Nanotech advancements: scientists harness nanotechnology to better diagnose and treat cancer.
Dean Ho, PhD, a professor in the division of oral biology and the division of advanced prosthodontics as well as codirector of The Jane and Jerry Weintraub Center for Reconstructive Biotechnology at the University of California at Los Angeles (UCLA) School of Dentistry, is excited about the promise nanotechnology holds in better treating and diagnosing cancer. “A major challenge in cancer therapy is drug resistance, and our group and others are finding that when drugs are modified with nanoparticles, they are less toxic and stay in the tumor longer,” he says. “You also can add targeting agents and antibodies to focus drug delivery more effectively.” Dr. Ho's work involves nanoscale, diamond-like particles called nanodiamonds. They resemble mini soccer balls and are made from a carbon material that is well tolerated in living organisms. He and his colleagues have used nanodiamonds to deliver doxorubicin, a highly toxic cancer drug. The synthesis of the 2, known as NDX, has been studied in a variety of cancers, including those of the breast, blood, liver, and brain, generating promising results. In the realm of imaging, Dr. Ho's research team also has investigated the use of nanodiamonds in helping to better locate tumors and significantly reduce the toxicity of dyes that are injected into patients for magnetic resonance imaging. Dr. Ho began his research on nanodiamonds while at Northwestern University in 2007. “Taking this sustainable biomaterial made from mining and refining operations and watching it go from just a proof of concept to showing it's safe in large animals has been a very interesting clinical journey,” he says. “Hopefully, in the next 9 to 12 months we'll have a small clinical study.” His work is just one example of the many research projects being performed across the country that are developing nanomedical approaches to combatting cancer. The first nano drugs approved by the US Food and Drug Administration (FDA) for the treatment of patients with cancer were doxorubicin in 1995 and paclitaxel in 2005. Since that time, the field has continued to evolve. The National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer has been leading funding efforts in the use of nanotechnology since 2004. The Alliance will start its third funding cycle next year and at press time was about to issue its latest grants solicitation. “Round 1 was very open, and in round 2 we suggested focusing on 4 tumor types with low survival rates: ovarian, pancreatic, lung, and brain,” says Piotr Grodzinski, PhD, director of the Alliance. “We are continuously encouraging translational work and having academics involved in the program reach out for alternative funding to move the technology to the translational and even commercial phase.” Toward that end, the Alliance funds 9 centers of excellence at academic medical centers across the country charged with developing nanotechnology applications for clinical oncology. One example of a technology that is already in clinical trials was developed by Robert Langer, ScD, codirector of the MIT (Massachusetts Institute of Technology)- Harvard Center of Cancer Nanotechnology Excellence in Cambridge, Massachusetts. Dr. Langer, who began working on nanotechnologies in the 1970s, helped to lay much of the groundwork for the field. He and his Harvard Medical School colleague Omid Farokhzad, MD, founded BIND Therapeutics in 2007 to develop innovative pharmaceutical products based on nanomedicine. Their second-generation therapeutics, known as accurins, are polymeric nanoparticles designed to deliver a payload to the tumor site and have prolonged circulation in the bloodstream. Accurins are designed to target tumors at the tissue, cellular, and molecular levels. They also have been engineered for controlled and timely release. BIND Therapeutics has collaborated or is collaborating with Amgen, Pfizer, AstraZeneca, and Roche to develop these therapeutics. The company is conducting 2 phase 2 trials of 40 patients each in the second-line treatment of non-small cell lung cancer and the first-line treatment of metastatic, castrate-resistant prostate cancer. They expect to report top-line results from these studies later this year. Other investigators who have developed promising nanotechnologies for cancer include Mark Davis, PhD, of the California Institute of Technology (Caltech) in Pasadena, California, who has developed a nanoparticle for the delivery of chemotherapeutics and small interfering RNA (siRNA), which is currently being tested in clinical trials; Chad Mirkin, PhD, of Northwestern University in Chicago, Illinois, who has designed a wide range of diagnostic devices for the detection of biomarkers; and James Heath, PhD, also of Caltech, who has developed devices that monitor levels of protein in the blood and in single cells, which are being used in immunotherapy clinical trials. “We have a good mix of diagnostic and therapeutic discoveries that are becoming more practical,” Dr. Grodzinski says, noting that in therapeutics, promising new nanoparticle platforms not only appear to reduce side effects but also enable greater accumulations of drugs at the tumor site. He points to 2 other NCI Alliance nanotechnology initiatives that are helping to advance the field. The first, known as the Nanotechnology Characterization Lab (NCL), performs preclinical efficacy and toxicity testing of nanoparticles. The NCL serves as a resource for cancer researchers investigating nanoscale particles and devices and is a collaboration between the NCI, the National Institute of Standards and Technology, and the FDA. The second is a public-private industry partnership known as Translation of Nanotechnology in Cancer. The consortium brings together government entities as well as pharmaceutical, biotechnology, and other health care-related companies to expose them to and seek their input on future directions of nanotherapeutics. Dr. Grodzinski hopes to see more clinicians involved in the early development of cancer nanotechnologies well before the clinical trial stage. “We need to have a broader exposure of these technologies to practicing clinicians so they can guide the selection of the application and become more involved in the design process,” he says. Drs. Grodzinski, Langer, and Ho agree that nanotechnology faces the same challenges as other new cancer treatments and diagnostics in terms of funding, regulatory pathways, and weighing risks versus benefits. Nevertheless, they anticipate seeing FDA approvals for some of these new nanoparticles and devices within the next 5 years. Although it is not completely clear how these materials might affect patients in the long term, that should not discourage scientists and clinicians from working to bring them into the clinic, Dr. Ho says. “People should embrace [nanotechnology] and learn as much as they can about it, because the benefits are there.” Our group and others are finding that when drugs are modified with nanoparticles, they are less toxic and stay in the tumor much longer. — Dean Ho, PhD Below are 2 recent nanotechnology drug developments in the treatment of cancer. In recent years, scientists have developed nanoparticles that deliver 1 or 2 chemotherapy drugs, but they have been unable to make particles that can deliver a larger number of drugs in a precise ratio. Recently, chemists at MIT in Cambridge, Massachusetts, have accomplished that goal. Senior author Jeremiah Johnson, PhD, an assistant professor of chemistry at MIT, and colleagues published an article in the Journal of the American Chemical Society describing how they were able to load their particles with 3 drugs commonly used to treat ovarian cancer.1 Dr. Johnson says he believes their research is the first example of a nanoparticle that delivers a precise ratio of 3 drugs and can release them in response to 3 different triggering mechanisms. The particles could potentially be designed to deliver more than 3 drugs, which would enable new treatments that could more effectively kill cancer cells while avoiding the side effects of traditional chemotherapy, he says. The investigators reported that the nanoparticles were able to more effectively kill ovarian cancer cells than particles with only 1 or 2 drugs. They have begun testing in tumors in animals. The work of encapsulating small drug molecules inside of, or chemically attaching them to, the nanoparticles becomes increasingly difficult with each new drug that is added. Dr. Johnson and his colleagues created a new type of particle that would enable the loading of many different drugs. Rather than building the particle and attaching drug molecules, they created building blocks that already include the drug and can be joined together in a very specific structure. In that way, scientists can control how much of each drug is loaded into the particle. The building block includes the drug molecule, a linking unit that can connect to other blocks, and a chain of polyethylene glycol that helps protect the protein from being broken down in the body. Hundreds of these molecules can be linked using an approach the researchers developed called “brush-first polymerization.” The study involved creating particles that carried cisplatin, doxorubicin, and camptothecin, which are used alone or in combination to treat ovarian cancer. The particles contained a ratio of the maximum tolerated dose of each drug, each of which had its own release mechanism. Cisplatin and camptothecin were designed to be released quickly whereas doxorubicin was designed to be released only when ultraviolet light shines on the particle. Once the drugs are released, polyethylene glycol is easily biodegradable, they say. The team is now working on particles that carry 4 drugs as well as ways with which to tag the particles with molecules, thereby allowing them to target tumors by interacting with proteins found on cell surfaces. Dr. Johnson adds that the nanoparticles could enable large-scale testing of potential new cancer treatments. A drug delivery system using nanomedicine technologies can precisely target cancer cells in the bone and increase bone strength to prevent the disease's progression, according to a study published recently in the Proceedings of the National Academy of Sciences.2 Researchers from Brigham and Women's Hospital and the Dana-Farber Cancer Institute in Boston, Massachusetts, developed stealth nanoparticles made of a combination of clinically validated biodegradable polymers and alendronate, which is a therapeutic agent that belongs to the bisphosphonate class of drugs. Bisphosphonates bind to calcium, which is highly concentrated in bones. The surface of the nanoparticles is decorated with alendronate, which can kill the tumor cells and stimulate new bone growth. Co-lead author Michaela Reagan, PhD, of the Dana-Farber Cancer Institute Center for Hematologic Oncology, notes that few treatment options exist for patients with bone cancer. At the same time, her colleague and co-lead author, Archana Swami, PhD, of the Brigham and Women's Hospital Laboratory of Nanomedicine and Biomaterials, says that bone is a favorable microenvironment for cancer cells that migrate from tumors such as those from the breast, prostate, and blood. The team tested the nanoparticles in mice with multiple myeloma. The mice were initially pretreated with nanoparticles loaded with the anticancer drug bortezomib before being injected with myeloma cells. The treatment led to slower cancer growth and longer survival. The drug also enhanced the strength and volume of the bone. The study authors add that their work provides proof of concept that targeting the bone marrow niche can prevent or delay bone metastasis and will pave the way for future clinical trials.
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