Pictures of the Future    Spring 2007

Zeroing in on Cancer

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 (www-dep.iarc.fr). "In Germany alone, 425,000 people per year are newly diagnosed with cancer," says Dr. Christoph Alexiou, chief physician and director of the Laboratory for Nanotechnology and Local Tumor Therapy at the Ear, Nose and Throat Clinic of the Erlangen University Hospital in Germany.

Conventional cancer treatment today usually calls for the surgical removal of malignant tumors and then, if necessary, administration of radiotherapy or chemotherapy. These methods cure approximately half of all cancers.

But the other half involve tumors 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 treatment have frequently been associated with serious side effects. "The goal is to find the best possible balance between therapeutic benefit and toxic effect," says Alexiou. "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, localized chemotherapeutic methodology since 1996 (for details, see  box). 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 tumor 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 tumor region while at the same time minimizing the side effects of chemotherapy."

From Heavyweight to Featherweight. From December 2003 through December 2006, Alexiou, Siemens Corporate Technology, Siemens Medical Solutions, and others have participated in a nanomagnetic medicine project sponsored by the German Federal Ministry of Education and Research (BMBF). The project is designed to advance MDT technologies.

"Until now, MDT studies have been conducted worldwide with permanent magnets or large electromagnets, the latter being as large as 1.5 t," says Schmidt. "Because of their weight, however, such magnets are in a fixed position, which means that the patient must be repositioned frequently during treatment."

Considering these limitations, Siemens researchers have 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-light-weight magnet benefits from the use of advanced materials and simulation-based design optimization. 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 Groups, 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 cell phone," in the medical engineering field.

"Thanks to its light weight and optimized pole tip, a physician can handle the new magnet easily and can position it exactly over a tumor. This makes it possible to reliably treat even small lesions," says Alexiou. Adds Wolfgang 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 (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 tumors after only a single dose of the nanoparticle-medication combination. "In addition, we’ve found evidence of much better efficacy with only one-fifth the medication that would otherwise conventionally be used," says Alexiou.

At the moment, research is concentrating on tumors near the surface, such as head, neck and skin carcinomas, as well as some breast cancers. In the future, however, deeper tumors will also be treated with this new method. "In order to accomplish that, we will have to build a magnet that delivers its maximum field a few centimeters away from the tip," says Schmidt, who has already developed concepts along these lines.

Alexiou also has ambitious plans. "Depending on funding, we hope to conduct preliminary clinical trials on humans in two to three years. In the future, we will also be able to couple various other therapeutic agents with magnetic nanoparticles, such as radioactive substances for radiotherapy or genes for gene therapy. In each case, the therapeutic agents will be introduced into the tumor in a targeted manner. In addition, we would like to combine MDT with hyperthermia because each additional effect improves patient outcome," says Alexiou.

Human Trials. In local hyperthermia, magnetic nanoparticles are heated by an external magnetic field, which weakens the tumor and enhances the cytotoxic effect of the chemotherapeutic drugs. In contrast to MDT, in which an inhomogeneous magnetic field is used, a homogeneous alternating field is needed for hyperthermia. This is the only way to induce motion in the nanoparticles containing iron, which ultimately generate heat.

Berlin-based MagForce Nanotechnologies is currently conducting research in this field. "With our method, we can reach any tumor in the body and heat it," explains CEO and researcher Dr. Andreas Jordan. "Our treatment methodology involves two components: a therapeutic system at the core of which is a magnetic field applicator developed specially for the purpose, and nanoparticles."

The two components have been tested on humans in several clinical trials since March 2003 in Europe. In July 2006, MagForce Nanotechnologies and Siemens signed a declaration of intent with the goal of jointly developing MagForce therapeutic systems and cooperating in the production and distribution of these systems. "We expect to save a lot of time by taking advantage of Siemens’ extensive experience and contacts. This will allow us to concentrate even more intensely on the development of our nanoparticles," says Jordan.

To prepare a treatment, a radiologist takes three-dimensional images of the position and properties of a tumor using conventional imaging methods. Next, the patient receives an injection—directly into the tumor—of a liquid containing tiny particles of iron oxide. The particles are then heated by an externally applied magnetic field for about 70 minutes.

Cooking Cancers. "Depending on the type and position of a tumor, nanotechnological cancer therapy can be used as a supplementary or stand-alone therapeutic method," says MagForce Nanotechnologies CEO Jordan. He explains that when cancer cells are heated to 46 °C (hyperthermia), their repair mechanisms are inactivated, thus enhancing the cytotoxic effect of an accompanying radiotherapy or chemotherapy. "Furthermore," adds Jordan, "If the tumor is not situated directly next to major blood vessels or nerves, we heat its cancer cells to more than 70 °C (thermoablation), which causes irreparable damage to the cell structure. In essence, its cells are cooked."

The special advantage here is that the nanoparticles are surrounded by a shell of silane—a hydrogen-silicon compound—and certain biomolecules. "Rapidly dividing cancer cells like to eat this shell, so to speak, and actively incorporate it into their own structure, whereas healthy cells do not do this. This strategy allows us, for the first time, to very selectively attack cancer cells," says Jordan.

Since no side effects have occurred in clinical trials, the procedure can be repeated several times. In the case of a glioblastoma, for example, which is an extremely malignant brain tumor, treatment has prolonged survival time by half a year. This type of tumor cannot generally be cured, and even when the tumor is completely removed, new lesions develop rapidly because individual tumor cells have already migrated through healthy brain tissue prior to surgery.

Jordan is convinced that, "In less than ten years, our nanoparticle therapy will be as significant as radiotherapy is today—but without the radiation exposure." What’s more, he expects that in the future "we will be able to load nanoparticles with drugs that are activated on site by heat. This would greatly increase the tolerability and efficacy of chemotherapy," he says.

Although MagForce Nanotechnologies and the ENT Clinic in Erlangen have taken two different approaches, they are nevertheless reaching for the same goal: effective, life-saving therapies for many people who have cancer.
                                                                                                           Ulrike Zechbauer