The purpose of this expert review is to discuss the impact of nanotechnology in the treatment of the major health threats including cancer, infections, metabolic diseases, autoimmune diseases, and inflammations. Indeed, during the past 30 years, the explosive growth of nanotechnology has burst into challenging innovations in pharmacology, the main input being the ability to perform temporal and spatial site-specific delivery. This has led to some marketed compounds through the last decade. Although the introduction of nanotechnology obviously permitted to step over numerous milestones toward the development of the "magic bullet" proposed a century ago by the immunologist Paul Ehrlich, there are, however, unresolved delivery problems to be still addressed. These scientific and technological locks are discussed along this review together with an analysis of the current situation concerning the industrial development.

Nanotechnology: intelligent design to treat complex disease.

Summary: By incorporation of surface-modified superparamagnetic nanoparticles into shape memory polymer matrices, remote actuation of complex shape transitions by electromagnetic fields is possible. The composite thermosets of oligo(e-caprolactone)dimethacrylate/butyl acrylate contain between 2 and 12 wt.-% magnetite nanoparticles serving as nanoantennas for magnetic heating. It is shown that the particles are dispersed homogenously within the matrix and that the basic thermal and mechanical properties of the polymer matrix are maintained. The specific loss power of the particles is determined to be 30 W · g−1 at 300 kHz and 5.0 W. During the shape transition at 43 °C, no further temperature increase is observed.

Electromagnetic Activation of Shape Memory Polymer Networks Containing Magnetic Nanoparticles

Magnetic nanoparticles have been widely investigated for their great potential as mediators of heat for localised hyperthermia therapy. Nanocarriers have also attracted increasing attention due to the possibility of delivering drugs at specific locations, therefore limiting systematic effects. The enhancement of the anti-cancer effect of chemotherapy with application of concurrent hyperthermia was noticed more than thirty years ago. However, combining magnetic nanoparticles with molecules of drugs in the same nanoformulation has only recently emerged as a promising tool for the application of hyperthermia with combined chemotherapy in the treatment of cancer. The main feature of this review is to present the recent advances in the development of multifunctional therapeutic nanosystems incorporating both magnetic nanoparticles and drugs, and their superior efficacy in treating cancer compared to either hyperthermia or chemotherapy as standalone therapies. The principle of magnetic fluid hyperthermia is also presented.

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Magnetic nanoparticle-based therapeutic agents for thermo-chemotherapy treatment of cancer

Magnetic nanoparticles are increasingly used for clinical applications such as drug delivery, magnetic resonance imaging and magnetic fluid hyperthermia. A novel method of interstitial heating of tumours following direct injection of magnetic nanoparticles has been evaluated in humans in recent clinical trials. In prostate cancer this approach has been investigated in two separate phase I studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of an alternating magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography was validated. Limiting factors of the new approach at present are patient discomfort at high magnetic field strengths and irregular intratumoural heat distribution. Until these limitations are overcome and thermoablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localised prostate cancer.

Magnetic nanoparticle hyperthermia for prostate cancer

Magnetic fluids (MF) have a potential for hyperthermia due to their good power absorption capabilities. Recent in vitro experiments with the so-called 'Magnetic Fluid Hyperthermia (MFH)' have shown that human tumour cells are homogeneously inactivated after AC magnetic field excitation of extracellular MF. The aim of the present study was the evaluation of a high dose MFH on intramuscularly implanted mammary carcinoma of the mouse. The tumours originated from initial in vivo passages of a spontaneous parent tumour. Because of larger variations of tumour growth in this rather primary model, logistic regression of non-averaged volumes was performed for each treatment modality. All growing tumours were randomized 30 days after transplantation (day of treatment) with an overall size distribution between 12M00mm3. An intratumoural steady state temperature of 47 f 1.O"C was maintained for 30 minutes with whole-body AC magnetic fields of 6-12.5 kA/m at 520 kHz. The magnetic fluid was #P6, which is a high biocompatible dextran magnetite. #P6 was given intratumourally (1.5 x lo-' mg ferrite/mm3) 20-30 minutes before excitation and was combined with magnetic targeting (50mT), which yielded a 2.5-fold enhancement of the intratumoural iron concentration. Histological examinations of tumour tissue after intralesional ferrofluid administration alone indicated deep infiltration of the fluid into the carcinoma tissue, but no evidence of tissue damage as compared with untreated controls. In contrast, widespread tumour necrosis was observed after MFH. After application of either dextran or ferrofluid alone (no difference, p = 0.665), tumour growth was slightly delayed in comparison with untreated controls 0) < 0.001). In contrast to the good fit of the controls (R = 0.924.87), tumour growth after MFH was much more heterogeneous; some tumours showed no evidence for regrowth at 50 days whereas others had grown quite readily. This most probably reflected the critical problem of homogeneity of the intratumoural MF distribution, which was also confirmed qualitatively by Magnetic Resonance Imaging (MRI), heterogeneous pigmentation of MFH treated tumours, and up to 1°C differences between temperature probes in the same tumour during AC magnetic field application. However, a quantitative comparison between intratumoural MF-heterogeneity and tumour response could not be performed in this study. Despite these current limitations, the regression analysis of the MFH data yielded a smaller tumour volume of about 1000mm3 at 50 days growth time in contrast to all three controls. In conclusion, encouraging results have been obtained, which show, that one single high dose MFH is already able to induce local tumour control in many cases within 30 days after treatment. To overcome the uncertainties of intratumoural MF heterogeneity, advanced intralesional application methods are currently under development.

Effects of Magnetic Fluid Hyperthermia (MFH) on C3H mammary carcinoma in vivo

A short review is given on current conventional hyperthermia technology. As an alternative, heat can also be generated by a magnetic fluid, which is excited by an externally applied AC magnetic field. In contrast to regional Radiofrequency (RF-) systems, Magnetic Fluid Hyperthermia (MFH) is not limited by electric (E-)field boundary effects and heterogeneous tissue conductivity. MFH may become interesting especially for tumors which currently cannot, or only with highly invasive procedures, be treated with hyperthermia, e.g. bone tumors, intrathoracal tumors, tumors of the base of the scull and of the brain. Current physical and biological results of MFH with carcinoma cells in vitro and experimental tumors in vivo are presented. Deeper insights into the mechanism of magnetic fluid power absorption, the use of Magnetic Resonance Imaging (MRI) for treatment planning, advancements of AC magnetic field applicator technology, intracellular hyperthermia, and options for magnetic fluid conjugates with isotopes and drugs are tasks for future research.

H. Faehling

Papers

Magnetic Fluid Hyperthermia (MFH)