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Posted: Mar 01, 2016

 
Researchers involved in a national effort to develop cancer treatments that harness nanotechnology are recommending pivotal changes in the field because experiments with laboratory animals and efforts based on current assumptions about drug delivery have largely failed to translate into successful clinical results.
The assessment was advanced in a perspective piece that (“Targeting the Tumor Microenvironment”; pdf) appeared in the National Cancer Institute’s Cancer Nanotechnology Plan 2015, a 10-year roadmap concerning the use of nanotechnology to attack cancer.

The complex microenvironment of tumors is presenting a challenge in developing effective anticancer treatments


The complex microenvironment of tumors is presenting a challenge in developing effective anticancer treatments that attempt to harness nanotechnology. Researchers are recommending pivotal changes in the field of cancer nanotechnology because experiments with laboratory animals and efforts based on current assumptions about drug delivery have largely failed to translate into successful clinical results. (Image: Bumsoo Han, Kinam Park, Murray Korc) (click on image to enlarge)

Researchers are trying to perfect “targeted delivery” methods using various agents, including an assortment of tiny nanometer-size structures, to selectively attack tumor tissue. However, the current direction of research has brought only limited progress, according to the authors of the article.

“The bottom line is that so far there are only a few successful nanoparticle formulations approved and clinically used, so we need to start thinking out of the box,” said Bumsoo Han, a Purdue University associate professor of mechanical and biomedical engineering.

One approach pursued by researchers has been to design nanoparticles small enough to pass through pores in blood vessels surrounding tumors but too large to pass though the pores of vessels in healthy tissue. The endothelial cells that make up healthy blood vessels are well organized with tight junctions between them. However, the endothelial cells in blood vessels around tumors are irregular and misshapen, with loose gaps between the cells.

“We should realize that having a specific nanosize or functionality alone is not enough to guarantee good drug delivery to target tumors,” said Kinam Park, a professor of pharmaceutics and Purdue’s Showalter Distinguished Professor of Biomedical Engineering. “The tumor microenvironment is just too complex to overcome using this strategy alone.”

The two authored the article with Murray Korc, the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine.

The authors pointed out that research with laboratory mice has rarely translated into successful clinical results in humans, suggesting that a more effective approach might be to concentrate on research using in-vitro experiments that mimic human physiology. For example, one new system under development, called a tumor-microenvironment-on-chip (T-MOC) device, could allow researchers to study the complex environment surrounding tumors and the barriers that prevent the targeted delivery of therapeutic agents.

The approach could help drug makers solve a daunting obstacle: even if drugs are delivered to areas near the target tumor cells, the treatment still is hindered by the complex microenvironment of tumors.

“We used to think that if we just killed the tumor cell it would cure the cancer, but now we know it’s not just the cancer cells alone that we have to deal with,” Korc said. “There are a lot of different cells and blood vessel structure, making for a complex environment that supports the cancer cells.”

An “extracellular matrix” near tumors includes dense collagen bundles and a variety of enzymes, growth factors and cells. For example, surrounding pancreatic tumors is a “stromal compartment” containing a mixture of cells called stromal cells, activated cancer-associated fibroblasts and inflammatory immune cells.

“Particularly for pancreatic cancer, the stromal tissue is much bigger than the tumor itself,” Korc said.

In addition, a compound called hyaluronic acid in this stromal layer increases the toughness of tumor microenvironment tissue, making it difficult for nanoparticles and drugs to penetrate.

“It’s dense, like scar tissue, so it’s more difficult for drugs coming out of the blood vessel to diffuse through this tissue,” Han said.

Another challenge is to develop water-soluble drugs to effectively deliver medicines.

“The cancer drugs need to be aqueous because the body resorbs them better, but a lot of the current chemotherapy drugs have low solubility and usually need different types of solvents to increase their solubility,” Park said.

The T-MOC approach offers some hope of learning how to design more effective cancer treatments.

“Recent advances in tissue engineering and microfluidic technologies present an opportunity to realize in-vitro platforms as alternatives to animal testing,” Park said. “Tumor cells can be grown in 3D matrices with other relevant stromal cells to more closely mirror the complexity of solid tumors in patients. The current ability of forming 3D-perfused tumor tissue needs to be advanced further to create an accurate tumor microenvironment.”

Such a major shift in research focus could play a role in developing personalized medicine, or precision medicine, tailored to a particular type of cancer and specific patients. More effective treatment might require various “priming agents” in combination with several drugs to be administered simultaneously or sequentially.

“This kind of research currently involves a very large number of experiments, and it makes animal testing expensive and time consuming,” Park said. “Moreover, small animal data have not been good predictors of clinical outcome. Thus, it is essential to develop in-vitro test methods that can represent the microenvironment of human tumors.”

Source: By Emil Venere, Purdue University

Drug Delivery 050815 onereallytin 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 , this process can cause big problems.

Drug Delivery 050815 onereallytin

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.

One (really tiny) step closer to nano-sized cancer drug delivery
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 – 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?

One (really tiny) step closer to nano-sized cancer drug delivery
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 , 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 research, as her ideas continue to develop.

Explore further: Nano packages for anti-cancer drug delivery


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