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From OncoLog, September 2010, Vol. 55, No. 9

Tiny Particles, Vast Potential
Coming soon to the clinic: nanoparticles that deliver therapy straight to tumor cells, bypassing normal cells and many toxic effects

By Sunita Patterson

Photo: Gold nanoparticles
Gold nanoparticles, shown here in a mouse melanoma cell by transmission electron microscopy, can kill cancer cells when heated with near-infrared light. Reprinted with permission from Lu W, et al. Clin Cancer Res 2009;15(3):876–886.

Nanotechnology has become a buzzword in the energy, computing, and fabrication fields. And now the potential use of nanotechnology in cancer therapy is also rapidly advancing. The advances build on our emerging understanding of the molecular attributes of particular tumors and our growing ability to target and even manipulate those attributes. Therapies at the nano scale—in particular, those using nanoparticles—may enable a new precision and specificity in targeting tumor cells.

At The University of Texas MD Anderson Cancer Center, investigators are working on nanotherapies from many different perspectives. Nanoparticles are being made of gold, biodegradable lipids, chitosan, and various other materials. Nanoparticles are being tested as vehicles for drugs, as packages for gene therapy, or as anticancer weapons themselves, activated at just the right time using radio waves or near-infrared light. And within the next year or two, several of these therapies will be available to patients in clinical trials. We highlight a few of the developing therapies here.

The blueprint

Nanoparticles are so small they are measured in nanometers (a nanometer is a millionth of a millimeter); many have diameters in the range of 5–200 nm. At that size, the particles are small enough to evade uptake by the liver and spleen, enabling them to stay in the bloodstream longer. They’re also able to take advantage of a unique opportunity: they can fit through the holes in the walls of the permeable, or “leaky,” blood vessels that tend to form in tumors. When nanoparticles are injected intravenously, they flow right on through normal blood vessels, which have tight walls without holes, but selectively diffuse through the permeable vessels out into tumors. This selective targeting of tumor cells without affecting normal cells means that the therapy can be concentrated at the site of disease and that the systemic side effects of the therapy may be minimal.

Making a therapeutic nanoparticle involves three basic considerations. First is the design of the nanoparticle itself. The material should be biocompatible, safe to use, able to remain intact until it reaches the intended target, and, once used, able to be excreted or degraded by the body. Second, the nanoparticle should preferentially accumulate in the tissue of interest. It’s common to add a targeting mechanism that, like a homing device, will find cancer cells and ignore normal cells. Finally, there must be a way to activate the particle’s therapeutic potential once it has reached the target. The particle may self-destruct, or it may be activated by an external force.

Cooking tumors with gold

Two MD Anderson research groups are applying this blueprint to nanoparticles made of gold, a biocompatible material already used to treat rheumatoid arthritis. The treatments under development at MD Anderson involve injecting gold nanoparticles into the body, where they find their way to tumor cells. An energy source, such as radio waves or near-infrared light, is then applied to the body externally. As the radiation penetrates the body, the gold nanoparticles heat up, in effect “cooking” the tumor from the inside out.

Within the next few years, Steven A. Curley, M.D., a professor in the Department of Surgical Oncology, will initiate a clinical trial involving solid gold nanoparticles and radio waves. “We’re finding that if we can target the gold nanoparticles to cancer cells and then treat them with a noninvasive radiofrequency field,” Dr. Curley said, “it can completely control and destroy the cancer cells. And the radio waves are not harmful to patients or healthy tissue.”

To increase the chances of the gold particles concentrating in cancer tissue, Dr. Curley and his team attach cancer cell–targeting antibodies and proteins to the nanoparticles. “It’s very simple chemistry to add targeting molecules to the particle surface,” he said. “For targets, we’re looking for molecules that are abnormally expressed on the surface of the cancer cells.”

The story of this therapy’s genesis has been told on 60 Minutes. Inventor John Kanzius designed the prototype radiofrequency device in 2003. An MD Anderson patient with non-Hodgkin lymphoma, he was motivated to find a treatment that lacked the side effects of chemotherapy. The first nanoparticles tested with the device were carbon particles provided by Rice University professor Richard E. Smalley, Ph.D. Dr. Smalley, who was also an MD Anderson cancer patient at the time, had been awarded the 1996 Nobel Prize in Chemistry for his role in the discovery of the complex carbon molecule buckminsterfullerene, or the “buckyball.” The size, stability, and hollow structure of buckyballs and related carbon molecules make them attractive for nanotechnology research.

Neither Mr. Kanzius nor Dr. Smalley lived to see the new photothermal therapy tested in patients, but Dr. Curley has continued to pursue that aim. “This therapy has potential for treating not only localized tumors—such as pancreatic, hepatocellular, colorectal, breast, and prostate cancers—but also bloodborne cancers such as lymphomas and leukemias,” he said.

Gold nanoparticles with antibodies specific to pancreatic cancer have been successfully tested by the team in cultures of human cancer cells and in mice and rabbits. Carbon nanoparticles have successfully destroyed liver tumors in rabbits, but those particles must undergo further toxicity testing before they can be considered for clinical use. Other ideas being tested by Dr. Curley’s team include attaching additional elements, such as the monoclonal antibody cetuximab and siRNA (see box, “Using siRNA to Silence Genes”), to the surface of nanoparticles to make cancer cells more sensitive to the heat.

A one-two punch

The idea of combining modalities at the nano level is also being tested by Chun Li, Ph.D., a professor in the Department of Experimental Diagnostic Imaging. Rather than solid gold particles and radio waves, Dr. Li and his team are working with hollow gold particles and near-infrared light. The group has fabricated and tested nanospheres (also called nanoshells or nanocages) of various thicknesses to take advantage of the near-infrared region of the electromagnetic spectrum. “At that wavelength, you have minimal absorption and scattering by tissue and water, so the light is able to penetrate deeper, and you have high absorption by the gold nanospheres,” explained Dr. Li. Near-infrared radiation is already used in some clinical applications.

Photo: Nanoliposomes
Researchers hope to deliver siRNA to cancer cells using nanoliposomes like the ones shown in this freeze-fracture electron micrograph.

In an experiment reported in Clinical Cancer Research, Dr. Li’s team tested the effectiveness of nanosphere delivery and activation in a mouse melanoma model. To heighten the selective delivery of the nanoparticles, they added a peptide that targets the melanocortin type 1 receptor, which is overexpressed in melanoma. “We found a very high level of accumulation of the particles in tumors,” explained Wei Lu, Ph.D., an instructor in the Department of Experimental Diagnostic Imaging and the first author of the report. Treated tumors had much larger areas of necrosis after irradiation than did controls.

The hollowness of the particles offers a variety of possible ways to improve the efficiency of the treatment. “If you put a chemotherapy drug inside a nanosphere and then expose it to light, the drug can be released as the particle heats up,” Dr. Li said. Cells that aren’t killed by the heat may succumb to the chemotherapy. To test this concept of a one-two punch, Dr. Li and colleagues introduced gold nanospheres loaded with doxorubicin or paclitaxel into MDA-MB-231 breast cancer cells. Cells that were incubated with the nanospheres and irradiated with near-infrared light demonstrated increased apoptosis—cell death—caused by both photothermal ablation and drug cytotoxicity. The paclitaxel-loaded nanospheres were also tested in mice injected with MDA-MB-231 cells and were found to delay tumor growth.

Another version of the one-two punch involves loading nanospheres with siRNA rather than a drug. In April, Dr. Li’s team published in Cancer Research the results of experiments in a HeLa cervical cancer xenograft model in mice. The team used siRNA that targets the NF-κB p65 subunit, which is thought to play a role in transcription of genes important in inflammation and cancer. Expression of NF-κB p65 receptors was reduced in tumors treated with the nanospheres and near-infrared radiation but was not affected in non-irradiated tumors.

The precision of the near-infrared light delivery allows both temporal and spatial control of nanoparticle activation. An advantage of this approach is that if nanoparticles do end up in normal tissue in a part of the body that is not irradiated, they will not be activated. “The nanoparticles are not going to have any effect if they’re not exposed to near-infrared light,” said Dr. Li. In the siRNA experiment, the nanospheres did not cause side effects in the liver, spleen, kidneys, or lungs.

Dr. Lu noted, “Any siRNA should be able to work with this technology. We think that because we can control the time and location of expression, it might be possible to deliver siRNAs in a sequential fashion by incorporating two different siRNAs and using different wavelengths of light to activate them.”

Furthermore, the Cancer Research article reported the potential of a one-two-three punch: combining photothermal ablation, siRNA release, and release of a chemotherapeutic agent, irinotecan. The team believes that the photothermal and siRNA treatments sensitized the cervical cancer cells to chemotherapy.

Biocompatible and biodegradable

The concept of a therapy-loaded nanoparticle is being pursued by other MD Anderson researchers who are using different materials. Gabriel Lopez-Berestein, M.D., a professor in the Department of Experimental Therapeutics, has spent 25 years working with lipids and other biocompatible materials for delivery of therapeutic agents. He and Anil Sood, M.D., a professor in the Departments of Gynecologic Oncology and Cancer Biology, are developing two different types of therapeutic nanoparticles loaded with siRNA.

The nanoparticle closest to being available for clinical use is a nanoliposome made of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). This neutral lipid-based molecule has no net charge and therefore escapes filtering by immune cells. The group recently completed tests of this nanoliposome loaded with siRNA targeting the gene for EphA2, a protein involved in tumor growth, invasion, and angiogenesis. “EphA2 is present at high levels in a lot of tumors, but it’s virtually absent in normal adult tissues,” said Dr. Sood, “so from a toxicity perspective we thought that it was attractive.” The nanoliposomes successfully accumulated in ovarian tumors in animal studies. “With this tiny fatty particle, the neutral nanoliposome, the siRNA is protected in the body,” added Dr. Lopez-Berestein. “It doesn’t break down, and this particular lipid is taken up avidly by ovarian cancer cells.” In mice, tumor growth was reduced after treatment, and more so when the siRNA was combined with chemotherapy or with a second form of siRNA that targets a different gene. Extensive toxicology testing of the DOPC-EphA2 nanoliposomes has been conducted in mice and nonhuman primates.

More Therapeutic Nanoparticle Research Projects at MD Anderson
(Opens in new window)

Liposomal applications, such as intravenous liposomal doxorubicin injection, are already approved for clinical use, and Drs. Lopez-Berestein and Sood plan to open a nanoliposome clinical trial within a year.

Another nanoparticle the two physician-scientists are developing is made of chitosan, a polysaccharide found in crustacean exoskeletons. Chitosan nanoparticles are loaded with a different siRNA, one that targets a gene that is important in cancer cells and in tumor blood vessels. In an orthotopic ovarian cancer mouse model, the chitosan nanoparticle delivered siRNA not only into tumor cells but also into blood vessels, and the target gene was shut down. The team hopes to bring this therapy to a clinical trial within 2 years.

Drs. Sood and Lopez-Berestein continue to tweak their nanoparticle treatments to improve the treatments’ efficiency. Like Dr. Li’s group, they are attaching markers to the particles that can increase the particles’ odds of reaching tumor cells. Drs. Sood and Lopez-Berestein will also continue to test different combinations of siRNAs customized to particular tumor types. “An advantage of this modality is you can target pretty much any gene of interest,” said Dr. Sood, “so it offers a lot of flexibility.”

Many possibilities

In addition to these and other therapeutic applications, nanoparticles are proving useful for imaging. “They have the potential to be multifunctional,” Dr. Curley said. For example, nanoparticles are being developed to concentrate a fluorescent or contrast agent in tumor cells, providing better detail on computed tomography and magnetic resonance imaging scans. “With our colleagues in the Department of Imaging Physics,” said Dr. Li, “we’re looking at combining therapy and diagnostics—theranostics.” The same particles would be used for imaging and for treatment; infrared light would be applied to the locations shown by either positron emission tomography or photoacoustic tomography to contain cancer cells. These approaches are being tested in small-animal models.

No one innovation discussed here is likely to become the single standard nano modality of the future. Rather, customized approaches to nanotherapy may emerge in which physicians identify the specific characteristics of an individual patient’s cancer, select a modality that targets that specific set of characteristics, and select a nanoparticle that works best with that modality.

A critical mass of interest and funding has contributed to the profusion of nanomedicine projects. MD Anderson is involved in the Alliance for Nano-Health, an effort involving hundreds of researchers within eight institutions centered on Houston’s Texas Medical Center. Headed by Mauro Ferrari, Ph.D., a professor in the Department of Experimental Therapeutics, the alliance’s goal is to foster collaboration on nanotechnology applications in medicine. “We’re trying to join forces to gain a deeper understanding of how nanomaterials interact with the body, how they are transported to the cells, and how they are cleared from the body,” Dr. Li said.

These small particles have the potential to make a large impact in the clinic soon.

Using siRNA to Silence Genes

Considering it was once classified as “junk,” small interfering RNA (siRNA) has come a long way in garnering researchers’ respect.

Anil Sood, M.D., explained what siRNA is. “There’s a lot of genetic material that is noncoding, meaning it’s not involved in making proteins. People thought that it had no purpose. It turns out that a lot of this so-called junk DNA actually plays a role in regulating or controlling the activity or the levels of many of the genes that do make proteins.” siRNA is one form of this noncoding genetic material; microRNA is another. It is unknown how many of these noncoding RNAs control genes or pathways that drive tumor growth.

siRNAs, which are 20–26 bases long, bind to specific messenger RNAs (mRNAs) and break them down so the mRNAs aren’t translated into proteins. siRNAs can be used to manipulate target genes in a strategy called RNA interference. “RNA interference offers an opportunity for shutting off, or silencing, genes,” Dr. Sood said. Dr. Sood, along with George A. Calin, M.D., Ph.D., an associate professor in MD Anderson’s Department of Experimental Therapeutics, heads the Center for RNA Interference and Non-Coding RNAs, a collaborative effort among five Houston-area research centers focused on understanding these RNAs’ roles in cancer initiation, progression, and dissemination.

A challenge of developing therapy with siRNA has been figuring out how to deliver it to the tumor site. “One of the limitations of using siRNA is that if you just inject naked siRNA into the body, it gets broken down within minutes—it has no real stability,” Dr. Sood said. “It gets excreted by the kidneys very quickly. So we needed a way to protect these particles so that they can be present in the body long enough to get to the needed site and actually get inside the tumor cells.” Nanoparticles—whether made of gold, lipid, chitosan, or another material—may offer the protection needed to make siRNA therapy possible.

For more information, call Dr. Curley at 713-794-4957, Dr. Li at 713-792-5182, Dr. Lopez-Berestein at 713-792-8140, or Dr. Sood at 713-745-5266.

Other articles in OncoLog, September 2010 issue:


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