While there are hundreds of types of nanoparticles in use, Koo chose to study quantum dots, submicroscopic bits of semiconductors that glow brightly under ultraviolet light. The fluorescent particles — which contained cadmium, selenium, zinc and sulfur — could easily be measured and imaged in the tests. In addition, the team treated the surface of the quantum dots with three different polymer coatings — one positively charged, one negatively charged and one neutral.

“In industrial applications, nanoparticles are often coated with a polymer to increase solubility, improve stability, enhance properties and for other reasons,” said study co-author Pedro Alvarez, professor and chair of Rice’s Department of Civil and Environmental Engineering. “We expect surface coatings to play a significant role in whether and how nanomaterials may accumulate in food webs.”

Previous lab studies had suggested that the neutral coatings might cause the nanoparticles to aggregate and form clumps that were so large that they would not readily move from a plant’s roots to its leaves. The experiments bore this out. Of the three particle types, only those with charged coatings moved readily through the plants, and only the negatively charged particles avoided clumping altogether. The study also found that the type of coating impacted the plants’ ability to biodegrade, or break down, the quantum dots.

Koo and colleagues found caterpillars that fed on plants containing quantum dots gained less weight and grew more slowly than caterpillars that fed on untainted leaves. By examining the caterpillar’s excrement, the scientists were also able to estimate whether cadmium, selenium and intact quantum dots might be accumulating in the animals. Again, the coating played an important role.

“Our tests were not specifically designed to measure bioaccumulation in caterpillars, but the data we collected suggest that particles with positively charged coatings may accumulate in cells and pose a risk of bioaccumulation,” Koo said. “Based on our findings, more tests should be conducted to determine the extent of this risk under a broader set of ecological conditions.”

The researchers have a couple of images illustrating their work,

The buildup of fluorescent quantum dots in the leaves of Arabidopsis plants is apparent in this photograph of the plants under ultraviolet light. Credit: Y. Koo/Rice University

The buildup of fluorescent quantum dots in the leaves of Arabidopsis plants is apparent in this photograph of the plants under ultraviolet light. Credit: Y. Koo/Rice University

And, there’s a caterpillar,

Cabbage looper

Cabbage looper

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

Fluorescence Reports Intact Quantum Dot Uptake into Roots and Translocation to Leaves of Arabidopsis thaliana and Subsequent Ingestion by Insect Herbivores by Yeonjong Koo, Jing Wang, Qingbo Zhang, Huiguang Zhu, E. Wassim Chehab, Vicki L. Colvin, Pedro J. J. Alvarez, and Janet Braam. Environ. Sci. Technol., Just Accepted Manuscript DOI: 10.1021/es5050562 Publication Date (Web): December 1, 2014

Copyright © 2014 American Chemical Society

This paper is open access but you must be registered on the website.

One final thought about the research, it did take place in a laboratory environment and there doesn’t seem to have been any soil involved so the uptake can not be directly compared (as I understand matters) to the uptake characteristics where plant cultivation requires soil. This seems to have been a study involving hydroponic framing practices.