Many cancer patients survive treatment only to have a recurrence within a few years. Recurrences and tumor spreading are likely due to cancer stem cells that can be tough to kill with conventional cancer drugs. But now researchers have designed nanoparticles that specifically target these hardy cells to deliver a drug. The nanoparticle treatment, reported in the journal ACS Nano, worked far better than the drug alone in mice.
Anti-cancer drugs can often shrink tumors but don’t kill cancer stem cells (CSCs). Although CSCs might only make up a small part of a tumor, their resistance to drugs allows them to persist. They can then cause a tumor to regrow or spread cancerous cells throughout the body. Xiaoming He and colleagues wanted to develop a nanoparticle system to overcome these cells’ defenses.
The researchers packaged the anti-cancer drug doxorubicin into nanoparticles coated with chitosan, a natural polysaccharide that can specifically target CSCs. Once in the acidic environment of the tumor, the nanoparticles degraded and released the drug. Tests on tiny, tissue-like clumps of both normal and cancer stem cells in vitro and on human breast tumors grown in mice showed the therapy successfully killed CSCs and destroyed tumors. The mice showed no obvious side effects.
Explore further: Nano packages for anti-cancer drug delivery
More information: Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells ACS Nano, Article ASAP
Tumor reinitiating cancer stem-like cells are responsible for cancer recurrence associated with conventional chemotherapy. We developed a doxorubicin-encapsulated polymeric nanoparticle surface-decorated with chitosan that can specifically target the CD44 receptors of these cells. This nanoparticle system was engineered to release the doxorubicin in acidic environments, which occurs when the nanoparticles are localized in the acidic tumor microenvironment and when they are internalized and localized in the cellular endosomes/lysosomes. This nanoparticle design strategy increases the cytotoxicity of the doxorubicin by six times in comparison to the use of free doxorubicin for eliminating CD44+ cancer stem-like cells residing in 3D mammary tumor spheroids (i.e., mammospheres). We further show these nanoparticles reduced the size of tumors in an orthotopic xenograft tumor model with no evident systemic toxicity. The development of nanoparticle system to target cancer stem-like cells with low systemic toxicity provides a new treatment arsenal for improving the survival of cancer patients.
The latest version of a microfluidic device for capturing rare circulating tumor cells (CTCs) is the first designed specifically to capture clusters of two or more cells, rather than single cells. The new device, called the Cluster-Chip, was developed by the same Massachusetts General Hospital (MGH) research team that created previous microchip-based devices. Recent studies by MGH investigators and others have suggested that CTC clusters are significantly more likely to cause metastases than single circulating tumor cells.
13 May 2015
Photoacoustic imaging is a ground-breaking technique for spotting tumors inside living cells with the help of light-absorbing compounds known as contrast agents. A*STAR researchers have now discovered a way to improve the targeting efficacy and optical activity of breast-cancer-specific contrast agents using conjugated polymer nanoparticles.
Generating photoacoustic signals requires an ultrafast laser pulse to irradiate a small area of tissue. This sets off a series of molecular vibrations that produce ultrasonic sound waves in the sample. By ‘listening’ to the pressure differences created by the acoustic waves, researchers can reconstruct and visualize the inner structures of complex objects such as the brain and cardiovascular systems.
Diagnosing cancer with photoacoustic imaging requires contrast agents that deeply penetrate tissue and selectively bind to malignant cells. In addition, they need a high optical response to near-infrared laser light, a spectral region that is particularly safe to biological materials. Traditional contrast agents have been based on gold and silver nanostructures, but the complex chemical procedures needed to optically tune these nanocompounds have left researchers looking for alternatives.
Photoacoustic imaging of model breast cancer cells in mice reveals that a polymer-based contrast agent can illuminate tumor sites within one hour. Credit: Dove Medical Press Limited
Malini Olivo and her colleagues from the A*STAR Singapore Bioimaging Consortium and the A*STAR Institute of Materials Research and Engineering investigated different contrast agents based on conjugated polymers. These organic macromolecules, which contain alternating double and single carbon bonds, have delocalized electrons in their frameworks that can produce useful optical properties such as photoluminescence. The researchers identified a conjugated polymer known as PFTTQ—a compound with multiple aromatic rings, alkyl chains, sulfur and nitrogen atoms—as a promising in vivo photoacoustic agent because of its biocompatible structure and light absorption that peaks in the near-infrared range.
To direct this contrast agent to cancer cells, the team synthesized ‘dot’-like nanostructures with an inner core of PFTTQ surrounded by water-soluble polyethylene glycol chains, terminated by an outer layer of folate molecules—a vitamin that specifically binds to folate receptor proteins commonly expressed by breast cancer tumors. Experiments with MCF-7 model breast cancer cells implanted in mice revealed the merits of this approach: in just one hour after administering the folate–conjugated polymer dots, strong photoacoustic signals emerged from the tumor positions. The folate functionality played a critical role in this bioimaging procedure, quadrupling the photoacoustic signals compared to unmodified PFTTQ dots.
“The folate–PFTTQ nanoparticles have great potential for diagnostic imaging and other biomedical applications,” says Olivo. “We are working to expand the library of biocompatible polymers to use as molecular photoacoustic contrast agents.”
More information: “Molecular photoacoustic imaging of breast cancer using an actively targeted conjugated polymer.” International Journal of Nanomedicine 10, 387–397 (2015). dx.doi.org/10.2147/IJN.S73558
08 May 2015
Summary: Some substances, when they undergo a process called ‘rapid-freezing’ or ‘supercooling,’ remain in liquid form — even at below-freezing temperatures. A new study is the first to break down the rules governing the complex process of crystallization through rapid-cooling.
Its findings may revolutionize the delivery of drugs in the human body, providing a way to ‘freeze’ the drugs at an optimal time and location in the body.
Water, when cooled below 32°F, eventually freezes — it’s science known even to pre-schoolers. But some substances, when they undergo a process called “rapid-freezing” or “supercooling,” remain in liquid form — even at below-freezing temperatures.
The supercooling phenomenon has been studied for its possible applications in a wide spectrum of fields. A new Tel Aviv University study published in Scientific Reports is the first to break down the rules governing the complex process of crystallization through rapid-cooling. According to the research, membranes can be engineered to crystallize at a specific time. In other words, it is indeed possible to control what was once considered a wild and unpredictable process — and it may revolutionize the delivery of drugs in the human body, providing a way to “freeze” the drugs at the exact time and biological location in the body necessary.
The study was led jointly by Dr. Roy Beck of the Department of Physics at TAU’s School of Physics and Astronomy and Prof. Dan Peer of the Department of Cell Research and Immunology at TAU’s Faculty of Life Sciences, and conducted by TAU graduate students Guy Jacoby, Keren Cohen, and Kobi Barkai.
Controlling a metastable process
“We describe a supercooled material as ‘metastable,’ meaning it is very sensitive to any external perturbation that may transform it back to its stable low-temperature state,” Dr. Beck said. “We discovered in our study that it is possible to control the process and harness the advantages of the fluid/not-fluid transition to design a precise and effective nanoscale drug encapsulating system.”
For the purpose of the study, the researchers conducted experiments on nanoscale drug vesicles (fluid-filled sacs that deliver drugs to their targets) to determine the precise dynamics of crystallization. The researchers used a state-of-the-art X-ray scattering system sensitive to nanoscale structures.
“One key challenge in designing new nano-vesicles for drug delivery is their stability,” said Dr. Beck. “On the one hand, you need a stable vesicle that will entrap your drug until it reaches the specific diseased cell. But on the other, if the vesicle is too stable, the payload may not be released upon arrival at its target.”
“Supercooled material is a suitable candidate since the transition between liquid and crystal states is very drastic and the liquid membrane explodes to rearrange as crystals. Therefore this new physical insight can be used to release entrapped drugs at the target and not elsewhere in the body’s microenvironment. This is a novel mechanism for timely drug release.”
All in the timing
The researchers found that the membranes were able to remain stable for tens of hours before collectively crystallizing at a predetermined time.
“What was amazing was our ability to reproduce the results over and over again without any complicated techniques,” said Dr. Beck. “We showed that the delayed crystallization was not sensitive to minor imperfection or external perturbation. Moreover, we found multiple alternative ways to ‘tweak the clock’ and start the crystallization process.”
The researchers are investigating an appropriate new nano-capsule capable of releasing medication at a specific time and place in the body. “The challenge now is to find the right drugs to exploit our insights for the medical benefit of patients,” said Dr. Beck.
- Guy Jacoby, Keren Cohen, Kobi Barkan, Yeshayahu Talmon, Dan Peer, Roy Beck. Metastability in lipid based particles exhibits temporally deterministic and controllable behavior. Scientific Reports, 2015; 5: 9481 DOI: 10.1038/srep09481
08 May 2015
But because the blood containing the drug travels all round your body only a small percentage of the initial dose actually reaches the desired location.
For over-the-counter drugs like paracetamol or ibuprofen, with very few side-effects, this doesn’t matter too much.
But when it comes to cancer drugs, which can affect healthy cells just as much as cancer cells, this process can cause big problems.
Partly because drugs are diluted in their blood, cancer patients need to take these drugs in particularly high doses – and this can cause seriously unpleasant side effects.
But Professor Sonia Trigueros, co-director of the Oxford Martin Programme on Nanotechnology, is inching closer to developing a nano-scale drug delivery system with the aim of specifically targeting cancer cells.
Working with a team of chemists, engineers and physicists, Trigueros has embarked on an ambitious mission to tackle cancer at the ‘nano’ level – less than 100 nanometers wide. For context, this is super-tiny: a nanometre is a thousandth of a thousandth of a millimetre.
There’s still a long way to go, but Trigueros is making decent headway, and has recently tackled a major problem of working at a nano level. And at this year’s Wired Health conference – which looked at the future of health care, wellbeing and genomics – she told us about her recent progress, and her visions for the future.
At the nano level
Some of us will remember the periodic table displayed in our science classrooms which told us about the properties of each element. But working on a nano level everything changes, and elements behave completely differently.
Elements have different properties at the nano level than they do at the micro level, explained Prof Trigueros to the Wired Health 2015 audience.
This poses big problems for researchers trying to make nano-scale devices, which can be made out of a number of different materials, including gold, silver and carbon. All these materials are highly unstable at the nano level.
“After you make the nanostructures you only have minutes to a couple of days to work,” she said. They are really unstable, especially when you put them in water.”
This isn’t ideal, considering our bodies are made up mostly of water.
Trigueros’ recent work has focused on trying to stabilise tiny tubes made of carbon, called carbon nanotubes, which hold drugs inside the tube so they can be delivered into cancer cells.
She has now found a way of keeping them stable for more than two years and in temperatures up to 42ºC.
To do this, she wraps DNA around the structures, like a tortilla wraps around the fillings of a burrito.
While this accomplishes the goal of keeping the nanostructures stable inside the body this doesn’t do much good if the DNA can’t unwrap to deliver the drugs. But, according to Trigueros, she has shown that, once inside a cell, the DNA easily unwinds and releases its payload.
Truly targeted drug delivery
So how does it all work? How do the drugs get into the cancer cells? Trigueros’s nanotubes exploit the differences between cancer cells and healthy cells – in this case, differences in the membranes that hold them together.
“Cancer cells are more permeable than normal cells so the nanotubes can get through the cell membrane. And once they are in, they unwrap and deliver drug,” explained Trigueros.
Exploiting differences in their permeability is one way to target the cancer cells, but Trigueros explains that there is more than one way to create a truly targeted drug delivery system.
“We can attach whatever we want on DNA,” she said. “So you can attach a protein that recognises cancer cells”.
From theory to reality
While this all sounds great in theory, will it actually work in reality?
Trigueros has now started preliminary tests on laboratory grown lung cancer cells, she told us during an interview. And this has shown tentative promise, she says, citing unpublished data on their effectiveness at killing these cells in the lab.
Others are cautiously optimistic. “This is a really exciting prospect,” says Professor Duncan Graham, nanotechnology expert and advisor to Cancer Research UK.
“A common concern with carbon nanotubes is toxicity, but when coated with DNA this concern could be removed,” he explains, “and it also addresses a fundamental issue, which is that they collect into clusters that become a solid mass and so are unable to leave the body.”
In theory, once Trigueros’s nanotubes have finished their job they are tiny enough (50 nanometres) to be excreted through urine.
This isn’t the first time carbon nanotubes have been used in cancer research: a US research team has used them, for example, to target and collect images of tumours in mice. But the combination of drug delivery and cancer-specific targeting is what interests Professor Graham.
“Unlike previous work using carbon nanotubes, this approach is set to target the tumour specifically, potentially meaning fewer side effects and a lower dosage. I look forward to seeing this in animal models which is where the real proof of activity lies,” he said.
But he’s cautious, stressing that Trigueros’s work has not yet been peer-reviewed and published.
Next Trigueros is aiming towards starting animal trials and, eventually, she wants to begin clinical trials in patients – that is if everything goes well.
She hopes to focus on how nanostructures could be used to cross the blood-brain barrier – the brain’s highly selective ‘bouncer’ that only lets certain molecules across. This has been notoriously difficult to get past, making targeting cancers in the brain more difficult.
But there is a still a long way to go and a lot of problems to tackle. In the shorter term, we’ll be keeping an eager eye on her drug delivery research, as her ideas continue to develop.
Explore further: Nano packages for anti-cancer drug delivery