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
24 Jun 2015
The nanowires respond to an electromagnetic field generated by a separate device, which can be used to control the release of a preloaded drug. The system eliminates tubes and wires required by other implantable devices that can lead to infection and other complications, said team leader Richard Borgens, Purdue University’s Mari Hulman George Professor of Applied Neuroscience and director of Purdue’s Center for Paralysis Research.
“This tool allows us to apply drugs as needed directly to the site of injury, which could have broad medical applications,” Borgens said. “The technology is in the early stages of testing, but it is our hope that this could one day be used to deliver drugs directly to spinal cord injuries, ulcerations, deep bone injuries or tumors, and avoid the terrible side effects of systemic treatment with steroids or chemotherapy.”
The team tested the drug-delivery system in mice with compression injuries to their spinal cords and administered the corticosteroid dexamethasone. The study measured a molecular marker of inflammation and scar formation in the central nervous system and found that it was reduced after one week of treatment. A paper detailing the results will be published in an upcoming issue of the Journal of Controlled Release and is currently available online.
IMAGE: An image of a field of polypyrrole nanowires captured by a scanning electron microscope is shown. A team of Purdue University researchers developed a new implantable drug-delivery system using the… view more
Credit: (Purdue University image/courtesy of Richard Borgens)
The nanowires are made of polypyrrole, a conductive polymer material that responds to electromagnetic fields. Wen Gao, a postdoctoral researcher in the Center for Paralysis Research who worked on the project with Borgens, grew the nanowires vertically over a thin gold base, like tiny fibers making up a piece of shag carpet hundreds of times smaller than a human cell. The nanowires can be loaded with a drug and, when the correct electromagnetic field is applied, the nanowires release small amounts of the payload. This process can be started and stopped at will, like flipping a switch, by using the corresponding electromagnetic field stimulating device, Borgens said.
The researchers captured and transported a patch of the nanowire carpet on water droplets that were used used to deliver it to the site of injury. The nanowire patches adhere to the site of injury through surface tension, Gao said.
The magnitude and wave form of the electromagnetic field must be tuned to obtain the optimum release of the drug, and the precise mechanisms that release the drug are not yet well understood, she said. The team is investigating the release process.
The electromagnetic field is likely affecting the interaction between the nanomaterial and the drug molecules, Borgens said.
“We think it is a combination of charge effects and the shape change of the polymer that allows it to store and release drugs,” he said. “It is a reversible process. Once the electromagnetic field is removed, the polymer snaps back to the initial architecture and retains the remaining drug molecules.”
For each different drug the team would need to find the corresponding optimal electromagnetic field for its release, Gao said.
This study builds on previous work by Borgens and Gao. Gao first had to figure out how to grow polypyrrole in a long vertical architecture, which allows it to hold larger amounts of a drug and extends the potential treatment period. The team then demonstrated it could be manipulated to release dexamethasone on demand. A paper detailing the work, titled “Action at a Distance: Functional Drug Delivery Using Electromagnetic-Field-Responsive Polypyrrole Nanowires,” was published in the journal Langmuir.
Other team members involved in the research include John Cirillo, who designed and constructed the electromagnetic field stimulating system; Youngnam Cho, a former faculty member at Purdue’s Center for Paralysis Research; and Jianming Li, a research assistant professor at the center.
For the most recent study the team used mice that had been genetically modified such that the protein Glial Fibrillary Acidic Protein, or GFAP, is luminescent. GFAP is expressed in cells called astrocytes that gather in high numbers at central nervous system injuries. Astrocytes are a part of the inflammatory process and form a scar tissue, Borgens said.
A 1-2 millimeter patch of the nanowires doped with dexamethasone was placed onto spinal cord lesions that had been surgically exposed, Borgens said. The lesions were then closed and an electromagnetic field was applied for two hours a day for one week. By the end of the week the treated mice had a weaker GFAP signal than the control groups, which included mice that were not treated and those that received a nanowire patch but were not exposed to the electromagnetic field. In some cases, treated mice had no detectable GFAP signal.
Whether the reduction in astrocytes had any significant impact on spinal cord healing or functional outcomes was not studied. In addition, the concentration of drug maintained during treatment is not known because it is below the limits of systemic detection, Borgens said.
“This method allows a very, very small dose of a drug to effectively serve as a big dose right where you need it,” Borgens said. “By the time the drug diffuses from the site out into the rest of the body it is in amounts that are undetectable in the usual tests to monitor the concentration of drugs in the bloodstream.”
Polypyrrole is an inert and biocompatable material, but the team is working to create a biodegradeable form that would dissolve after the treatment period ended, he said.
The team also is trying to increase the depth at which the drug delivery device will work. The current system appears to be limited to a depth in tissue of less than 3 centimeters, Gao said.
- Wen Gao, Richard Ben Borgens. Remote-controlled eradication of astrogliosis in spinal cord injury via electromagnetically-induced dexamethasone release from “smart” nanowires. Journal of Controlled Release, 2015; 211: 22 DOI: 10.1016/j.jconrel.2015.05.266