Magnetic fluid hyperthermia (MFH): Cancer treatment with AC magnetic field
induced excitation of biocompatible superparamagnetic nanoparticles
Andreas Jordan, et al, University Clinic Charité, Faculty of the Humboldt Universität zu Berlin, Germany, Journal of Mangetism and Magnetic Material 201 (1999) 413-419.
Hypertehermia is a cancer therapy, that consists on heating certain organs or tissues to temperatures between 41ºC and 46ºC causing moderate cellular inactivaton in a dose-dependent manner. It acts influencing biomolecules, especially regulatory proteins involved in cell growth, differentiation and the expression of certain receptor molecules, then causing alterations in the cell cycle and can even induce apoptosis.
The classical hyperthermia induces almost reversible damage to cells and tissues, but as an adjunct it enhances radiation injury of tumor cells and chemotherapeutic efficacy.
Modern clinical hyperthermia trials focus mainly on the optimization of thermal homogeneity at moderate temperatures (42-43ºC) in the target volume, a problem which requires extensive technical efforts and advanced therapy and thermometry systems.
It is mainly accepted that preferentially the problems of physical power deposition still limit the clinical outcome, not only because thermal underdosage of critical regions often yields recurrent tumor growth, there are also large limitations on the body target sites, which are too difficult to treat, like brain tumors. In the 1960’s it was the first tried to perform hyperthermia with magnetizable microparticles, which were
heated by an externally applied AC magnetic field, and it was reported which H field amplitudes and frequencies are tolerable in humans. Based on Brown and Neél relaxivity, it was shown, that subdomain particles (nanometer in size) absorb much more power at tolerable AC magnetic fields than is obtained by well known hysteresis heating of multidomain particles.
Tumor cells could be loaded with thousands of particles, which would become activated only by a specific signal, yielding the death of all particles containing cells as soon as an AC magnetic field is applied. Daughter cells from a particle containing parent cells should therefore contain up to 50 % of the particle amount of the parent cell. Hence, particle loaded tumor cells may not only contain the “markers
for their own death, the descendants would still have a higher risk of dying form future AC magnetic field applications. It is therefore an exciting challenge for future research to increase the biological efficacy and particle SAR in order to achieve advanced magnetic fluids of which only a few particles are required for selective tumor cell inactivation.
Systematic in vitro studies were presented showing consistently, that inactivation of cancer cells with AC magnetic field excited nanoparticles is equal to the best homogeneous heating. i.e. water bath heating, for a given time temperature schedule. According to these encouraging in vitro results, a homogeneous cell or tissue inactivation was expected in vivo, too, if the fluid could be administered almost homogeneously throughout the target region.
As a pre condition, the technology of AC magnetic field application is currently under development. If an almost regional AC magnetic field application could be realized, migration of any ferrofluid to distant locations could be neglected. Many aspects have to be considered, like E-field shielding of the “patient”,
heat loss of the core material, mechanical stress of the overall construction and more. The second component of MFH, the magnetic fluid is currently optimezed, too. Since we know form theoretical estimations, that for a given excitation frequency ;* and “ideal” core size d* exists, which
yields maximum SAR (Specific Absorption Rate), and almost sharp core size distribution is required in order to minimize the terapeutic metal oxide mass required for a given target volume. The second aspect is the shell of the nanoparticles in a magnetic fluid. It supports colloidal stabilization, but it has also a contribution to the power absorption due to the Brownian relaxation process. From the theorical point of view, it is largely interesting how the core interacts exactly within the shell in an AC magnetic field. If the core exhibits an oscillation within the shell depending on excitation frequency and core magnetization, some optimization parameters related to the viscosity and structure of the shell material are expected. Therefore, more physical studies are required to exactly describe nanoparticle oscillation with respect to power absortion in AC mangetic fields around 50-100 kHz, using different shells of different hydrodynamic behaviour. Additionally, modifications of core magnetization could further enhance the specific power absortion, but again, biocompatibility rules out many of the promising elements, e.g. a cobalt dotation.
Two different ferrofluids were used in the article study: magnetite particles with aminosilan type shell (#BU48, core diameter 10 nm/hydordyn. 30nm) with largely positive surface charges and of a magnetite with dextrran type shell (# P6, core diameter 3 nm/hydrodyn. 70 nm) with a neutral to negative surface charge.
stPrimary human glioblastoma cells originaed form intraoperative material were maintained in the 0 to 1
passage and nanoparticles uptake in vitro was compared to the uptake of established normal neuronal cells of the cerebral cortex and a fibroblast line (EBF). The cells grew in presence of 0.6 mg ferrite per ml medium for 2-8 days and uptake of each cell type was compared to similar cells in normal medium (controls). In a preliminary set of in vitro experiments, largely higher uptake of the positive charged aminosilan particles in comparison to the dextran magnetite (up to 1000 fold) was observed with the primary glioblastoma cells. Also larger uptake of both particle types was observed into glioblastoma cells compared with normal neuronal cells and fibroblast (about 500-2000 fold). If this observed differential particle endocytosis could be validated by further systematic series of experiments, this would be a new strategy of particle targeting, unlike conventional methods, e.g. monoclonal antibodies. Obviously, both particle species induce different cellular adhesion and internalization processes, which may become especially important in view of diagnostic and therapeutic purposes. However, further pharmacological studies must show, how blood circulation time and scavenging activity of the reticuloendothelial system may limit this promising approach in vivo.
In conclusion, the generation of functionalized surfaces of those particles for cancer cell targeting is the next challenge for the future. Nanotechnology will offer new strategies towards these functionalized particles systems, which might be able to circumvent the known scavenging effects of the reticuloendothelial system. The ensemble of biological strategies, clinical hyperthermia experience, the discovery of the “thermal bystander effect”, combined with methods of interventional radiology, microsurgery and the use of precisely operating navigation systems, will give us new weapon against cancer, which is called MFH.