Nanoparticle-based drug is less harmful to fertility

20th May 2013

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From nanoparticles in new drugs and novel therapeutics, to imaging at the cellular level and understanding how bacteria work, nanotechnology is at the heart of many biotechnology advances.

A nanoparticle-based chemotherapy drug designed by Northwestern Medicine, part of Northwestern University in the USA, has been designed to be less toxic to the fertility of young women. It is the first cancer drug tested while in development for its effect on fertility using a novel in vitro test. Current tests of this sort are both time and resource intensive.

"Our overall goal is to create smart drugs that kill the cancer but don't cause sterility in young women," said Teresa Woodruff, a co-principal investigator of the study and chief of fertility preservation at Northwestern University Feinberg School of Medicine. A paper describing the work was published on March 20 in the journal PLOS ONE.

The scientists hope their integration of drug development and reproductive toxicity testing is the beginning of a new era in which chemotherapy drugs are developed with an eye on their fertotoxity (fertility toxicity).

As cancer survival rates increase, the effect of cancer treatments on fertility is critically important to many young patients.

The new initiative involves the chemotherapy drug arsenic trioxide being packed into a very tiny Trojan horse called a nanobin. This consists of nano-size crystalline arsenic particles densely packed and encapsulated in a fat bubble.

The fat bubble, a liposome, disguises the deadly cargo - half a million drug molecules.

The fat bubble is hundreds of times smaller than the average human cell. It is the perfect size to pass through holes in the leaky blood vessels that rapidly grow to feed tumours.

The local environment of the tumour is often slightly acidic; it is this acid that causes the nanobin to release its drug cargo and deliver a dose of arsenic where it is needed.

The scientists show that this approach to packaging and delivering the active drug has the desired effect on the tumour cells while preventing damage to ovarian tissue, follicles, or eggs.

Cancer theranostics

Researchers based in the School of Medicine (Institute of Molecular Medicine) and the Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN) at Trinity College Dublin (TCD) are working to develop new nanoscale materials, with a particular focus on the new device and sensor technology, biotechnology and medical technology sectors.

Research fellow Adriele Prina-Mello focuses on functional biomaterials, diagnostic devices, and multifunctional nanomaterials for theranostic (a combination of diagnostics and therapy) solutions in the treatment of cancer.

Particle size

Fundamental in this work is the understanding of particle size, size distribution and of hydrodynamic response of nanoparticles dependent on their degree of aggregation.

Additionally, being able to measure zeta potential and track particle behaviour in viscous or physiologically relevant media informs the increasing characterisation demands of the nanomedicine community (Fig. 1).

Here pressure is on tools providers to offer the most comprehensive and low volume testing of sometimes very expensive samples.

"Our main motivation for such levels of characterisation is determined by the potential use, applicability, and safety aspect linked to nanosize materials.

"This allows for further modification of the particle surface coating/moieties in order to get closer to the suitable candidate for diagnostic, monitoring and therapeutic application for nanomedicine and or biomedical research and also clinical translation," he says.

To help achieve this, he uses NanoSight's nanoparticle tracking analysis (NTA).This detects and visualises populations of nanoparticles in liquids down to 10 nm, dependent on material, and measures the size of each particle from direct observations of diffusion.

Additionally, NanoSight measures concentration and a fluorescence mode differentiates suitably-labelled particles within complex background suspensions.

Zeta potential measurements are similarly particle-specific. It is this particle-by-particle methodology that takes NTA beyond traditional light scattering and other ensemble techniques in providing high-resolution particle size distributions and validates data with information-rich video files of the particles moving under Brownian motion.

"NanoSight allows for the identification of heterogeneity in particle size, poly-dispersity and counting with simultaneous zeta potential measurement. Furthermore, the use of small sample volumes compared to other techniques allows for cost effective, daily and routine characterisation," added Prina-Mello.

Regenerative medicine

The promise of repairing damaged hearts through regenerative medicine - infusing stem cells into the heart in the hope that these cells will replace worn out or damaged tissue - has yet to meet with clinical success. At large part of this failure is thought to be as a result of faulty initial cell placement. But a highly sensitive visualisation technique developed by Stanford University School of Medicine scientists may help overcome that hurdle.

Ultrasound tracking

The new technique employs a trick that marks stem cells so they can be tracked by standard ultrasound as they are squeezed out of the placement needle, allowing their more precise guidance to the spot they are intended to go, and then monitored by magnetic-resonance imaging (MRI) for weeks afterward.

To make this possible, the scientists designed and produced a specialised imaging agent in the form of nanoparticles whose diameters clustered in the vicinity of just below one-third of a micron - less than one-three-thousandth the width of a human hair, or one-thirtieth the diameter of a red blood cell.

The acoustic characteristics of the nanoparticles' chief constituent, silica, allowed them to be visualised by ultrasound; they were also doped with the rare-earth element gadolinium, an MRI contrast agent.

The Stanford group showed that mesenchymal stem cells - a class of cells often used in heart-regeneration research - were able to ingest and store the nanoparticles without losing any of their ability to survive, replicate and differentiate into living heart cells.

Upon infusing the imaging-agent-loaded stem cells from mice, pigs or humans into the hearts of healthy mice, the scientists could watch the cells via ultrasound after they left the needle tip and, therefore, better direct them to the targeted area of the heart wall. Two weeks later, the team could still get a strong MRI signal from the cells.

The technique is described in a study published on 20 March in Science Translational Medicine.

Testing the new imaging method in humans is probably three to five years off, say the team.

Microbial nanowires

When researchers at the University of Massachusetts Amherst led by microbiologist Derek Lovley discovered that the bacterium Geobacter sulfurreducens conducts electricity very effectively along metallic-like 'microbial nanowires', it was a shock to conventional biochemical wisdom.

"It goes against all that we are taught about biological electron transfer, which usually involves electrons hopping from one molecule to another," Lovley says.

"So it wasn't enough for us to demonstrate that the microbial nanowires are conductive and to show with physics the conduction mechanism, we had to determine the impact of this conductivity on the biology."

"We have now identified key components that make these hair-like pili we call nanowires conductive and have demonstrated their importance in the biological electron transport. This time we relied more on genetics. I think most biologists are more comfortable with genetics rather than physics," Lovley adds.

The ability of protein filaments to conduct electrons in this way not only has ramifications for scientists' basic understanding of natural microbial processes but practical implications for environmental clean-up and the development of renewable energy sources as well, he adds.

Cleaning groundwater

Lovley's UMass Amherst lab has already been working with US federal agencies and industry to use Geobacter to clean up groundwater contaminated with radioactive metals or petroleum and to power electronic monitoring devices with current generated by the microbe.

His group has also recently shown that Geobacter uses its nanowires to feed electrons to other microorganisms that can produce methane gas.

This is an important step in the conversion of organic wastes to methane, which can then be burned to produce electricity.

A nono-sclae solution to image cellular processes

European scientists are in the process of developing a novel sensing principle at the nano-scale level which will allow cellular processes - particularly those implicated in cancer - to be monitored much more closely.

The EU-funded Dinamo project is developing biocompatible fluorescent nanodiamond particles (fNDs) for imaging biomolecular interactions in cells. This approach has potential applications in cancer research for detecting the intracellular processes leading to tumour development.

Important properties of the nanoparticles include their capacity to be functionalised at the cell surface and to act as carriers for targeted drug delivery.

The Dinamo consortium has developed these nanoparticles from cost-effective commercial high-pressure high-temperature (HPHT) diamond technology.

Following optimisation of the fND production and fluorescence attachment processes, scientists have generated biocompatible particles that could be visualised by confocal microscopy.

Additionally, various chemistries have been explored for the functionalisation of fNDs. Of particular interest so far are fluorinated particles and those that could be used to detect DNA.

An important achievement of the project is the application of fNDs for monitoring cellular processes. This is achieved through fluorescent fNDs coupled to specific probes that interact with various biomolecules. This leads to fluorescence resonance energy transfer (FRET), which is in turn exploited for intracellular detection.

A successful application of this method consisted of the targeting of fNDs to cancer breast cells.

The Dinamo intracellular biosensors, operating at the cell or the molecular level, could attract a lot of interest with potentially important applications in the fields of cancer diagnostics and therapy.

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