Nanoparticle therapy could deliver double blow to cancer

 

A new cancer therapy using nanoparticles to deliver a combination therapy direct to cancer cells could be on the horizon, thanks to research from the University of East Anglia.

The new therapy, which has been shown to make breast cancer and prostate cancer tumours more sensitive to chemotherapy, is now close to entering clinical trials.

And scientists at UEA’s Norwich Medical School have confirmed that it can be mass-produced, making it a viable treatment if proved effective in human trials.

Using nanoparticles to get drugs directly into a tumour is a growing area of cancer research. The technology developed at UEA is the first of its kind to use nanoparticles to deliver two drugs in combination to target cancer cells.

The drugs, already approved for clinical use, are an anti-cancer drug called docetaxel, and fingolimod, a multiple sclerosis drug that makes tumours more sensitive to chemotherapy.

Fingolimod cannot currently be used in cancer treatment because it also supresses the immune system, leaving patients with dangerously low levels of white blood cells.

And while docetaxel is used to treat many cancers, particularly breast, prostate, stomach, head and neck and some lung cancers, its toxicity can also lead to serious side effects for patients whose tumours are chemo-resistant.

Because the nanoparticles developed by the UEA team can deliver the drugs directly to the tumour site, these risks are vastly reduced. In addition, the targeted approach means less of the drug is needed to kill off the cancer cells.

“So far nobody has been able to find an effective way of using fingolimod in cancer patients because it’s so toxic in the blood,” explains lead researcher, Dr. Dmitry Pshezhetskiy from the Norwich Medical School at UEA.

“We’ve found a way to use it that solves the toxicity problem, enabling these two drugs to be used in a highly targeted and powerful combination.”

The UEA researchers worked with Precision NanoSystems’ Formulation Solutions Team who used their NanoAssemblr technology to investigate if it was possible to synthesise the different components of the therapy at an industrial scale.

Following successful results on industrial scale production, and a published international patent application, the UEA team is now looking for industrial partners and licensees to move the research towards a phase one clinical trial.

Also included within the nanoparticle package are molecules that will show up on an MRI scan, enabling clinicians to monitor the spread of the particles through the body.

The team has already carried out trials in mice that show the therapy is effective in reducing breast and prostate tumours. These results were published in 2017.

“Significantly, all the components used in the therapy are already cleared for clinical use in Europe and the United States,” says Dr. Pshezhetskiy. “This paves the way for the next stage of the research, where we’ll be preparing the therapy for patient trials.”

“New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth,” by Heba Alshaker, Qi Wang, Shyam Srivats, Yimin Chao, Colin Cooper and Dmitri Pchejetski was published in Breast Cancer Research and Treatment on 10 July 2017.

“Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer,” by Qi Wang, Heba Alshaker, Torsten Böhler, Shyam Srivats, Yimin Chao, Colin Cooper and Dmitri Pchejetski was published in Scientific Reports on 19 July 2017.

 Explore further: Lipid molecules can be used for cancer growth

More information: Heba Alshaker et al. New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth, Breast Cancer Research and Treatment (2017). DOI: 10.1007/s10549-017-4380-8

Qi Wang et al. Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer, Scientific Reports (2017). DOI: 10.1038/s41598-017-06142-x

Read more at: https://phys.org/news/2018-08-nanoparticle-therapy-cancer.html#jCp

Nanorobots successfully target and kill cancerous tumors

Science fiction no more

In an article out today in Nature Biotechnology, scientists were able to show tiny autonomous bots have the potential to function as intelligent delivery vehicles to cure cancer in mice.

These DNA nanorobots do so by seeking out and injecting cancerous tumors with drugs that can cut off their blood supply, shriveling them up and killing them.

“Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth,” the paper explains.

DNA nanorobots are a somewhat new concept for drug delivery. They work by getting programmed DNA to fold into itself like origami and then deploying it like a tiny machine, ready for action.

DNA nanorobots, Nature Biotechnology 2018

The scientists behind this study tested the delivery bots by injecting them into mice with human breast cancer tumors. Within 48 hours, the bots had successfully grabbed onto vascular cells at the tumor sites, causing blood clots in the tumor’s vessels and cutting off their blood supply, leading to their death.

Remarkably, the bots did not cause clotting in other parts of the body, just the cancerous cells they’d been programmed to target, according to the paper.

The scientists were also able to demonstrate the bots did not cause clotting in the healthy tissues of Bama miniature pigs, calming fears over what might happen in larger animals.

The goal, say the scientists behind the paper, is to eventually prove these bots can do the same thing in humans. Of course, more work will need to be done before human trials begin.

Regardless, this is a huge breakthrough in cancer research. The current methods of either using chemotherapy to destroy every cell just to get at the cancer cell are barbaric in comparison. Using targeted drugs is also not as exact as simply cutting off blood supply and killing the cancer on the spot. Should this new technique gain approval for use on humans in the near future it could have impressive affects on those afflicted with the disease.

New nanoparticle technology developed to treat aggressive thyroid cancer

Immunofluorescence images of cells (nuclei shown in blue; actin shown in green; BRAF shown in red). Left: control; right: after treatment with nanoparticles that silence BRAF. Credit: Jinjun Shi, Brigham and Women’s Hospital

Anaplastic thyroid cancer (ATC), the most aggressive form of thyroid cancer, has a mortality rate of nearly 100 percent and a median survival time of three to five months. One promising strategy for the treatment of these solid tumors and others is RNA interference (RNAi) nanotechnology, but delivering RNAi agents to the sites of tumors has proved challenging. Investigators at Brigham and Women’s Hospital, together with collaborators from Massachusetts General Hospital, have developed an innovative nanoplatform that allows them to effectively deliver RNAi agents to the sites of cancer and suppress tumor growth and reduce metastasis in preclinical models of ATC. Their results appear this week in Proceedings of the National Academy of Sciences.

“We call this a ‘theranostic’ platform because it brings a therapy and a diagnostic together in one functional nanoparticle,” said co-senior author Jinjun Shi, PhD, assistant professor of Anesthesia in the Anesthesia Department. “We expect this study to pave the way for the development of theranostic platforms for image-guided RNAi delivery to advanced cancers.”

RNAi, the discovery of which won the Nobel Prize in Physiology or Medicine 10 years ago, allows researchers to silence mutated genes, including those upon which cancers depend to grow and survive and metastasize. Many ATCs depend upon mutations in the commonly mutated cancer gene BRAF. By delivering RNAi agents that specifically target and silence this mutated gene, the investigators hoped to stop both the growth and the spread of ATC, which often metastasizes to the lungs and other organs.

When RNAi is delivered on its own, it is usually broken down by enzymes or filtered out by the kidneys before it reaches tumor cells. Even when RNAi agents make it as far as the tumor, they are often unable to penetrate or are rejected by the cancer cells. To overcome these barriers, the investigators used nanoparticles to deliver the RNAi molecules to ATC tumors. In addition, they coupled the nanoparticles with a near-infrared fluorescent polymer, which allowed them to see where the nanoparticles accumulated in a mouse model of ATC.

By measuring the glow from the near-infrared fluorescent polymer, the team verified that nanoparticles had reached the primary site of ATC in the thyroid. The team found that the nanoparticles circulated for long periods of time in the blood stream and accumulated at high concentrations in the tumors.

In addition, the team reports evidence that BRAF had been successfully silenced at these sites. They found that, for cells grown in a dish and treated with the nanoparticles containing RNAi agents, cell growth was drastically slowed and the number of cancer cells that were able to migrate decreased by as much as 15-fold. In mouse models, tumor growth was also slowed and fewer metastases formed.

In order to translate the new platform into clinical applications, the research team notes the importance of having an imaging diagnostic that will allow them to quickly assess which patients most likely to benefit from RNAi nanotherapeutics.

“Most patients who present to surgeons with anaplastic thyroid cancer are out of options and this new research gives these patients some options. Having an approach that allows us to rapidly visualize and simultaneously deliver a targeted therapy could be critical for the efficient treatment of this disease and other lethal cancers with a poor prognosis,” said co-senior author, Sareh Parangi, MD, associate professor in the MGH Department of Surgery.

Explore further: Chemistry trick may herald transformational next-generation RNAi therapeutics aimed at cancer, viral infections

More information: Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1605841113

Journal reference: Proceedings of the National Academy of Sciences

Provided by: Brigham and Women’s Hospital

 

Chitosan Coated, Chemotherapy Packed Nanoparticles may Target Cancer Stem Cells

Chitosan coated, chemotherapy packed nanoparticles may target cancer stem cells

COLUMBUS, Ohio – Nanoparticles packed with a clinically used chemotherapy drug and coated with an oligosaccharide derived from the carapace of crustaceans might effectively target and kill cancer stem-like cells, according to a recent study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). Cancer stem-like cells have characteristics of stem cells and are present in very low numbers in tumors. They are highly resistant to chemotherapy and radiation and are believed to play an important role in tumor recurrence. This laboratory and animal study showed that nanoparticles coated with the oligosaccharide called chitosan and encapsulating the chemotherapy drug doxorubicin can target and kill cancer stem-like cells six times more effectively than free doxorubicin.

The study is reported in the journal ACS Nano.

“Our findings indicate that this nanoparticle delivery system increases the cytotoxicity of doxorubicin with no evidence of systemic toxic side effects in our animal model,” says principal investigator Xiaoming (Shawn) He, PhD, associate professor of Biomedical Engineering and a member of the OSUCCC – James Translational Therapeutics Program.

“We believe that chitosan-decorated nanoparticles could also encapsulate other types of chemotherapy and be used to treat many types of cancer.”

This study showed that chitosan binds with a receptor on cancer stem-like cells called CD44, enabling the nanoparticles to target the malignant stem-like cells in a tumor.

The nanoparticles were engineered to shrink, break open, and release the anticancer drug under the acidic conditions of the tumor microenvironment and in tumor-cell endosomes and lysosomes, which cells use to digest nutrients acquired from their microenvironment.

He and his colleagues conducted the study using models called 3D mammary tumor spheroids (i.e., mammospheres) and an animal model of human breast cancer.

The study also found that although the drug-carrying nanoparticles could bind to the variant CD44 receptors on cancerous mammosphere cells, they did not bind well to the CD44 receptors that were overexpressed on noncancerous stem cells.

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Funding from an American Cancer Society Research Scholar Grant (No. 120936-RSG- 11-109-01-CDD) and a Pelotonia postdoctoral fellowship supported this research.

Other researchers involved in this study were Wei Rao, Hai Wang, Jianfeng Han, Shuting Zhao, Jenna Dumbleton, Pranay Agarwal, Jianhua Yu and Debra L. Zynger of Ohio State; Wujie Zhang of Milwaukee School of Engineering; Gang Zhao of University of Science and Technology of China; and Xiongbin Lu of The University of Texas MD Anderson Cancer Center.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State’s cancer program as “exceptional,” the highest rating given by NCI survey teams. As the cancer program’s 306-bed adult patient-care component, The James is a “Top Hospital” as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.

Nanoparticles target and kill cancer stem cells that drive tumor growth

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
DOI: 10.1021/nn506928p

Abstract
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.

Journal reference: ACS Nano

A*STAR: Detecting Breast Cancer Using Nanoscale Polymers (Contrasting Agents & Photacoustic Imaging)

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.”

Explore further: Dual-action chemical agents improve a high-resolution and noninvasive way to detect cancer

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

‘Super-Cool’ way to Deliver Drugs

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.

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Story Source:

The above story is based on materials provided by American Friends of Tel Aviv University. Note: Materials may be edited for content and length.

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Journal Reference:

1. 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

Nano-Sized Cancer Drug Delivery: One Step Closer

When you take a drug, it travels through your bloodstream, dissolving and dispersing, and eventually reaching its designated target area.

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.

Credit: Professor Sonia Trigueros

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?

Attaching proteins to DNA could create a truly targeted drug delivery system. Credit: Professor Sonia Trigueros

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 steps

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

Provided by Cancer Research UK

Nano packages for anti-cancer drug delivery

Cancer stem cells are resistant to chemotherapy and consequently tend to remain in the body even after a course of treatment has finished, where they can often trigger cancer recurrence or metastasis. A new study by researchers from the A*STAR Institute of Bioengineering and Nanotechnology has found that using nanoparticles to deliver an anti-cancer drug that simultaneously kills cancer cells and cancer stem cells significantly reduces the recurrence and metastasis of lung cancer.

The drug phenformin is very effective against cancer stem cells. It is related to the popular anti-diabetic drug metformin but is 50 times more potent against cancer cell lines. However, phenformin is too toxic in its free form to be administered to patients at the doses required to kill both normal cancer cells and cancer stem cells. Now, Yi Yan Yang and her colleagues at the Institute of Bioengineering and Nanotechnology in Singapore have found a way to overcome this problem — using self-assembling polymer nanoparticles to deliver the drug (“Phenformin-loaded polymeric micelles for targeting both cancer cells and cancer stem cells in vitro and in vivo”).

Phenformin-loaded nanoparticles kill both cancer cells and cancer stem cells, leading to tumor regression. (Image: A*STAR Institute of Bioengineering and Nanotechnology)

In the first study to use polymer nanoparticles to deliver phenformin to target both cancer cells and cancer stem cells, Yang and co-workers found that phenformin-loaded nanoparticles targeted both kinds of cancer cells in a mouse model of human lung cancer.

The nanoparticles released the drug in a sustained manner due to their hydrophilic shells, which “prevent enzymatic degradation of the cargo and protein adsorption onto the nanoparticles,” explains Yang. “This also prolongs blood circulation so that the cargo-loaded nanoparticles have enough time to accumulate in tumor tissues.”

This delivery method enabled Yang and her team to arrest the growth of cancer and cancer stem cells when the nanoparticles were delivered to implanted human lung cancer in mice.

“The results showed that the phenformin-loaded nanoparticles were more effective than free phenformin in inhibiting the growth of both cancer stem cells and normal cancer cells,” Yang says. Moreover, the nanoparticles did not induce the liver toxicity observed in systemically administered phenformin.

The method can also be extended to other drugs. The team has used the nanoparticle-based delivery system in a mouse model of human breast cancer to deliver the anti-cancer drug, doxorubicin — another drug that is toxic at certain doses but is capable of killing cancer stem cells. “The combination shrank tumors by more than 40 per cent and was more effective than treatment with either drug alone,” says Yang.

The team is now seeking to collaborate with pharmaceutical companies to bring this technology to human clinical trials.

Source: A*STAR

Read more: Nano packages for anti-cancer drug delivery

Plasmonic nanocrystals for combined photothermal and photodynamic cancer therapies

Photothermal therapy (PTT) is a form of cancer treatment where a therapeutic agent absorbs energy from photons and dissipates it partially in the form of heat. When the therapeutic agents, for instance nanoparticles, are located in close vicinity to the tumor site, the temperature increase can lead to cell damage, i.e. it kills the cancer cell. Research on PTT has made a huge progress thanks to various near-infrared light (NIR) absorbing – i.e. plasmonic – nanomaterials that have been developed in the past years. A similar approach uses light instead of heat and is called photodynamic therapy (PDT). This technique requires the use of a chemical compound – also known as photosensitizer – with a particular type of light to kill cancer cells.

The photosensitizer in the tumor absorbs the light and generates reactive oxygen species (ROS) – such as hydroxyl radical, singlet oxygen, as well as peroxides – that destroy nearby cancer cells. While these techniques have been around for years, more recently the use of nanomaterials such as various forms of gold nanoparticles (rods, cages, spheres), quantum dots or iron-oxide nanoparticles has allowed researchers to refine their therapeutic methods with a view to also explore the mechanisms behind the efficacy. Scientists also developed combinations of nanomaterial-mediated PTT and organic photosensitizer-mediated PDT to achieve synergistic therapeutic effects.

However, most of these approaches achieved only tumor suppression rather than complete destruction, especially under low laser dose conditions. Among the nanomaterials used, copper sulfide nanocrystals stand out because they can efficiently absorb near-infrared light at the 700-1100 nm range, which is considered as ‘transparent’ to human tissue at this energy level. Another reason that these plasmonic nanocrystals have attracted much attention as materials for PTT is their small size, which leads to the possibility of deeper tumor permeation. Previous reports have correlated photo induced cell death to the photothermal heat mechanism of copper sulfide nanocrystals, but no evidence of their photodynamic properties had been reported yet. In a new study, reported in the January 20, 2015 online edition of ACS Nano (“Plasmonic Copper Sulfide Nanocrystals Exhibiting Near-Infrared Photothermal and Photodynamic Therapeutic Effects”), an international team of researchers led by Drs. Teresa Pellegrino, Huan Meng, and Huiyu Liu, used abiotic assays, cultured cancer cells, and a melanoma animal model to demonstrate the PTT activity of copper sulfide nanocrystals. The paper lays out the working principle of colloidal, NIR plasmonic copper sulfide nanocrystals exploitable for both PDT and PTT therapy with NIR activation.

Schematic of the combined photothermal and photodynamic therapy. (Reprinted with permission by American Chemical Society) This is the first report that under a NIR light radiation copper sulfide nanocrystals (Cu2-xS) achieve efficient cancer destroying efficacy via PTT and PDT mechanisms both in vitro and in vivo. “Our findings demonstrated the dual functionalities of copper sulfide nanocrystals, which are capable of melanoma cancer inhibition under NIR irradiation via photothermal therapy and photodynamic therapy mediated mechanisms,” Huiyu Liu, an Associate Professor at the Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, tells Nanowerk. “This is the first report demonstrating that the leakage of copper ions from copper sulfide nanocrystals could enhance the ROS generation under NIR light irradiation, which serves as a new mechanism in addition to the sole PTT mechanism.” Investigating the ROS generation mechanism, the researchers were able to show that the reduction of dissolved Cu2+ ions leads to Cu+ ions which further interact with the biological redox molecules, i.e. ascorbic acid and glutathione, and thus trigger the ROS generation. “Interestingly” Liu notes, “while we worked with a scenario involving nanoparticles, our theory behind the ROS generation is supported by a classic chemistry study, also known as Haber-Weiss cycle, proposed by Kadiiska et al. more than 20 years ago (“In vivo evidence of hydroxyl radical formation after acute copper and ascorbic acid intake: electron spin resonance spin-trapping investigation”). Based on the promising effect of photothermal therapies, the research team is confident that their dual functional Cu2-xS nanocrystals could lead to an even more potent platform for cancer treatment. “We are also considering to perform additional acute and chronic tests for our platform including the use of multiple melanoma animal models to confirm our findings in B16 murine model,” says Liu. “Based on our proof-of-principle results, further studies are required to evaluate and optimize the PTT, or PDT, or dual functional platforms as we demonstrated in various cancer models, i.e. melanoma and head and neck carcinoma, with a view to also look at nanosafety in an acute and chronic phase.” She adds that, from a manufacture perspective, it is necessary to consider the scalability of nanomaterial production as well as quality control.

By M. Berger Nanowerk