This article originally appeared in the April 2012 print edition of DOTmed Business news.

Advances in the field show promise for what seemed like wishful thinking only a century ago.

Glioblastoma, the brain tumor that killed U.S. Senator Edward “Ted” Kennedy in
2009, is one of the most common—and most aggressive—types of brain tumor there is. Once a diagnosis is confirmed, a patient’s typical course of treatment is surgery. But tumor removal is a tactile and visual procedure. Oftentimes, a surgeon can’t recognize and remove every single piece of cancerous tissue. In turn, this can cause tumor re-growth in a patient and the causalities that may follow.



Nanomedicine, or the application of science at the nanometer or molecular scale, has the potential to change this. Using nanotheranostics – a combining of therapeutic and diagnostic techniques in nanomedicine – researchers at Stanford University have developed an imaging technology that specifically detects Glioblastoma cancer cells, along with a novel approach to destroying them.

“We have nanoparticle-based imaging agents that can be injected into tumor sites,” says Dr. Demir Akin, deputy director of Stanford University’s Center for Cancer Nanotechnology Excellence and Translation. “Because tumor sites have leaky blood vessels due to the gaps between the cells, the nanoparticles can go through those gaps.”

According to Akin, paired with infrared light, nanoparticles built to locate and infiltrate cancer cells can be used in an imaging capacity (the diagnostic portion) and since the infrared light is absorbed by the nanoparticles, the tissue containing the particles is, in turn, heated. Ultimately, this leads to the destruction of the metastatic tumor tissue.

“It is impossible to say how many nanomedicine research projects are ongoing globally at the current time, but it is certainly a rapidly expanding field,” says Ruth Duncan, co-author of “Nanomedicine(s) under the Microscope,” which provides a review of the history and evolution of nanomedicines, as well as the emerging opportunities to come.

Duncan says that nanotechnologies are being developed for applications in health care and medicine in several different ways. Nanomedicine can provide new surgical tools and devices that can be used outside the patient, and it can offer biomaterials to aid in tissue repair and drug delivery (often combined with cell therapy). As for disease, innovations are three-fold: diseases can be more accurately imaged and monitored during treatment, and therapies can be individualized and precisely targeted for better outcomes.

Duncan points out that more than 40 nanomedicine products have already been approved for clinical use. Among the oldest are the iron nanoparticles used to treat anemia. However, many of these first-generation medicines have been directed toward cancer. Liposomal and nanoparticle anti-cancer agents are routinely used, as are polymer conjugates of proteins.

The anticancer therapies Doxil (nano-liposomes) and Abaxane (albumin-based nanoparticles) are perhaps the most well-known. Doxil was first approved by the Food and Drug Administration in 1995 to treat AIDS-associated Kaposis sarcoma, but it is now widely used to treat a variety of different cancers. The FDA approved Abraxane in 2005 to treat metastatic breast cancer and it has since entered subsequent trials to test for additional treatment uses.

Following the money
It’s hard to predict when other nanomedicines might enter the market in the coming years and decades. What is clear, however, is the growing amount of nanomedicine projects underway in the U.S.

If numbers are any indication, the National Nanotechnology Initiative — part of the NIH —reported a major jump in funding: from $50 million in 2003 to roughly $500 million for 2011, the last year data were available.

Around 70 nanomedicine projects, of an estimated 250 through the NIH, support nanomedicine and cancer. And many of these projects have entered clinical trials.

“I’d say it’s a mix of applied research and some translational projects to create a new body of knowledge, but also to develop concepts for the clinical environment,” says Dr. Piotr Grodzinski, director of the National Cancer Institute’s Alliance for Nanotechnology in Cancer Program. The program supports several interdisciplinary academic centers involved with nanomedicine and cancer, as well as individual research and training programs in the field.

A few factors account for the increased amount of attention and resources that
nanomedicine advocates have bestowed upon cancer. Grodzinski says that from a budgetary standpoint, it helps that there’s already a vast workforce in place dedicated to oncology issues. In addition, the mortality rate for cancer is still high and there’s an unmistakable need for more successful treatment options despite several in-roads over the past 25 years to advance cancer therapies.

“Everyone knows the side effects of chemotherapy are terrible. Nanoparticle-based delivery for a therapeutic approach can give you more localized delivery and therefore, more effective treatment with fewer side effects,” says Grodzinski.

Nanoparticles as imaging agents
In addition to imaging and treating Glioblastoma brain tumors, the research team at Stanford University is currently working with the FDA to get the go-ahead to carry out additional clinical trials for a nanoparticle-based imaging agent that can detect colorectal cancer at an early stage.

Molecules that can report the cancer-lesion sites are a
promising way to catch the cancer early, and it’s something that colonoscopy can’t do because lesions are too small to be recognized by the unaided human eye. Stanford researchers have engineered nanoscale gold balls and attached them with a tag molecule that can recognize these cancer cells.

“The nanoparticles can detect the cancer cells and bind to them. It’s highly specific and sensitive binding. We’ve shown this in pre-clinical studies at Stanford and in human trials at the VA Hospital,” says Akin.

But there’s another reason this technology stands apart from other imaging agents using nanoparticles: These particular nanoparticles prove non-toxic in studies conducted on mice in Dr. Sam Gambhir’s lab at Stanford. Gambhir is the lead researcher on this project, as well as many others that Stanford has initiated involving early detection of cancer through nano-sensing imaging platforms.

Nanomedicine under the microscope
Safety is a key concern when any medical breakthrough is introduced, and nanotechnology receives more scrutiny than most. Part of the reason may be related to its “newness” factor, and the fact that many nanomedicine characteristics are not well-known. But federal regulations are in place to understand these nanomaterials in the in vitro and in vivo environment, and any formulation that reaches the point of submission to the FDA requires a thorough investigation from a toxicology standpoint to move forward in the regulatory process.

Additionally, brand new organizations, such as the Nanotechnology Characterization Laboratory, have been set up to perform preclinical efficacy and toxicity testing on these nanoparticles with the goal of accelerating the transition of nanomedicine research into clinical applications.

Although several diagnostics and therapies for nanomedicine have entered Phase I or Phase II clinical trials, the journey of these new technologies from lab to marketplace can’t be truly realized until large-scale safety and efficacy studies are carried out.

The nano team
In order for nanomedicine’s clinical challenges to be met, experts in the field say it’s important to have all scientific communities on board, working together as teams.



“It is essential to bring together the academic, industrial, regulatory, and ethical and societal players relating to nanotechnology,” says Duncan.

Stanford University works collaboratively with other academic institutions on many of its nanomedicine projects. For example, researchers in Dr. Shan Wang’s lab at Stanford are developing magneto-nano protein chips, or sensors, to directly complement a bioassay test developed at CalTech. Essentially, this is a diagnostic technique that takes blood, serum or tissue samples from a patient and puts it on the magneto-nano sensor chip to detect the tumor markers. A biomarker is a measurable indication that correlates to a specific disease, in this case, brain tumor and lung cancer. And researchers are using biomarkers discovered by both institutions to diagnose cancer early and monitor treatment more effectively.

“This platform is unique because typically, these assays are done
with ELISA [the enzyme-linked immunosorbent assay] but the sensitivity is not great and the cross-reactivity of the detector antibodies causes problems in ELISA. But the magneto chip is immune to those and has clear and substantial advantages over many currently existing cancer detection technologies,” says Akin.

At the same time, these researchers are establishing the rules of assay comparisons between different labs and detection technologies, a major hurdle in and of itself in cancer detection and treatment areas.

From researcher to entrepreneur
It’s probably no surprise that many of these interdisciplinary teams want to advance their nanomedicine projects beyond the lab. And many have already taken the leap into the business world.

“We started the program [Nanotechnology for Cancer] seven years ago and I see more activity in the translational space now than in the beginning. There are a number of companies that have been established by these academic researchers,” says Grodzinski.

Stanford University licensed part of its magnetic bioassay chip technology to MagArray Inc., a startup company in Silicon Valley.

The founders of MagArray saw an opportunity in biomarker research, just as their colleagues did at Stanford. But they took it one step further by commercializing their product— a technology that is based on the computer disk drive industry that they have adapted for medical diagnostics.

“[The founders] took that same technology and realized that the sensor at the tip of the arm of a disk drive that goes back and forth could be embedded into chips. But instead of having a magnetic plate, you take nanoparticles and use those as a label. We can mix that with our sample and measure the presence of nanoparticles,” says MagArray CEO Luis Carbonell.

The end product is a biodetection chip that uses nanoparticles to zero in on proteins in a patient sample, and find tumor antigens—shed by cancer cells—in the blood with much greater sensitivity, adding to the growing body of nano-based diagnostic tools used to detect the presence of cancer at an early stage.

Dr. Robert Langer, the David H. Koch Institute Professor at the Massachusetts Institute of Technology, says that nanomedicine is transforming diagnostic and therapeutic capabilities for cancer through these ultra-rapid diagnostics. As a pioneer in the field of nanomedicine, with accomplishments spanning over 20 years, Langer’s research and subsequent business ventures seek a similar goal to create ultra-rapid diagnostics, in addition to brand new targeted therapies.

The basis of Langer’s work revolves around small interfering RNAs, discovered in the late 1990s. These tiny pieces of RNA have the ability to shut off specific genes, for example, an aggressive type of cancer. Along with Dr. Omid Farokhzad at Harvard, Langer has developed RNA molecules as tools to guide nanoparticles into cancer cells and deliver drug therapies more effectively.

As their research progressed, Langer and Farokhzad founded a Cambridge, Mass.-based company called BIND Biosciences to commercialize their product. The nanoparticles they’ve engineered are able to deliver higher and more effective doses of drugs to tumors, while at the same time sparing healthy tissue—something that chemotherapy treatment is not able to do and accounts for its adverse side-effects. They pack Docetaxel, a common cancer drug, into these specially engineered nanoparticles, which allows them to bind to the cancer cells and not the healthy cells. Phase I clinical trials are currently underway to look at safety and to determine proper dose design of these highly selective targeted therapeutics.

Langer is also involved with applications of nanomedicine beyond cancer therapies and diagnosis. Selecta Biosciences, another company he co-founded, has been working on developing synthetic vaccines and immunotherapies. This past November, the company announced a Phase I clinical trial to review the safety, tolerability and pharmacodynamic profile of SEL-068, a nicotine vaccine candidate for smoking cessation and relapse prevention. His third company, T2 Biosystems, engineers lab-quality diagnostic tools based on nanoparticle technology.

Nanomedicine’s Holy Grail
A futuristic view of nanomedicine might resemble something like a nanomachine that could precisely target diseased cells in the body, travel directly there, and repair them. If such a nanomachine existed, it would be the end of disease as we know it. The idea isn’t as farfetched as it might seem.



Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard have been able to engineer a DNA nanorobot with the ability to seek out specific cell targets and deliver molecular instruction, like telling the cancer cells to destroy themselves. Its basic sensing capabilities allow it to do this. The nanorobot can distinguish between different cells depending on what proteins are present on their surfaces. Shawn Douglas, who helped develop the technology, says the nanorobot is able to do this because it’s locked shut by special DNA sequences called “aptamers.” When the robot’s aptamer “locks” recognize the “key” proteins on a cell surface, they unzip and reveal the payload.

Tests using this nanorobot have only been conducted on leukemia and lymphoma cell cultures in the lab so far. In order to test on animals, the team will have to figure out how to make custom DNA synthesis cheaper, in addition to redesigning the nanorobot’s basic structure so that it can survive in the human bloodstream.

This nano-robot may have been what Dr. Paul Ehrlich imagined over 100 years ago when he coined the term “magic bullet.” Ehrlich, the founder of chemotherapy, is widely regarded as one of the grandfathers in the field of drug targeting. He first used this phrase “magic bullet” to describe his dream of localizing drugs specifically to their intended therapeutic target cell, or compartment of the cell. Many current nanomedicines in development today have been built upon several advanced drug delivery options that recall the early dream of Ehrlich.

The journey continues
Despite these breakthroughs, nanomedicine has a long way to go before its benefits can be fully realized. In an email to DOTmed Business News, a spokesperson for the National Nanotechnology Initiative’s Coordination Office said that funding for clinical trials and commercial success stories are among some of the current challenges.

“The field sentiment is that there are many very successful preclinical success stories, and some very interesting Phase I and Phase II studies being conducted. However, venture capital firms and pharmaceutical companies are waiting for an exemplary nanoparticle clinical success where a particle has been engineered with either a novel API and/or disease-specific targeting has been demonstrated before they make investments in this area,” the source said.

Although clinical trials have begun for many of these nanomedicine products, it’s likely to take years—and more testing—for a success to surface.

In order for nanomedicine to deliver on its promise to improve health care in the coming decades, necessary steps are needed to translate these ideas into clinical trials. Duncan includes responsible scientific experimentation in her recent assessment of nanomedicines.

“One of the main challenges, I believe, is the need for basic researchers to understand the difference between advances in nanoscience — which are many and brilliant — and the need for nanotechnologies that can be produced
on a commercial scale using a ‘quality-by-design’ approach’ to give safe and effective products that can be used in society to improve the diagnosis and treatment of diseases,” she says.

She’s also weary of academic research that can overhype a new cancer treatment, for example, and where the general public is often left with a false notion of the research. The job for academics, she explains, is to be honest about where they are on that journey from idea to patient.

Of course, there’s also the challenge to ease any and all concerns the public might hold about nanotechnology. NCI’s Grodzinsky says this will require a larger effort from the health care community, but also participation from practicing physicians in the years to come.