It has long been known that tumors respond to treatment with heat. Starting in 1987, Dr. Andreas Jordan began working together with physicians at the Charité University Medical Center in Berlin to improve existing systems for hyperthermia treatment, a partnership which continues today. However, with the prevailing technology of that time, not enough heat could be generated within the tumor, and only in the rarest cases could the minimum required tumor temperature of 43°C (110°F) be attained. Because of the imprecise application of heat, patients also suffered from side effects such as localized pain, redness or burns. It was then that Dr. Jordan first wrote of his ideas to dramatically transform the use of hyperthermia in cancer treatment.
Early research and development efforts
The basic idea was to find a way to generate warmth directly within the tumor and thus to heat it from the inside out. To do this, a magnetic substance would be placed there and stimulated by means of an external alternating magnetic field, without any direct contact. Dr. Jordan then began his long search for a suitable magnetic substance, conducting some one thousand experiments with potential materials from around the world. However, with all the conventional materials which were tested, a significant increase in tumor temperature could be attained only with impractically large amounts. One day, as a new sample which had arrived from Japan was placed into the alternating magnetic field, the heat which it generated was so great that it took only seconds to burst the test tube it was in. This new sample consisted of magnetic nanoparticles made of iron oxide coated with sugar. This was the first big step on the long road toward today’s Nano-Cancer® therapy.
The breakthrough of using nanoparticles
In subsequent tests, Dr. Jordan determined that the reason for the much higher heat generation was the nanoscale size of the particles, which heat up using a completely different mechanism than usual micron-sized particles. In 1993, he published a groundbreaking paper in the International Journal of Hyperthermia in which he described this new mechanism as well as the “therapeutic window” for potential use in clinical applications. With this breakthrough, magnetically based thermotherapy became for the first time conceivable. The research work, which up to this point was based purely on physical chemistry, progressed to biological specimens in order to test whether the method could actually work in practice. A wide range of magnetic field generating devices were built to study the thermal properties of these iron oxide nanoparticles in cell and animal models under carefully controlled and reproducible conditions.
Pre-clinical studies
Various studies were conducted whereby the sugar-coated nanoparticles were injected directly into tumor tissue, until finally in 1996, the next breakthrough came: Experiments on mice with breast cancer provided the first clear evidence of efficacy. At a treatment duration of 30 minutes and a tumor temperature of 47°C (117°F), nearly every second mouse in the study could be cured of its tumor. It was also found that the initial distribution of nanoparticles in the tumor tissue was not uniform. As a result, these areas with a lower nanoparticle density were heated less than other areas, and the tumor growth in these less-heated areas was not completely stopped. However, it also was observed that with each repetition of the thermotherapy procedure, the nanoparticles penetrated deeper into the tumor tissue. Each time the tumor was heated with the magnetic field, the nanoparticles became more evenly distributed.
Pre-clinical studies
Since then, scientists at MagForce have learned that this tendency of the nanoparticles to spread out halts at the border between tumor tissue and healthy tissue. One of the reasons for this is that normal tissue is denser than tumor tissue, thus impeding further diffusion of the nanoparticles.
As an additional outcome of these studies on tumor treatment in animals, Dr. Jordan also had the opportunity to test many different experimental devices for generating the needed magnetic field, which could later be used to treat patients. In 1997, he obtained venture capital financing to establish a new company called "MFA Hyperthermiesysteme GmbH". While the basic research up to this point had been largely funded under a special project of the German Research Foundation, MFA Hyperthermiesysteme GmbH was now very specifically aimed at commercial product development.
Major advances in product development
At the end of 2002, MagForce received permission to begin testing its MFH®-300F magnetic field applicator on human subjects, and magnetic field-based thermotherapy for the first time entered clinical trials.
In parallel with the development and testing of the thermotherapy system, the company continued with advanced development of the magnetic nanoparticles. In his search for suitable nanoparticles, Jordan had been working since the mid-nineties with the Institute for New Materials (INM) in Saarbrücken, Germany. Among the early samples from the INM was a new kind of nanoparticle which demonstrated a surprising and very useful characteristic: Nanoparticles coated with aminosilane were absorbed by tumor cells in concentrations a million times greater than had ever been observed before.
Major advances in product development
Dr. Jordan founded a second company, MagForce Applications GmbH, in the year 2000 to drive forward with the advanced development of the nanoparticles specifically needed for the new cancer therapy method. As a starting point, Jordan acquired three licenses for internationally filed substance patents from the INM. On top of these came three more international patents developed and filed by the company itself, then two additional patent applications later in 2005. Armed with these patents and patent licenses, MagForce Applications GmbH began in earnest with its internal company efforts to develop and optimize iron oxide nanoparticles for clinical application. In parallel with this advanced development work, MagForce commissioned external certified laboratories to examine its nanoparticle formulations for toxicity and patient tolerance.
Clinical trials: The long road to regulatory approval begins
In 2001, the two companies – MFH Hyperthermiesysteme GmbH and MagForce Applications GmbH – were merged into a single new company called “MFH Magnetic Fluid Hyperthermia GmbH” so that commercialization could be more quickly driven forward. In early 2003, once all the requirements of the German Medical Devices Act (Medizinproduktegesetz) had been properly fulfilled and in-house production of the magnetic nanoparticles could be established, the company began the clinical trials which would be needed for regulatory approval of its Nano-Cancer® therapy. In June of 2004, Nanostart AG took a majority ownership position in the company, and the two predecessor companies which had been merged were renamed to “MagForce Nanotechnologies GmbH”. In October of 2005, MagForce Nanotechnologies was changed into a stock corporation (Aktiengesellschaft).