New Cancer Research – Converting Cancer Cells to Fat Cells to Stop Cancer’s Spread


A method for fooling breast cancer cells into fat cells has been discovered by researchers from the University of Basel.

The team were able to transform EMT-derived breast cancer cells into fat cells in a mouse model of the disease – preventing the formation of metastases. The proof-of-concept study was published in the journal Cancer Cell. 

Malignant cells can rapidly respond and adapt to changing microenvironmental conditions, by reactivating a cellular process called epithelial-mesenchymal transition (EMT), enabling them to alter their molecular properties and transdifferentiate into a different type of cell (cellular plasticity).

Senior author of the study Gerhard Christofori, professor of biochemistry at the University of Basel, commented in a recent press release: “The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating.”

“As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells,” he explained.

Epithelial-mesenchymal transition and cancer 

Cancer cells can exploit EMT – a process that is usually associated with the development of organs during embryogenesis – in order to migrate away from the primary tumor and form secondary metastases. Cellular plasticity is linked to cancer survival, invasion, tumor heterogeneity and resistance to both chemo and targeted therapies. In addition, EMT and the inverse process termed mesenchymal-epithelial transition (MET) both play a role in a cancer cell’s ability to metastasize.

Using mouse models of both murine and human breast cancer the team investigated whether they could therapeutically target cancer cells during the process of EMT – whilst the cells are in a highly plastic state. When the mice were administered Rosiglitazone in combination with MEK inhibitors it provoked the transformation of the cancer cells into post-mitotic and functional adipocytes (fat cells). In addition, primary tumor growth was suppressed and metastasis was prevented. 

Cancer cells marked in green and a fat cell marked in red on the surface of a tumor (left). After treatment (right), three former cancer cells have been converted into fat cells. The combined marking in green and red causes them to appear dark yellow. Credit: University of Basel, Department of Biomedicine

Christofori highlights the two major findings in the study: 

“Firstly, we demonstrate that breast cancer cells that undergo an EMT and thus become malignant, metastatic and therapy-resistant, exhibit a high degree of stemness, also referred to as plasticity. It is thus possible to convert these malignant cells into other cell types, as shown here by a conversion to adipocytes.”

“Secondly, the conversion of malignant breast cancer cells into adipocytes not only changes their differentiation status but also represses their invasive properties and thus metastasis formation and their proliferation. Note that adipocytes do not proliferate anymore, they are called ‘post-mitotic’, hence the therapeutic effect.”

Since both drugs used in the preclinical study were FDA-approved the team are hopeful that it may be possible to translate this therapeutic approach to the clinic. 

“Since in patients this approach could only be tested in combination with conventional chemotherapy, the next steps will be to assess in mouse models of breast cancer whether and how this trans-differentiation therapy approach synergizes with conventional chemotherapy. In addition, we will test whether the approach is also applicable to other cancer types. These studies will be continued in our laboratories in the near future.”

Journal Reference: Ronen et al. Gain Fat–Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis. Cancer Cell. (2019). Available at: https://www.cell.com/cancer-cell/fulltext/S1535-6108(18)30573-7 

Gerhard Christofori was speaking to Laura Elizabeth Lansdowne, Science Writer for Technology Networks

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Artificial synapses made from Zinc-Oxide nanowires – ideal candidate for use in building bioinspired “neuromorphic” processors


Image captured by an electron microscope of a single nanowire memristor (highlighted in colour to distinguish it from other nanowires in the background image). Blue: silver electrode, orange: nanowire, yellow: platinum electrode. Blue bubbles are dispersed over the nanowire. They are made up of silver ions and form a bridge between the electrodes which increases the resistance. Credit: Forschungszentrum Jülich

Scientists from Jülich together with colleagues from Aachen and Turin have produced a memristive element made from nanowires that functions in much the same way as a biological nerve cell.

The component is able to save and process information, as well as receive numerous signals in parallel. The resistive switching cell made from oxide crystal nanowires is thus an ideal candidate for use in building bioinspired “neuromorphic” processors, able to take over the diverse functions of biological synapses and neurons.

Computers have learned a lot in recent years. Thanks to rapid progress in artificial intelligence they are now able to drive cars, translate texts, defeat world champions at chess, and much more besides.
In doing so, one of the greatest challenges lies in the attempt to artificially reproduce the signal processing in the human brain.
In , data are stored and processed to a high degree in parallel. Traditional computers, on the other hand, rapidly work through tasks in succession and clearly distinguish between the storing and processing of information.
As a rule, neural networks can only be simulated in a very cumbersome and inefficient way using conventional hardware.

Systems with neuromorphic chips that imitate the way the  works offer significant advantages. These types of computers work in a decentralised way, having at their disposal a multitude of processors, which, like neurons in the brain, are connected to each other by networks. If a processor breaks down, another can take over its function.

What is more, just like in the brain, where practice leads to improved signal transfer, a bioinspired processor should have the capacity to learn.

“With today’s semiconductor technology, these functions are to some extent already achievable. These systems are, however, suitable for particular applications and require a lot of space and energy,” says Dr. Ilia Valov from Forschungszentrum Jülich. “Our nanowire devices made from zinc oxide crystals can inherently process and even store information, and are extremely small and energy efficient.”

For years, memristive cells have been ascribed the best chances of taking over the function of neurons and synapses in bioinspired computers. They alter their electrical resistance depending on the intensity and direction of the electric current flowing through them.

In contrast to conventional transistors, their last resistance value remains intact even when the electric current is switched off. Memristors are thus fundamentally capable of learning.

In order to create these properties, scientists at Forschungszentrum Jülich and RWTH Aachen University used a single zinc oxide nanowire, produced by their colleagues from the polytechnic university in Turin. Measuring approximately one 10,000th of a millimeter in size, this type of nanowire is over 1,000 times thinner than a human hair. The resulting memristive component not only takes up a tiny amount of space, but is also able to switch much faster than flash memory.

Nanowires offer promising novel physical properties compared to other solids and are used among other things in the development of new types of solar cells, sensors, batteries and computer chips. Their manufacture is comparatively simple. Nanowires result from the evaporation deposition of specified materials onto a suitable substrate, where they practically grow of their own accord.

In order to create a functioning cell, both ends of the nanowire must be attached to suitable metals, in this case platinum and silver. The metals function as electrodes, and in addition, release ions triggered by an appropriate electric current. The metal ions are able to spread over the surface of the wire and build a bridge to alter its conductivity.

Components made from single are, however, still too isolated to be of practical use in chips. Consequently, the next step being planned by the Jülich and Turin researchers is to produce and study a memristive element, composed of a larger, relatively easy to generate group of several hundred nanowires offering more exciting functionalities.

More information: Gianluca Milano et al, Self-limited single nanowire systems combining all-in-one memristive and neuromorphic functionalities, Nature Communications (2018).  DOI: 10.1038/s41467-018-07330-7

Provided by Forschungszentrum Juelich

Explore further: Scientists create a prototype neural network based on memristors

Researchers Develop a universal DNA Nano-signature for early cancer detection – University of Queensland


Killer T cells surround cancer cell. Credit: NIH

Researchers from the University of Queensland’s Australian Institute for Bioengineering and Nanotechnology (AIBN) have discovered a unique nano-scaled DNA signature that appears to be common to all cancers.

Based on this discovery, the team has developed a  that enables  to be quickly and easily detected from any tissue type, e.g. blood or biopsy.

The study, which was supported by a grant from the National Breast Cancer Foundation and is published in the journal Nature Communications, reveals new insight about how epigenetic reprogramming in cancer regulates the physical and chemical properties of DNA and could lead to an entirely new approach to point-of-care diagnostics.

“Because cancer is an extremely complicated and variable disease, it has been difficult to find a simple signature common to all cancers, yet distinct from healthy ,” explains AIBN researcher Dr. Abu Sina.

To address this, Dr. Sina and Dr. Laura Carrascosa, who are working with Professor Matt Trau at AIBN, focussed on something called circulating free DNA.

Like healthy cells,  are always in the process of dying and renewing. When they die, they essentially explode and release their cargo, including DNA, which then circulates.

“There’s been a big hunt to find whether there is some distinct DNA signature that is just in the cancer and not in the rest of the body,” says Dr. Carrascosa.

So they examined epigenetic patterns on the genomes of cancer cells and healthy cells. In other words, they looked for patterns of molecules, called methyl groups, which decorate the DNA. These methyl groups are important to cell function because they serve as signals that control which genes are turned on and off at any given time.

In healthy cells, these methyl groups are spread out across the genome. However, the AIBN team discovered that the genome of a cancer cell is essentially barren except for intense clusters of methyl groups at very specific locations.

This unique signature—which they dubbed the cancer “methylscape”, for methylation landscape—appeared in every type of breast cancer they examined and appeared in other forms of cancer, too, including prostate cancer, colorectal cancer and lymphoma.

“Virtually every piece of cancerous DNA we examined had this highly predictable pattern,” says Professor Trau.

He says that if you think of a cell as a hard-drive, then the new findings suggest that cancer needs certain genetic programmes or apps in order to run.

“It seems to be a general feature for all cancer,” he says. “It’s a startling discovery.”

They also discovered that, when placed in solution, those intense clusters of  cause cancer DNA fragments to fold up into three-dimensional nanostructures that really like to stick to gold.

Taking advantage of this, the researchers designed an assay which uses gold nanoparticles that instantly change colour depending on whether or not these 3-D nanostructures of cancer DNA are present.

“This happens in one drop of fluid,” says Trau. “You can detect it by eye, it’s as simple as that.”

The technology has also been adapted for electrochemical systems, which allows inexpensive and portable detection that could eventually be performed using a mobile phone.

So far they’ve tested the new technology on 200 samples across different types of human cancers, and . In some cases, the accuracy of cancer detection runs as high as 90%.

“It works for tissue derived genomic DNA and blood derived circulating free DNA,” says Sina. “This new discovery could be a game-changer in the field of point of care cancer diagnostics.” It’s not perfect yet, but it’s a promising start and will only get better with time, says the team.

“We certainly don’t know yet whether it’s the Holy Grail or not for all cancer diagnostics,” says Trau, “but it looks really interesting as an incredibly simple universal marker of cancer, and as a very accessible and inexpensive technology that does not require complicated lab based equipment like DNA sequencing.”

More information: Abu Ali Ibn Sina et al, Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker, Nature Communications(2018).  DOI: 10.1038/s41467-018-07214-w

Provided by University of Queensland

Explore further: New cancer monitoring technology worth its weight in gold

How nanotechnology research could cure cancer – genetic diseases


Genetic diseases may soon be a thing of the past thanks to nanotechnology, which employs tiny particles to manipulate cells and change our DNA.

Here is how cancer treatment often runs today: a patient develops an aggressive tumor. A surgeon operates to remove the tumor, but a few cancer cells remain, hiding in the body. Chemotherapy is administered, weakening both patient and cancer cells. But the cancer does not die; it comes back and eventually kills the patient.

Now imagine another scenario. After surgery, strands of DNA anchored in tiny gold particles are injected into the affected area. The DNA strands bind to the tumor cells, killing them directly, without the help of chemo. The healthy cells around the tumor cells, which don’t express the tumor gene, are untouched.

Just like that, all the tumor cell stragglers are rendered harmless, corrected on the genetic level. The patient is cured, and without having to endure months of chemotherapy and its brutal side effects: hair loss, nausea and extreme weakness.

The future of medicine won’t focus on treating the symptoms of a disease, according to reseachers: it will focus on curing it at the genetic level.

Nanotechnology, the science of working with particles that are one billionth of a meter, is enabling scientists to change gene expression on the cellular level, potentially curing a host of diseases.

“Nanotechnology medical developments over the coming years will have a wide variety of uses and could potentially save a great number of lives,” says Eleonore Pauwels, senior associate and scholar at the Wilson Center, an interdisciplinary policy research center.

The science of using nanoparticles got its start with a lecture by theoretical physicist Richard Feynman in 1959, but because of the technical challenges, it is only in the past 10 years or so that the technology has really taken off for practical medical applications.

Figuring out how to consistently create the right nanoparticle, get it into the right tissue, ensure it is not degraded and does what it was programmed to do, took some time.

The science of nanotechnology depends on the fact that when things get super small, they function differently. Protein, for example, is a naturally occurring nanoparticle. A single protein molecule is a very different entity than a human being, which is made up of many protein molecules.

Gold, which is used often in medicine, is red when broken down into tiny particles. That microscopic bright red color has been used for centuries to give red stained glass its color.

“Because of their small size, engineered nanomaterials have unique properties that do not exist at the larger scale: increased surface area, charge, reactivity and other physicochemical properties, all of which may affect how nanomaterials interact with biological entities, like cells,” says Sara Brenner, assistant professor of nanobioscience at SUNY Polytechnic Institute.

Scientists are learning to take advantage of those properties to create new treatments. One of the most powerful examples uses DNA, says Chad Mirkin, a professor at Northwestern University and director of the International Institute for Nanotechnology.

DNA is rod shaped and normally would not be able to enter cells, which have developed protection against entry from foreign DNA segments.

But by using nanotechnology, many little snippets of DNA can be attached to a tiny, round synthetic core. The receptors on cells that would block rod shaped DNA do not recognize the tiny spheres of DNA and allow it to enter.

Using that property, a whole new class of treatments for genetic diseases is being developed.

By being able to insert DNA into existing cells, scientists can “attack disease at its genetic root and turn off receptors that regulate how a cell functions, stopping a disease pathway in its tracks,” explains Mirkin.

Right now, most of the research into developing therapies using spheres of DNA is focused on disease of the liver, says Mirkin, as anything a person takes in is going to be processed in the liver. Another area of research into nanotech treatments is the skin, as the treatment can be applied topically, making it easy to target one area.

“Potential applications are virtually endless,” explains Brenner. “But some areas of investigation right now for gene therapy are cancer, diabetes, AIDS, cystic fibrosis and heart disease.”

As research into using nanoparticles advances, scientists hope to be able to not just turn off specific signals in cells, but also eventually insert genes to correct for defects and cure more complex diseases.

Called gene therapy, it would involve inserting larger fragments of DNA into cells that have faulty DNA. For example, cystic fibrosis is caused by a defective gene called CFTR. If scientists can figure out a way to get a non-defective copy of the gene into the cells and correct it, they could cure the disease.

“Approximately 4,000 diseases have been found to have a genetic component and are therefore potential targets for gene therapy,” according to Brenner.

While nanotechnology has the potential to revolutionize medicine and how we view treatment of diseases, there are still kinks to work out.

Some of the challenges with nanotechnology include how to get nanoparticles into the right cells and tissues, and how to get them into the cells safely without the nanoparticles degrading.

Nanotechnology is still in its infancy, however. It’s only recently that we were able to produce microscopes that allowed us to see and manipulate nanoparticles. 

Research requires bringing together a number of disciplines like chemistry, biomedical engineering, biology and physics. But pharmaceutical companies have already begun work on creating treatments using nanotech, and many are in various stages of development now. “It’s not a pipe dream,” says Mirkin. Being able to cure genetic diseases of all kinds is on the horizon.

University of Cambridge: Researchers to target hard-to-treat cancers


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A £10 million interdisciplinary collaboration is to target the most challenging of cancers using nanomedicine.

“We are going to pierce through the body’s natural barriers and deliver anti-cancer drugs to the heart of the tumour.” – George Malliaras

While the survival rate for most cancers has doubled over the past 40 years, some cancers such as those of the pancreas, brain, lung and oesophagus still have low survival rates.

Such cancers are now the target of an Interdisciplinary Research Collaboration (IRC) led by the University of Cambridge and involving researchers from Imperial College London, University College London and the Universities of Glasgow and Birmingham.

“Some cancers are difficult to remove by surgery and highly invasive, and they are also hard to treat because drugs often cannot reach them at high enough concentration,” explains George Malliaras, Prince Philip Professor of Technology in Cambridge’s Department of Engineering, who leads the IRC. “Pancreatic tumour cells, for instance, are protected by dense stromal tissue, and tumours of the central nervous system by the blood-brain barrier.”

The aim of the project, which is funded for six years by the Engineering and Physical Sciences Research Council, is to develop an array of new delivery technologies that can deliver almost any drug to any tumour in a large enough concentration to kill the cancerous cells.

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Chemists, engineers, material scientists and pharmacologists will focus on developing particles, injectable gels and implantable devices to deliver the drugs. Cancer scientists and clinicians from the Cancer Research UK Cambridge Centre and partner sites will devise and carry out clinical trials. Experts in innovative manufacturing technologies will ensure the devices are able to be manufactured and robust enough to withstand surgical manipulation.

One technology the team will examine is the ability of advanced materials to self-assemble and entrap drugs inside metal-organic frameworks. These structures can carry enormous amounts of drugs, and be tuned both to target the tumour and to release the drug at an optimal rate.

“We are going to pierce through the body’s natural barriers,” says Malliaras, “and deliver anti-cancer drugs to the heart of the tumour.”

Dr Su Metcalfe, a member of George Malliaras’s team and who is already using NanoBioMed to treat Multuple Sclerosis, added “the power of nanotechnology to synergise with potent anti-cancer drugs will be profound and the award will speed delivery to patients.”

Read Genesis Nanotech News Online: Our Latest Edition


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Discovery: How groups of cells are able to build our tissues and organs while we are still embryos – Understanding ‘how’ may help us treat Cancer more effectively


 

stemcell-collage2-feature-1170x400

Ever wondered how groups of cells managed to build your tissues and organs while you were just an embryo?

Using state-of-the-art techniques he developed, UC Santa Barbara researcher Otger Campàs and his group have cracked this longstanding mystery, revealing the astonishing inner-workings of how embryos are physically constructed.

Not only does it bring a century-old hypothesis into the modern age, the study and its techniques provide the researchers a foundation to study other questions key to human health, such as how cancers form and spread or how to engineer organs.

“In a nutshell, we discovered a fundamental physical mechanism that cells use to mold embryonic tissues into their functional 3D shapes,” said Campàs, a professor of mechanical engineering in UCSB’s College of Engineering who holds the Duncan & Suzanne Mellichamp Chair in Systems Biology. His group investigates how living systems self organize to build the remarkable structures and shapes found in nature.

cell biology UC Santa B download

Cells coordinate by exchanging biochemical signals, but they also hold to and push on each other to build the body structures we need to live, such as the eyes, lungs and heart. And, as it turns out, sculpting the embryo is not far from glass molding or 3D printing. In their new work,”A fluid-to-solid jamming transition underlies vertebrate body axis elongation,” published in the journal Nature, Campàs and colleagues reveal that cell collectives switch from fluid to solid states in a controlled manner to build the vertebrate embryo, in a way similar to how we mold glass into vases or 3D print our favorite items. Or, if you like, we 3D print ourselves, from the inside.

Most objects begin as fluids. From metallic structures to gelatin desserts, their shape is made by pouring the molten original materials into molds, then cooling them to get the solid objects we use.

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A fluid-to-solid jamming transition underlies vertebrate body axis elongation

As in a Chihuly glass sculpture, made by carefully melting portions of glass to slowly reshape it into life, cells in certain regions of the embryo are more active and ‘melt’ the tissue into a fluid state that can be restructured. Once done, cells ‘cool down’ to settle the tissue shape, Campàs explained.

“The transition from fluid to solid tissue states that we observed is known in physics as ‘jamming’,” Campàs said. “Jamming transitions are a very general phenomena that happens when particles in disordered systems, such as foams, emulsions or glasses, are forced together or cooled down.”

This discovery was enabled by techniques previously developed by Campàs and his group to measure the forces between cells inside embryos, and also to exert miniscule forces on the cells as they build tissues and organs. Using zebrafish embryos, favored for their optical transparency but developing much like their human counterparts, the researchers placed tiny droplets of a specially engineered ferromagnetic fluid between the cells of the growing tissue.

The spherical droplets deform as the cells around them push and pull, allowing researchers to see the forces that cells apply on each other. And, by making these droplets magnetic, they also could exert tiny stresses on surrounding cells to see how the tissue would respond.

“We were able to measure physical quantities that couldn’t be measured before, due to the challenge of inserting miniaturized probes in tiny developing embryos,” said postdoctoral fellow Alessandro Mongera, who is the lead author of the paper.

“Zebrafish, like other vertebrates, start off from a largely shapeless bunch of cells and need to transform the body into an elongated shape, with the head at one end and tail at the other,” Campàs said.

UC Santa B II Lemaire

The physical reorganization of the cells behind this process had always been something of a mystery. Surprisingly, researchers found that the cell collectives making the tissue were physically like a foam (yes, as in beer froth) that jammed during development to ‘freeze’ the tissue architecture and set its shape.

These observations confirm a remarkable intuition made by Victorian-era Scottish mathematician D’Arcy Thompson 100 years ago in his seminal work “On Growth and Form.”

Darcy Thompson Ms48534_13Read About: D’Arcy Wentworth Thompson

“He was convinced that some of the physical mechanisms that give shapes to inert materials were also at play to shape living organisms. Remarkably, he compared groups of cells to foams and even the shaping of cells and tissues to glassblowing,” Campàs said. A century ago, there were no instruments that could directly test the ideas Thompson proposed, Campàs added, though Thompson’s work continues to be cited to this day.

The new Nature paper also provides a jumping-off point from which the Campàs Group researchers can begin to address other processes of embryonic development and related fields, such as how tumors physically invade surrounding tissues and how to engineer organs with specific 3D shapes.

“One of the hallmarks of cancer is the transition between two different tissue architectures. This transition can in principle be explained as an anomalous switch from a solid-like to a fluid-like tissue state,” Mongera explained. “The present study can help elucidate the mechanisms underlying this switch and highlight some of the potential druggable targets to hinder it.”

Alessandro Mongera, Payam Rowghanian, Hannah J. Gustafson, Elijah Shelton, David A. Kealhofer, Emmet K. Carn, Friedhelm Serwane, Adam A. Lucio, James Giammona & Otger Campàs

Nature (2018)

DOI: 10.1038%2Fs41586-018-0479-2

Using PEG Nanotubes as Drug Delivery Systems


This article is based around a talk given by Ben Newland from Cardiff University, UK, at the NANOMED conference hosted by the NANOSMAT Society in Manchester on the 26-28th June 2018. In his talk, Ben talks about how he uses soft and flexible poly(ethylene glycol) (PEG) nanotubes to provide a sustained and localized delivery of therapeutic drugs.

Link to Original AZ Nano Article

Dr. Newland, a lecturer at Cardiff University, has been dealing with PEG nanotubes for approximately ten years after they came about as a side project to his other research. It should be noted that these nanotubes are not like carbon nanotubes, in that they are not electronically confined in 2 dimensions (i.e., a 1D material), nor are they carbon nanotubes functionalized with PEG at the surface. They are strictly hollow cylinders that are made entirely of PEG, and only bear the name nanotube because that is what they most closely resemble (without the capped end).

The research came about after previously working on carbon nanopipes, where a porous template was used to create hollow carbon nanostructures; in conjunction with another area of Ben’s research, which looks at using cyclized knotted polymers as drug delivery agents. To combine these areas, Ben poured a polymer solution (with a photo-initiator) into a porous template and shone UV light on it, which in turn cross-linked the polymers and created tube-like structures. This was the starting point of this research.

Since starting the research, Ben has incrementally polished the process and now produces polymer nanotubes which are 200 nm in diameter and up to 60 micrometers in length. Cyclized knot polymers are required to construct these nanotubes and can be made with commercially available PEG materials that contain di-vinyl groups. Different polymers have been trialed, and the PEG nanotubes were found to be the softest.

The possibility of using these for drug delivery applications came about after they were found to uptake rhodamine (a tracer dye). On the process side, Ben’s research team discovered that when the templates are dissolved (with sodium hydroxide) to leave just the nanotubes, the process breaks some of the ester bonds and creates an abundance of negative charges on the surface of the nanotubes.

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The anti-cancer drug, doxorubicin, was also found to be actively uptaken out of solution by the negatively charged nanotubes, and it is a straightforward procedure to determine the uptake and release of doxorubicin as it is intrinsically fluorescent and has a colored appearance. Ben’s work has led him to look at the release of doxorubicin from the nanotubes and found that they release most of the drug payload within the first five days, but there is a sustained delivery of 2-3 micrograms over 35 to 40 days. Some of the doxorubicin was found to stay in the nanotube, so while it is not perfect at the moment regarding the release, these nanotubes do show a lot of promise as new material as drug delivery agents.

One aspect of any delivery agent is that it needs to be biocompatible and low in cytotoxicity. In-vitro cell viability tests have been performed for these nanotubes at varying concentrations, and up to the point where the nanotubes are completely covering the cell. The results showed that even at the end (fully covered cells) the nanotubes did not kill the cell. Other cell viability studies on drug-loaded nanotubes found that the release of the drugs was killing the cells, and thus confirmed its position as a potential drug delivery agent.

The research has been taken further and has been tested on metastatic breast cancer cells in mice in conjunction with researchers from the University of Strathclyde. These studies have shown that the doxorubicin-loaded nanotubes reduced the tumor growth and reduced metastasis (the creation of secondary tumors away from the primary tumor site) in the mice.

Future studies will look at the cytotoxicity of the polymer nanotubes in-vivo and will look at how the drug release profile can be improved. Other areas will look at varying the size of the nanotubes, changing the chain length to alter the stiffness and entanglement of the nanotubes and looking at the effects of functionalizing the nanotubes with different nanoparticles.

Sources:

• NANOMED 2018: http://www.nanomed.uk.com/

• Ben Newland: http://www.newlandresearch.net/

Exploring Nanotechnology to Enhance Treatment, Diagnosis & Drug Discovery


What can you do with a liberal arts degree? Native New Yorker Daniel Heller, PhD, majored in history, added in some basic science courses, and started his working life as a middle school science teacher. After taking some additional chemistry coursework during non-teaching hours, Heller parlayed it all into a doctorate in chemistry from the University of Illinois.

Today he is a biomedical engineer at Memorial Sloan Kettering Cancer Center (MSKCC), New York City, where his Cancer Nanomedicine Laboratory team invents new technologies that can assist health care in helping human kind.

Heller chuckled when mentioning his circuitous life path and some of the stops along the way: performing as a wizard at a Renaissance Fair (“…liquid nitrogen turns into a pretty impressive potion…”), trying to master the Argentine tango, appreciating his brother’s equally non-traditional path as a drummer in heavy metal bands, and happily settling into married life with his wife who is a primary care physician.

In recent years, he has also managed to garner solid industry credentials in the form of awards, including the NSF CAREER Award (2018), Pershing Square Sohn Prize for Young Innovators in Cancer Research (2017), and NIH Director’s New Innovator Award (2012), among others.

“I like inventing,” Heller stated simply. “In my lab, we often think of ourselves as biomedical engineers whose primary goal is invent new technologies to improve cancer research, diagnosis, and therapy.

Only when I arrived at MSKCC did I realize how far that is from the way biologists think. I was trained that our goal is to invent, and to learn new science along the way, while a biologist’s goal is to understand nature and develop tools mainly as a means to an end. I didn’t have a huge biomedical background coming in, but by talking to the people around me at Sloan Kettering and Weill Cornell Medicine [where he is an Assistant Professor], I have learned a great deal.”

As detailed on his laboratory website (www.mskcc.org/research-areas/labs/daniel-heller), Heller and team are “… developing nanomedicines to target precision agents to disease sites, including to metastatic cancers. We are also addressing the problem of the early detection of cancer and other diseases by building implantable nanosensors.

To enable the discovery of new medicines, we also are inventing new nanosensors and imaging tools to accelerate drug development and biomedical research.”

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Nanoparticles in Treatment

Heller told Oncology Times that it all begins with interaction and collaboration. “We are lucky because we get to dig deep with the clinicians, clinician/scientists, and biologists to understand exactly what might be wrong with a particular mode of therapy,” said Heller of his development process. “An oncologist might talk to us about a drug or class of therapies that have particular problems and specific side effects, such as dose-limiting toxicity that prevents people from getting enough of a therapy to adequately inhibit the target in the tumor.”

He added that problems often stem from the fact that a drug negatively affects tissue that is not part of the tumor. “Can we avoid that one vulnerable tissue that will really mess up the use of this drug for treating the tumor? Can we prevent the drug from getting into that tissue?” asked Heller rhetorically. Clearly, he believes it is possible with the help of nanoparticles.

He noted that people erroneously think of nanoparticles as being “the smallest of the small.” But small molecule drugs, and even protein drugs, are much smaller than nanoparticles. Most drugs can diffuse all over the body. “But if we put the drug into a larger nanoparticle, we can keep it from spraying out over all the tissues,” detailed Heller.

His team also must consider how to deliver the nanoparticle containing the drug to a precise location in the tumor site, and whether there is a target that can lead it to that tumor site. “Most of the targets we are looking for are not on the tumor cells themselves, but on the blood vessels that are feeding the tumor,” said Heller. “Our targets are not drug targets, but rather gateways to the tumor, molecules on blood vessels in tumors sites, or sites of inflammation. Then we make sure that the nanoparticle has a molecule on the outside of it that can stick to those targets.”

The research takes the engineering team into the realms of vascular biology, vascular transport, and an understanding of how materials can get across the blood, across the blood/brain barrier, across the tumor barrier. “We are also exploring signaling pathways,” said Heller. “When trying to deliver a kinase inhibitor, for example, we must consider the target we are hitting, where else that target is in the body, and if there any other off-target proteins elsewhere in the body that the drug will hit. We also have to think about resistance mechanisms and compensatory pathways. So as a team we have been learning a lot of physiology.”

Heller says his 5-year-old laboratory contains requisite benches, a tissue culture room, and a studio equipped with lasers and optics for work on sensors. In the basement reside the all-important mice, critical to preclinical development and testing. Looking at target proteins in the body of a mouse, the team is able to determine if a drug encased in a nanoparticle hits the target, if it works better in a nanoparticle, and if it has the same side effects.

The eventual goal is to translate this understanding and these emerging technologies to clinical use and human patients. But it is a long row to hoe. “Once a technology is developed, it must go through the full ‘investigational new drug’ FDA process,” Heller lamented. “Even if a known compound is inside the particle, the whole particle is treated as a new drug.

That means we can’t just give it to clinicians to trial in patients; first the FDA must allow us to start a clinical trial.” Though regulatory delays are a frustration, the researcher said enthusiasm remains high because the potential of the new technologies is so powerful.

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Nanoparticles in Detection

The Cancer Nanomedicine Laboratory also maintains an interest in developing innovative approaches to cancer detection that is “… easier and more predictive. We found that we can detect some cancers earlier by measuring certain biomarkers in a person without having to take blood or biofluids to do it,” said Heller.

Instead, a tiny sensor made of carbon nanotubes is inserted inside a person. The nanotubes give off infrared light that can pass through tissues. “We can implant nanomaterial in a body, shoot light into it from outside the body, and then get a reading externally,” detailed Heller. “These nanomaterials are very sensitive to certain stimuli. We can put an antibody onto the surface of the nanotube and when it binds to an antigen we can see a signal change—a shift in the wavelength of the nanotube fluorescence—through the tissue.” (The team successfully detected ovarian cancer signaling changes in a mouse model. This work was detailed in a paper, Non-Invasive Ovarian Cancer Biomarker Detection via an Optical Nanosensor Implant, coauthored by Heller in Science Advances [2018;4(4):eaaq1090]).

Implications for future use of this technology in humans are significant. Heller said the first possible application could be in people with risk factors for certain diseases. “We could implant a biomarker or panel of biomarkers in people to detect early stage cancer, to measure cancer recurrence, or to monitor treatment and have earlier warning when therapy stops working.”

Asked how early the signaling changes would become apparent, Heller said it depends on the level of a given marker in the tissue. “With ovarian cancer, we would look at the technology as an intrauterine device, placed near the source of the cancer. If we were to wait for biomarkers to reach a high enough level to be detected in the blood, we likely would be dealing with late-stage cancer. If we can measure that biomarker right next to the ovaries or fallopian tube, we would see signal changes at an even earlier point in the life cycle of the cancer.”

Looking downstream of this work, Heller said the team is already questioning if it might be possible to insert a small sensor under the skin, in the blood, or even in a tattoo to measure all kinds of biomarkers, then report a whole panel in real time, at early stages, back to a wearable Fitbit-like device. “The long-term hope is to find super easy ways to measure lots of biomarkers in real time,” said Heller.

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Nanoparticles in Discovery

A third aspect of the work underway in Heller’s lab focuses on making research tools, specifically using carbon nanotubes as sensors in drug discovery assays. Heller believes the sensors will be able to measure things that have not been measurable before, or measured in ways that could not be accomplished before, such as in living cells and living tissue. “By measuring an analyte inside living cells or living tissue in mice, we gain the ability to do studies that cannot be done otherwise. This will allow us to address new hypotheses, and it will be helpful for drug development and for basic researchers at institutions such as MSKCC.”

Heller stressed that it is exactly institutions like MSKCC that can lead the way in helping biomedical engineers interact more fully with biomedical researchers. “Even though both of these concepts have the word ‘biomedical’ in them, ‘biomedical engineering’ departments come from engineering schools, while ‘biomedical research’ comes from places that often do not have engineering schools.

So there is a disconnect,” said Heller. “I realize how valuable it is to me as an engineering researcher to be in a biomedical institution and come in contact with the people who study biomedical questions and understand the medical problems. Biomedical institutions would benefit greatly from organized efforts to bring in engineering researchers whose goal it is to understand and make new technologies to address their problems.”

Heller laughed at the suggestion that some of the things he makes sound like cinematic props from the vintage sci-fi flick, The Incredible Voyage. “Sometimes people think we are the science fiction lab of Memorial Sloan Kettering,” he admitted with humor. And when asked if the younger history student/middle school teacher/or physical scientist in him ever thinks, “I can’t believe I am doing this kind of stuff,” he answered without hesitation, “Yeah, all the time. I think I have gotten to where I am by not defining myself. It’s important to be flexible. Where does it stop? It doesn’t. If you keep changing you can aspire to do anything you want.”

Valerie Neff Newitt is a contributing writer.

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