Keeping it small

Nanotechnology enables scientists to target cancer in new ways

Authors

  • Carrie Printz


Illustration 1.

From gold nanoparticles to programmable, wirelessly controlled microchips, the field of nanotechnology continues to offer new ways of diagnosing and treating cancer. Nanotechnology is defined as the science and engineering of manipulating matter at the molecular scale to develop devices with new chemical, physical, and biological properties. In cancer, it holds the promise of safer, more effective therapies.

“The advantage people often cite is that the therapy can be more selective by hurting fewer healthy cells than traditional therapy,” says Piotr Grodzinski, PhD, director of the National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer (“the Alliance”) in Bethesda, Maryland. “You also can accumulate more drug at the tumor site.”

Nanoparticles that can be used as chemotherapeutic drug carriers not only hold the promise of avoiding some of the toxic side effects of traditional therapy but also offer other potential advantages, including:

  • Protecting drugs from being degraded in the body before they reach their target;

  • Enhancing the absorption of drugs into tumors and cancerous cells; and

  • Enabling better control over the timing and distribution of drugs to the tumor, helping oncologists to better assess their effectiveness.

Targeted Therapies

The NCI's Alliance was initiated in 2004 with the goal of translating nanotechnology innovations to clinical applications in cancer biology and oncology. Since then, it has led to the publication of more than 1400 journal articles and the formation of close to 50 companies, many of which are working on clinical trials for drug delivery and evaluation of diagnostic techniques. Now in phase 2 of its efforts, the Alliance is encouraging researchers to create tools to diagnose and treat cancers with particularly poor prognoses, including brain, lung, pancreas, and ovarian tumors.

In addition, the Alliance supports the Nanotechnology Characterization Laboratory, which comprehensively characterizes nanoparticles and nanomaterials submitted by industry, government, and academia. These characterization efforts enable the understanding of the particles' basic mechanisms while ensuring that they are safe techniques. The laboratory has examined more than 250 formulations in the past 7 years, says Dr. Grodzinski.

The Alliance also funds 9 Centers of Cancer Technology Excellence, which are multidisciplinary centers focused on discovery and tool development of nanotechnology for clinical oncology. Among them is the Massachusetts Institute of Technology (MIT)-Harvard Center of Cancer Nanotechnology Excellence, of which Robert Langer, ScD, is a principal investigator. He and colleagues have developed targeted therapeutic nanoparticles with a homing molecule that enables them to specifically attack cancer cells. They are the first such particles to enter human clinical trials.

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[Nanotechnology therapy] can be more selective by hurting fewer healthy cells than traditional therapy. You also can accumulate more drug at the tumor site.Piotr Grodzinski, PhD

The advanced phase 1 trial has tested the particles in 22 patients, with promising results: tumor regression or stability and few side effects, says Dr. Langer. Each nanoparticle contains 1000 to 100,000 drug molecules. He describes it as a warhead that goes directly to the tumor vasculature, causing far fewer side effects than the drug itself. In this case, the drug was docetaxel, and the patients had already undergone traditional chemotherapy for advanced or metastatic tumors.

The trial was performed by researchers at BIND Biosciences, Cambridge, Massachusetts, a company cofounded by Dr. Langer and Omid Farokhzad, MD, in 2007. One of the challenges in developing the targeted nanoparticles, known as BIND-014, was to ensure that they could effectively evade macrophages and other immune system cells that might attack them. Researchers found a way to camouflage the nanoparticles. They also coated them with targeting molecules that recognize a protein called PSMA (prostate-specific membrane antigen), found abundantly on the surface of most prostate tumor cells as well as many other types of tumors. Because the therapy is more targeted than conventional treatment, Dr. Langer draws an analogy to hockey, noting, “you're getting a lot more shots on goal.”

He and Dr. Cima also recently announced the development of a programmable, wirelessly controlled microchip that would deliver drugs after implantation in a patient's body. They successfully used such a chip to administer daily doses of an osteoporosis drug normally given by injection, and published their results in the February 16 online edition of Science Translational Medicine.1The device could both improve telemedicine (delivering health care long distance) as well as ensure that patients comply with taking their drugs, says Dr. Langer.

Gene Regulation and Detection Technology

Meanwhile, researchers at the Northwestern University Center for Nanotechnology Excellence in Evanston, Illinois, are busy exploring ways to use spherical nucleic acids (SNAs) to both treat and diagnose cancer. In one study, for example, investigator Chad Mirkin, PhD, director of Northwestern University's International Institute for Nanotechnology, worked with MIT colleague Stephen Lippard, PhD, to develop gold nanoparticles as a delivery vehicle for a nontoxic form of platinum known as platinum(IV). The gold nanoparticles are coated with short pieces of nucleic acid to which the investigators chemically attach platinum(IV). The particles then circulate through the blood and enter tumor cells. Platinum(IV) undergoes a chemical reaction that converts it into platinum(II), which was more toxic than an equivalent dose of cisplatin.

SNAs are novel nanostructures composed of nanoparticle cores and densely functionalized, highly oriented nucleic acid shells, says Sarah Hurst, PhD, a research assistant at Northwestern University who works closely with Dr. Mirkin. “These materials have been shown to be highly efficacious in a number of gene therapy and intracellular detection schemes in part because of their ability to enter cells in high quantities without the use of transfection agents that are extremely toxic,” she says. “Advantageously, SNAs are also resistant to degradation once inside the cell and do not elicit an immune response, unlike free linear nucleic acids that traditionally have been used in these biomedical applications.” Dr. Hurst adds that SNAs also bind complementary strands at least 100 times tighter than their free linear counterparts.

In addition, SNAs serve as the basis for NanoFlares, which is a unique intracellular gene regulation and detection technology being developed by Northwestern University researchers. In this system, a short, fluorophorelabeled reporter strand is hybridized to the SNA and is quenched in close proximity to the gold nanoparticle surface. When the SNA enters the cell and encounters a genetic target of interest (such as a complementary messenger RNA strand), it binds to the SNA and kicks off a short reporter sequence. The fluorophore then lights up, because it is no longer quenched by the nanoparticle. This fluorescence can be used to quantify the amount of the particular messenger RNA that is present in the cell.

NanoFlares can be used to sort live cells based on their genetic content, so the cells can be used for subsequent analysis or culture, Dr. Hurst adds.

Reference

Ancillary