Size Matters

NGP. To those not yet familiar with nanotechnology, can you explain what it is and why, in particular, it could be of huge potential in the medical field?

AJ. For decades, it has been shown in numerous pre-clinical studies that heat is largely effective against cancer by sensitizing tumor cells for radiation and drugs (hyperthermia) and that higher temperatures destroy cancer cells directly (themoablation). But despite this fact, thermal therapy has not become a standard therapy in cancer treatment so far, be-cause the clinical efficacy was not as successful in randomized trials as it could have been expected from the biological point of view. The reason for this discrepancy is rather a technical issue because all devices available on the market are highly limited: all conven-tional heating devices define their target region according to contrast enhanced imaging, which sometimes matches with the tumor volume, but in most cases it does not. As a con-sequence, tumor cells are spared from the heat treatment and normal cells are damaged, if they are located near or within this target region. If normal tissue is undesirably heated, an increase of side effects occurs, especially in combination with drugs, which decreases the therapeutical advantage to comparative clinical studies. There has therefore been shown little or no benefit of thermotherapy so far. Since no therapy system is available on the market, which allows both hyperthermia and thermoablation, customers have to choose between either very expensive hyperthermia devices or much cheaper thermoab-lation apparatuses, neither of which are specific to treat local tumors.

Of course, MagForce Nanotherapy wasn’t an overnight success story; 18 years of R&D led to an all-in-one solution for thermotherapy. The cornerstones of this method, which for the first time enables the selective thermal treatment of a very broad range of tumors in every area of the body, are nano-scaled iron oxide particles with an intelligent shell struc-ture, a highly refined technique for generating alternating magnetic fields, and a clinically proven 3D planning software. MagForce Nanotherapy is a thermotherapy using tumor specific magnetic nanoparticles. In this new cancer therapy, nanoparticles are specifically directed into the tumor and then heated in an alternating magnetic field. Instillation of the magnetic fluid is performed according to plan (3D) using conventional imaging or intraop-eratively. The magnetic nanoparticles of MagForce Nanotherapy are dispersed in water and are made of iron oxide (15 nanometer diameter) with a patented (multi-) shell struc-ture. Due to their tiny size, the particles possess superparamagnetic properties, causing them to become excited in the alternating magnetic field and thus generate heat.

For the first time, the complete biologically approved benefit from heating of tumors is available to 100 percent. Due to the patented coating, the MagForce nanoparticles are taken up by tumor cells, rather than by normal cells of the same tissue type. The tumor cells thus contain millions of ‘antennas’, each to target the magnetic field energy. Because the tumor cells are not able to get rid of these particles, the MagForce Nanotherapy is re-peatable as often as necessary to destroy the tumor.

None of the patients in our clinical studies exhibited any severe side effects and in most cases there were no side effects at all, in contrast to all conventional heat treatments. Due to the patented particle coat adaptation process, we can modify particle surfaces for al-most all kinds of solid tumor cells.

The potential of the MagForce Nanotherapy implies its broad application comparable to the use of radiotherapy – but without the disadvantages of irradiation.

But this technology is able to do much better; our nanoparticles can carry drugs and genes specifically into tumor cells, even into the nucleus. By patented coupling between drug and particles, we have made them thermosensitive, so that heat releases the drugs within the cells after the magnetic field has been switched on. Using this kind of specific heat activa-tion, transfection rates of vectors, transported by our nanocarriers are increased. This is all no vision. MagForce nanoparticle innovations are all in preclinical testing for years (nanoparticle-drug-conjugates) or in clinical trials (thermotherapy).

NGP. To what extent are government policies and initiatives supporting R&D into nanotechnology, both in the US and around the world? Would you like to see greater support for research in medical applications?

AJ. We currently have great support from funding agencies in most industrial countries worldwide, as well as from governmental institutions. This is one of the reasons why Mag-Force could go the long way to develop its technology for broad medical applications, es-pecially against cancer. What we really need is not more R&D, but more products on the market exhibiting a performance and specificity to demonstrate how nanotechnology can improve medical products and pharmaceuticals instead of new visions or just a branding by using the prefix ‘nano’. Nanotechnology was the key for most of our developments from the physical, biological, chemical and medical point of view. Because we started at a time when nanotechnology was not just hype, we discovered the difference nanotechnology can make over conventional systems and what it means in terms of product performance and competition.

NGP. How important currently is nanotechnology to the field of cancer research and is there a growing interest in this?

AJ. Interest has increased dramatically during the past few years. Facing the known side effects of anti-cancer drugs, there is a large need for much higher specificity and efficacy. The paradoxon of high drug concentrations at the target site and almost unharmed normal tissue can be solved by nanoparticles. The sum of billions of nanoparticle surfaces in a small volume, say 1ml, is in the range of a tennis court, leaving a large space to couple tumor-specific ligands and effective drugs and genes to those carriers, which transport them to their target cells. The second point is the ‘intelligence’ of those nanoparticles, which may release drugs in response to external signals, temperature elevation or physio-logical conditions in tumor tissue and cells. Nano-liposomal formulations are already on the market but they still do not have the features mentioned before. However, as they have shown fewer side effects in clinical studies, this is the right way to go. Finally, there are strong economical arguments for the use of nanotechnology in drug development for cancer. Nano-carrier based drug targeting systems open a new perspective for conven-tional anti-cancer drugs, especially when they are about to loose their patent protection: introducing a new specificity and a new performance by coupling them to MagForce® nanoparticles brings up completely new products leading to new patent portfolios.

NGP. What kind of R&D and clinical trials are going on at MagForce?

AJ. MagForce Nanotherapy is the first nanotechnology-based local thermotherapy on tu-mors to enter clinical trials. Beginning in 2003, we started four different clinical trials to in-vestigate the feasibility of our new thermotherapy approach on different tumor entities. From March 2003 to June 2004 we performed the world’s first phase I trial on thermother-apy using magnetic nanoparticles with 14 glioblastoma multiforme patients. This demon-strated that intracranial thermotherapy using magnetic nanoparticles can be safely applied with therapeutic temperatures and without side effects, and clear signs of local efficacy could be observed.

A first efficacy study with patients suffering from recurrences of malignant gliomas started in January 2005. Two other feasibility trials started in 2004, which enrolled 21 patients suf-fering from non-resectable and pre-treated local relapses of different tumor entities and 10 patients with radio-recurrent prostate carcinoma. The objectives of these studies were treatment planning, application and subsequent control of the nanoparticle distributions in circumscribed lesions, and furthermore assessment of safety, quality and feasibility of the heating patterns achieved in situ.

The heat treatments were tolerated well with none or negligible side effects and the follow-up showed encouraging results for severe oncological diseases.

Another feasibility study investigated the selective hepatic arterial infusion of magnetic nanoparticles at the target site of patients with hepatocellular carcinoma (HCC). The study demonstrated that this local infusion of nanoparticles resulted in almost exclusive tumor targeting and concluded, that arterial embolization hyperthermia constitutes a promising treatment alternative for patients with HCC.

Besides these clinical activities, we have pre-clinical R&D programs about temperature dependent drug release, combined MRI/PET contrast agents, MRI labeling of tumor and normal cells as was as novel targeting structures of nanoparticles for certain tumor cells and new methods of particle-drug delivery. This is, why we believe that MagForce will add value to the generation of new pharmaceuticals in the near future.

NGP. Magforce recently received the Frost & Sullivan Technology Innovation Award. Why do you think you deserved this – what differentiates you from the competition in this field?

AJ. In addition to pioneering nanosolutions for cancer therapy, MagForce Nanotechnolo-gies also develops innovative tumour-specific therapeutics. The company has completed several studies in the field of cancer and tumour therapies and its products are undergoing clinical trials. While its main product and the nanoparticle formulation MFL AS are likely to be commercialised by 2007, the company has already developed two innovative technolo-gies for glioblastoma (an aggressive form of brain tumour) and prostate carcinoma. Fur-ther indications are currently tested in other clinical trials or are in preparation.

Whereas other companies are still in the stage of in vitro or first animal experiments or have just visions with their nanoparticle formulations, we are at an advanced stage of clini-cal trials in Europe and all production plants are already in place for the nanoparticle for-mulations as well as for the devices and accessories. This makes MagForce Nanotech-nologies AG number one worldwide in nanotechnology-based thermotherapy.

Setting new benchmarks

• Good tolerability
• No adverse effects
• Minimally invasive instillation of the nanoparticles
• Homogeneous temperature distribution within the tumor due to homogeneous dis-tribution of the nanoparticles
• Precise in 3D plannable application points, particle dosing, and temperature distri-bution before treatment ever starts (MagForce NanoPlan®)
• Free choice of the treatment temperature by variation of the magnetic field strength and the dosage of the nanoparticles
• Treatments can be repeated any number of times after a single application of the magnetic fluid since the particles remain in place for an extended period
• Local tumor treatment with adequate protection of surrounding healthy tissue
• Simple to use and effective in combination with radio- and chemotherapy