The control of matter on the atomic and molecular scale continues to trickle into med-tech companies' portfolios of enabling technologies. It's changing the way devices are developed and is expected to vastly improve the entire spectrum of diagnostics and treatments for virtually every disease and condition.

That's a huge pill to swallow, (though the technology we're talking about here is so small), but the wow factor is hard to deny.

Take for example a recent breakthrough at Arizona State University (Phoenix) in which researcher Wayne Frasch, PhD, has developed a nanodevice that employs a molecular motor to be used as part of comparatively inexpensive biosensor that could revolutionize health screenings for diseases like anthrax, AIDS, cancer and Methicillin-resistant Staphylococcus aureus (MRSA).

It starts with the world's tiniest rotary motor, a biological engine measured on the order of molecules. Frasch used the enzyme, F1- ATPase — just 10 nm to 12 nm in diameter — which has an axle that spins and produces torque. F1-ATPase breaks down adenosine triphosphate (ATP) to adenosine diphospahte (ADP), releasing energy. Previous studies of its structure and characteristics have been the source of two Nobel Prizes awarded in 1979 and 1997.

But it was through Frasch's own detailed study of the rotational mechanism of the F1-ATPase — which operates like a three-cylinder Mazda rotary motor — that he showed the enzyme can be armed with an optical probe (gold nanorods) and manipulated to emit a signal when it detects a single molecule of target DNA, such as staph.

The whirling nano-sized device actually emits a pulsing red signal that can then be seen with a microscope and, voila!, infections such as MRSA are spotted.

The technology was developed with initial funding from the U.S. Air Force Office of Scientific Research and the Department of Defense. But Frasch is now moving beyond proof of concept, has developed a prototype and is spinning out a new company, to be unveiled in May, with support from Science Foundation Arizona (Phoenix) and an undisclosed venture capital firm.

Frasch's nanodevice can detect MRSA infections within 20 minutes at $1 a pop, far exceeding the detection limits of conventional polymerase chain reaction (PCR) technology which often costs $90 per test, requires expensive lab equipment, specially trained personnel and takes hours to days to get results.

MRSA and other infections garnered in hospital settings are the fourth leading cause of death in the U.S., and they cost an average of $57,000 per patient for diagnosis and treatment, according to the Centers for Disease Control and Prevention (Atlanta).

"MRSA costs U.S. hospitals $30 billion to treat patients each year," Frasch told BB&T. "Current technology takes up to a couple of days. To stem the rapid spread of MRSA, we need diagnoses faster."

What's also unique about Frasch's nanomotor-charged biosensor is that it will be inexpensive to produce and portable, meaning it could be used in places such as Africa, to more cost-effectively screen for AIDS.

"I think we're really going to be competitive in applications in remote locations where they need cheaper instruments," he said. "You just need a cheap microscope with a digital camera interfaced with a computer and another compartment for sample preparation from crude sample [blood or tissue] to prepare the slide."

The nanoparticles Frasch uses in the test kit are the "secret sauce" and, "quite frankly, making the particles so that they are useful for this assay is something that's unique to our lab and our project. The company will have exclusive rights on the manufacture and supply of these nanoparticles. It's the critical part of making this whole thing work."

Human-generated electricity for implants

Another product under development that's incorporating nanotechnology is one which aims to solve a problem presented by implanted devices such as pacemakers, implantable cardioverter defibrillators, drug pumps and neurostimulators.

Working collaboratively with the NASA Ames Research Center for Nanotechnology, and with $5.7 million backing from Boston Scientific (Natick, Massachusetts), Biophan Technologies (Rochester, New York) is developing a power source for implantable devices capable of generating electricity from body heat.

The need for a reliable electrical power source that does not require periodic surgical removal and replacement is obvious. Lithium batteries used in pacemakers have a useful life of five to seven years; ICDs, drug pumps, and neurostimulators have much shorter replacement intervals due to higher power drain.

"This is the most active nanotechnology related device that we're working on," John Lanzafame, CEO of Biophan, told BB&T. "It's an extension of existing technology that enables the use of heat to generate electricity. Applications of nanomaterials enable an improvement of efficiency. It's a nanotechnology application to thermal electric materials that are low tech in their larger scale applications. We're reduces the size of the materials for a thermal electric element — a chip that would be implanted body with thin film [nanometer size] coatings."

Lanzafame declined to reveal further details of the implant, which is about the size of a quarter, but said, "We're pushing the limits in terms of size and efficiency. It's really still in the material development stage and we can't offer guidance yet on when we'll get into trials."

Biophan's biothermal power source is expected to provide at least twice the service life of existing batteries, and potentially many times more; reduced life-cycle costs, including the costs and risks of surgical procedures required for conventional battery replacement; and the reduction or elimination of potentially toxic materials found in conventional batteries.

Biophan has other nanotechnology-related products in the works, including nanomagnetic drug carriers that offer the possibility of improved drug efficacy and reduced toxicity by delivering pharmaceuticals to the exact location of need and releasing them at the appropriate time and nanomagnetic drug-eluting devices designed for improved drug-elution for medical devices such as stents and orthopedic implants, with greater control over the release of drugs.

Both of these projects are in earlier development stages than the biothermal power source and don't seem to have the same kind of heavyweight financial backing .... at least not yet.

Celsion on to Phase III with ThermoDox

Other companies are well beyond the development stage — such as Celsion (Columbia, Maryland), incorporating nanotechnology into a treatment for liver cancer and jumping head first into Phase III trials.

It's the ability to engineer smaller drug delivery vessels, liposomes, that is enabling Celsion to better target commonly used cancer drugs for more effective outcomes. Combining this with radiofrequency ablation (RFA) results in a one-two punch against deadly malignancies.

Celsion said it is skipping Phase II trials and moving directly into a 600-patient Phase III study, a move decided upon after the company examined Phase I data indicating that the therapy reduced tumor size. Those results were released in late March at the 33rd annual scientific meeting of the Society for Interventional Radiology (Fairfax, Virginia).

Celsion is working with the FDA under a special protocol agreement and is skipping to Phase III because, "We believe the doxorubicin's mechanism of action and safety profile are already well understood by medical and regulatory community," Michael Tardugno, president/CEO of Celsion told BB&T.

Celsion has employed 100 nm liposomes to deliver the cancer drug, ultimately creating a new drug, ThermoDox.

Computed tomography images of liver lesions from the Phase I study — treating patients with primary and metastatic liver cancer — were presented at SIR in a program entitled "Imaging Features in Patients undergoing Liver RFA plus Heat Deployed Nanoparticles." It included images that showed differences in the X-ray appearance and size of tumors following treatment the ThermoDox/RFA treatment, compared to tumors of other patients treated with RFA alone.

Liposomes are nanoparticles, artificial vesicles composed of one or more concentric phospholipid bilayers, used in drug delivery. Many liposomal drugs do not actively target organ-specific tumors.

Multiple imaging agents

While Celsion has combined nanoparticles with RFA to treat disease, a number of companies are employing molecular agents to enhance diagnostic imaging, ultimately hanging a crisp Bullseye target on disease with a level of clarity unmet by current imaging agents.

Iron oxide nanoparticles, fluorescent nanoprobes, gadofullerenes, nanorods, dendrimers, semiconductor nanocrystals and quantum dots are all being used in products that are well on their way down the development and regulatory pipeline.

But these diagnostics developers are facing a variety of challenges along the way, not the least of which are regulatory speed bumps. For example, AMAG Pharmaceuticals (Cambridge, Massachusetts) is battle-weary in its efforts to advance Combidex, a molecular imaging agent consisting of iron oxide nanoparticles for use in conjunction with magnetic resonance imaging (MRI) to aid in the differentiation of cancerous from normal lymph nodes.

AMAG first submitted Combidex to the FDA in March 2005, but the agency asked for more clinical data to prove Combidex's effectiveness. Then, late last year, AMAG's European marketing partner Guerbet (Paris) withdrew its application for Combidex (known as Sinerem in Europe) with regulators there after they indicated it was not effective.

"We had planned to wait and see how Guerbet's application procedure went," AMAG president/CEO Brian Pereira, MD, told BB&T. "Unfortunately, the panel there found that, on the sensitivity side, the evidence was not absolutely convincing. Guebert withdrew the application. Now they will go and fix the problems and resubmit the application. At this point in time, we'll wait to see what Guebet plans to do."

As Combidex now hesitates in the wings, Kereos (St. Louis) is headed into Phase I trials with its targeted nanoparticles that help to illuminate tumors. Dubbed KI-0001, Kereos' lead candidate allows earlier detection and diagnosis of a wide variety of solid tumors by highlighting the vasculature around tumors to help detect much smaller cancers around one to two millimeters — in an MRI.

"KI-0001 is going to be effective in a number of ways," Kereos' president/CEO Robert Beardsley, PhD, told BB&T. "It can be used for cancer staging of tumors. An oncologist looks at a tumor to determine if it has spread or is contained, and how big is it. With this agent, you are better able to find how far this tumor has spread. Another purpose of great value is that if the tumor is not a living tumor, if it's a cyst, it won't light up so you're also going to get this positive confirmation that this is or is not a living tumor.

Avastin is expensive; it can cost up to $100,000 per year for the biotech drug developed by Genentech (South San Franciso). Beardsley pointed that that, in addition to treatment advantages, KI-0001 could help reduce healthcare expenses

Kereos' KI-0001 is a targeted nanoparticle based on a ligand-targeted emulsion technology. Individual emulsion particles consist of a perfluorocarbon core surrounded by a lipid monolayer. This lipid layer both stabilizes the particle and provides a virtually unlimited number of anchoring sites for targeting ligands and payload molecules. The result is an oil-in-water emulsion of particles with an average size of approximately 250 nm.

"We've had some very good conversations with the FDA, Beardsley said. "The challenges are that you've got something that's more complex than a normal imaging agent." He said he expects clinical trial sites to start using KI-0001 while imaging patient by the first quarter of 2009.

Regulatory mountains to climb

"Major hurdles still stand in the way of the public, industry and government in obtaining a better understanding of the risks posed by nanomaterials and how to limit those risks," PEN director David Rejeski said. But a company such as Kereos (St. Louis), which is headed into Phase I trials with its targeted nanoparticles that help to illuminate tumors, are simply bracing themselves and flat out expect to be under the microscope.

"I'm sure we will have additional scrutiny," Kereos' president/CEO Robert Beardsley, PhD, told BB&T. "The FDA has been driven politically to have zero tolerance in respect to making any kind of mistakes."

In the area of medical devices the critical issue for nanotechnologies is the lack of risk-research for nano-scale materials, said Julia Moore, deputy director of the Project on Emerging Nanotechnologies at the Woodrow Wilson International Center for Scholars (Washington).

Moore said the organization doesn't anticipate a lot of problems with nanotechnology — or "nano-dangers" — but that more research is needed in this area so FDA can regulate these products.

"The agency needs that added expertise and those resources to be able to continue to ensure the safety of the product," Moore said. She acknowledged that FDA is in the process of gathering information but "has not one dime for risk-research on nano-material. So yes, they are doing things, but they clearly don't have the resources to do what is needed and necessary."

Biophan CEO John Lanzafame agrees that there's still much work to be done at the FDA.

"It's early in the game for us," said Lanzafame, whose company, as noted previously, is developing a body-heat source of power source for implantable devices. "I think there have been improvements in that area, but as you get down into nanomaterials, there are more questions raised than answered regarding concerns about toxicities. There have been improvements at the FDA, but that's there's still room for better understanding."

Others company leaders are more positive about surfing the rugged regulatory waves.

BB&T asked Pereira of AMAG if his has come up against added challenges in trying to get a product approved that contains nanotechnology.

"Not really," he said.

AMAG has been working since 2005 to get Combidex approved. The molecular imaging agent consists of iron oxide nanoparticles for use in conjunction with MRI to aid in the differentiation of cancerous from normal lymph nodes. The company received an approvable letter, but then was asked by the FDA to provide more proof of effectiveness. "The FDA is quite knowledgeable about what the product is," he said. "Lay persons' concerns about nanotechnology are not quite translated into pharmaceutical arena."

What's ironic is that public fear of nanotechnology developments are coming very much late in this particular technology game.

"I think we do not know how many products are actually on the market today that use nanotechnology," Pereira pointed out. "Nanotechnology has been a label some people choose to flaunt and others choose not to. What is already out there that is nanotech is completely unclear."

WWC's Moore said an analysis on the Project on Emerging Technologies was conducted using 2006 data and found that more than 130 nano-based drugs and delivery systems and about 125 devices or diagnostic tests were in development. But that was based on 2005 data, not yet updated.