Nipping deadly diseases in the bud

  • With the help of PET/CT images and marker substances, physicians can determine if and where metastases have formed in the body of a cancer patient. Image credit: Siemens PoF
  • A prototype MR/ PET unit combines MR and PET images of the human brain in a single image (see above) that describes both anatomy and physiology. Image credit: Siemens
  • Diagnosing Alzheimer"â„¢s with PET. A new marker structure binds to plaques (yellow and red on right) typical of Alzheimer"â„¢s. (A: Healthy control; B: Mild cognitive impairment; C: Alzheimer's Disease.) Image credit: Siemens
  • Iron-bearing nanoparticles could be injected directly into the brain tumour and then heated using a focused magnetic field. The heat can weaken and even kill cancer cells. Image credit: Magforce Nanotechnologies
  • Tumour tissue imbued with magnetic nanoparticles. Image credit: Siemens
Date:31 July 2007 Tags:, , , , ,

Researchers are going to battle against deadly diseases, developing biomarkers that bind to key substances associated with Alzheimer’s, cancer and heart disease. As they learn to visualise these biomarkers with refined imaging technologies, they are discovering how to identify initial changes in cell metabolism, and opening the door to new therapies

Dangerous diseases often develop slowly, and can take several years before their first symptoms appear. Long before that happens, however, the body’s metabolism begins to change.

With a view to detecting illnesses when metabolic changes begin to occur – and thereby improve the probability of successful treatment – experts from a variety of clinical and research fields have been working together for several years to identify and detect biomarkers produced by cancers before tumours develop and spread, and to identify the earliest indications of plaque deposits in blood vessels before coronary vessels are compromised.

The key to early disease detection is molecular medicine, a field that is rapidly gaining in importance due to the evolving convergence of three previously separate fields. These fields are diagnostics (lab-based analysis of liquids and tissues), knowledge-based information technology, and, above all, diagnostics imaging.

One of the best-established molecular imaging technologies is positron emission tomography (PET). Here, a marker such as radioactively tagged sugar 2-deoxy-2 (F-18) fluoro-D-glucose is injected. Because cancer cells have a higher metabolism than other cells, and thus consume more glucose, the marker tends to accumulate in such cells, which light up in a PET image as the marker decays, releasing its gamma rays. PET detectors absorb these rays and convert them into weak flashes of light that a computer converts into images.

Starting in the mid-1980s, researchers began using PET to track sugar metabolism in the brain. Since the mid-1990s, PET has been used clinically to locate primary tumours and metastases and to indicate – depending on tumour size – whether cancer therapies are effective. But PET is ineffective when used alone because it merely shows the presence of abnormal metabolism, and does not reveal the exact position of the tumour within the body. Anatomical information, the location of internal organs, and even the body’s outlines are often missing from PET images.

In the late 1990s, Siemens Medical Solutions developed a device consisting of a PET unit and a computer tomograph. Known as the biograph, the device directly links PET and CT, which it uses to examine the same body segment. The result is a high-resolution CT image, produced in one imaging sweep, that displays a tumour and its metabolic activity (through PET) in its exact position. Such an image makes it easier for surgeons to, for example, plan operations.

The combined technology has been dramatically successful. “We now almost exclusively sell PET units with CT functionality,” says Siemens’s Dr Hartwig Newiger. In spite of the biograph’s success, however, researchers want to achieve more. For instance, they would like to improve its operating speed. They are also working on more efficient algorithms in order to improve contrast resolution and recognition of specific details. Such algorithms are important, says Newiger, because the resolution of whole-body PET systems is physically limited to two to four millimetres. That level of resolution has more or less already been achieved.

Because of these limitations, small structures may appear as larger spots in PET images. But thanks to CT, with its resolution of up to 150 m, fine substructures and their relationship to surrounding tissues can be exactly visualised.

A picture of Alzheimer’s
Medical specialists also want to be able to make more precise statements regarding certain metabolic processes that cannot be identified with FDG. Medical Solutions is working with renowned research institutes around the world to develop new marker substances that will be able to pinpoint and make visible even very small metastases and individual tumours, while at the same time identifying the type of tumour in question.

In 2005, following years of collaborative development work, Siemens acquired CTI Molecular Imaging, Inc, one of the world’s leading manufacturers of PET devices and PET marker substances. Experts from the resulting hybrid organisation – Siemens Medical Solutions Molecular Imaging – are now developing technologies that make the most of recent hardware developments to better visualise new, radioactively-tagged biomarkers.

Siemens is also working closely with independent molecular imaging specialists such as Professor Michael Phelps from the Department of Molecular and Medical Pharmacology at the University of California in Los Angeles, and Professor Ralph Weissleder, Director of the Centre for Molecular Imaging Research at Massachusetts General Hospital in Boston. In the December 2006 issue of the , scientists working with Phelps reported on a new Alzheimer’s marker developed in co-operation with Siemens.

The new marker binds specifically with proteins called amyloid plaques that build up in the brains of Alzheimer’s patients. When tagged with a short-lived radioactive substance, the markers can be clearly visualised in PET scans, thus indicating damaged areas. Thanks to this evolving technology, patients suspected of having Alzheimer’s can be clearly distinguished from patients with other types of dementia, and from healthy subjects, thereby opening the door to future targeted treatments. Researchers believe such markers will make it possible in the future to identify Alzheimer’s several years before the onset of symptoms.

Understanding metabolism
Ralph Weissleder has been working with Siemens since 2003. He is involved in the development of markers and pre-clinical contrast media for testing with animals, and also works on integrating different imaging technologies such as magnetic resonance tomography and iron nanoparticles. He believes molecular imaging is one of the most promising research areas in medicine today, offering the potential not only of early identification of many diseases, but also of improved diagnostic and therapeutic accuracy.

“Molecular imaging can help to significantly reduce unnecessary treatments and surgery,” Weissleder explains. In the future, he says, fluorescent probes will be able to zero in on cancer cells, allowing surgeons to detect and eliminate cancer cells that might otherwise have been left behind, thus significantly improving the probability of long-term recovery.

With an eye on the vast field of biomarkers, Siemens is expanding its molecular imaging R&D centre in Los Angeles. The centre has already received FDA approval to start clinical trials on a new imaging biomarker for Alzheimer’s disease. One of the challenges in developing new biomarkers is how to gain an understanding of underlying metabolic processes in order to identify substances that will bind to key elements of such processes.

Such substances can then be synthesised with the help of specific chemical reactions (so-called “click chemistry”), after which they can be marked with a radioactive isotope. FL-thymidine (FLT) is a very promising new biomarker candidate that is now being studied by Siemens researchers. FLT penetrates into the interior of a cell and works at the molecular level. The molecule is similar to thymidine, one of the building blocks of DNA. It accumulates particularly in those areas where DNA is produced in large quantities; in other words, in tumours. FLT is also better than FDG at identifying cell growth and distinguishing it from infections.

Fluorine-18 (18F) is a key isotope used in conjunction with PET scanning. But like other PET isotopes, it requires the use of a particle accelerator (cyclotron) to produce it – devices that are beyond the capabilities of many hospitals. With this in mind, Siemens has spent years building up an order-and-supp
ly network for PET isotopes. Known as PETNET, the network is well established in the United States, the UK and South Korea. (Not surprisingly, Siemens also sells cyclotrons to hospitals and laboratories.) These units are connected to Explora biomarker production machines, which automatically attach the isotope generated in the cyclotron to a carrier substance.

Radioactive markers are also used with another imaging method known as single photon emission computed tomography, or SPECT. The advantage of such markers is that they do not require a cyclotron for their production, as the radioactive isotope most frequently used with SPECT – technetium-99m (99mTc) – can be produced with a relatively small “generator”.

Pinpointing effective medications
diagnostics and devices such as Inveon are suitable for diverse pre-clinical research applications because many basic biochemical processes in humans and mice are very similar, explains Dr Antje Schulte, who is responsible for product support at the company’s research centre at Erlangen, Germany. Among the phenomena they’re studying are brain structures that give rise to Alzheimer’s disease, receptors for addictive drugs, and the effectiveness of new cancer medications.

Says Schulte: “In the past, PET, SPECT and CT were mostly used by research institutes as basic research tools; today, more and more pharmaceutical companies are employing the devices for product-related research purposes.”

Pharmaceutical companies also want to find out if a substance is suitable for use as a medication, or whether it would be better to abandon it immediately. That’s because the sooner a substance can be excluded, the more money can be made available for the study of more promising candidates.

Dr Bernd Pichler of the University of Tbingen, Germany, was responsible for setting up Siemens’ European training and reference lab in that city. Molecular imaging is one focus of Pichler’s work, and with it he has examined phenomena such as oxygen-starved tumours, known as hypoxic tumours. “Remarkably, tissue areas subject to poor circulation like these are especially resistant to radiation treatment and chemotherapy.”

The goal here is to locate hypoxic areas using specific markers so as to be able to combat tumours with a more targeted approach. Such an approach would also ensure that healthy tissues, and the patient’s body as a whole, would be exposed to the least possible amount of medical treatment. With this in mind, researchers are developing entirely new, combined devices for small animal imaging that will put MR and PET scanning into a single device.

In addition to visualising soft tissues, MR can be used for imaging the circulatory system when employed in conjunction with a contrast medium. This can, among other things, facilitate identification of otherwise hard-to-detect hypoxic tumours. Siemens and the University of Tbingen plan to begin testing a prototype MR/PET scanner that will be used exclusively for studies of the human brain.

MR is also becoming more important in molecular imaging. Says Dr Robert Krieg, head of Molecular MRI in Erlangen: “The great thing about MR is that it can be used to pinpoint disease markers.” For instance, a patient can be injected with a contrast medium that is designed to accumulate only in tumour tissue, while producing a clear signal that is captured in an MR image. New types of contrast media are much more specific, however, because they deliver images of the patient’s entire anatomy as well as the target tissue’s physiological activity after just one sweep of the body by the imaging device.

Known as mMRI (molecular Magnetic Resonance Imaging), the development of specific molecular markers is expected to open up a range of new diagnostic and therapeutic possibilities. “However,” cautions Dr Arne Hengerer, mMRI project manager at Med, “it will definitely take at least eight years for the first mMRI markers to reach the market.”

Iron nanoparticles
There are already several promising approaches. For example, an mMRI marker consisting of an iron nanoparticle that’s absorbed by macrophages (immune cells found primarily in lymph nodes) is now being clinically tested. But if a node harbours cancer cells, the number of immune cells in it declines. Thus, if injected nanoparticles are not absorbed by a lymph node, it is an indication of metastatic cancer, since cancers spread primarily via the lymph nodes.

Another mMRI contrast medium is being developed by Nano AG, a consortium led by Siemens’ Hengerer. Under development is a new medium that contains iron oxide nanoparticles designed specifically to home in on so-called “vulnerable plaques” in blood vessels. These plaque deposits are unstable and thus capable of triggering clotting that can suddenly block a vessel, resulting in heart attack or stroke.

If doctors could recognise vulnerable plaques at an early stage and distinguish these deposits from relatively harmless stable plaques, patients could be treated with special medications and might be able to avoid life-threatening clotting incidents. And that’s precisely the goal set by Nano AG.

Iron oxide contrast media now being studied indicate just how valuable the combination of advanced imaging and targeted contrast media promises to be in terms of understanding disease pathology, accurately diagnosing conditions, and ultimately developing treatments that stop diseases before they pose a life-threatening risk.

– Tim Schrder

Zeroing in on cancer
Researchers have developed iron nanoparticles that zero in on tumours. The particles can be used as drug delivery vehicles or can be exposed to focused magnetic fields, thereby delivering lethal heat to hard-to-reach lesions

Cancer is the second leading cause of death after heart disease. Each year, on a worldwide basis, almost seven million people die of the consequences of cancer, according to the Globocan 2002 database of the International Agency for Research on Cancer.

Conventional cancer treatment today usually calls for the surgical removal of malignant tumours and then, if necessary, the administration of radiotherapy or chemotherapy. These methods cure about half of all cancers. But the other half involves tumours that are located in sensitive areas, such as near an important nerve or blood vessel. Here, chemotherapy and radiotherapy remain the treatments of choice. However, these treatments have frequently been associated with serious side effects.

Says Dr Christoph Alexiou, chief physician and director of the Laboratory for Nanotechnology and Local Tumour Therapy at Erlangen University Hospital in Germany: “The goal is to find the best possible balance between therapeutic benefit and toxic effect. Physicians and medical researchers have, therefore, focused on the development of drug targeting methods that are designed to increase the concentration of the active ingredient in a cytotoxic medication on the target while limiting its effects on surrounding, healthy tissues.”

With this in mind, Alexiou has been working on a new, localised chemotherapeutic methodology since 1996. Known as magnetic drug targeting (MDT), the method is based on the application of a magnetic field to guide iron particles loaded with a therapeutic agent to a tumour – and hold them there.

“In order to expose the particles to the highest possible traction force, MDT uses magnets with inhomogeneous fields,” explains Dr Wolfgang Schmidt, an expert in magnet design at Siemens Corporate Technology in Erlangen. “The goal of MDT is to concentrate the active ingredient specifically in the tumour region while at the same time minimising the side effects of chemotherapy.”

From heavyweight to featherweight
From December 2003 to December 2006, Alexiou and other researchers participated in a nanomagnetic medicine project sponsored by the German Federal Ministry of Education and Research. The project was designed to advance MDT technologies.

Says Schmidt: ”
Until now, MDT studies have been conducted worldwide with permanent magnets or large electromagnets, the latter being as large as 1,5 tons. Because of their weight, however, such magnets are in a fixed position, which means that the patient must be repositioned frequently during treatment.” Intent on circumventing these limitations, Siemens researchers tried a different approach. They designed and built a unique pivotable electromagnet that has a readily accessible pole tip and weighs in at a mere 47 kg, yet maintains a high field gradient.

The new, ultra-lightweight magnet benefits from the use of advanced materials and simulation-based design optimisation. It is also the product of years of experience in magnet engineering. In fact, its developers drew on experience developing magnetic systems for various Siemens projects, such as a supporting magnet for the maglev train and a magnet for improving traction between a locomotive and the track.

Now they have achieved what Alexiou calls “a true quantum leap, like that from the first portable telephone to the cellphone”, in the medical engineering field. “Thanks to its light weight and optimised pole tip, a physician can handle the new magnet easily and can position it exactly over a tumour. This makes it possible to reliably treat even small lesions,” says Alexiou. Adds Schmidt: “Our new magnet could easily be integrated into a hybrid clinical device consisting of a C-arm, the magnet, and a magnetic resonance tomograph.”

Findings developed on animal models (specifically, squamous epithelial carcinoma in a rabbit) indicate that chemotherapy without side effects is achievable with MDT. “We have not found any side-effects in either the experimental animals themselves or in their blood workups,” reports Alexiou.

Complete remission with a single dose
But there’s more. In contrast to traditional chemotherapies, which involve multiple applications, researchers have achieved a complete remission of tumours after only a single dose of the nanoparticle-med

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