Magnetic nanoparticle hyperthermia: A new frontier in biology and medicine?

It is a pleasure to serve as Editor for this special issue of the International Journal of Hyperthermia which summarises concepts and recent progress in the development of magnetic iron oxide nanoparticles for hyperthermia. I am confident that readers specialising in various clinical, scientific, and engineering disciplines will benefit from the contributions provided by this international cast that includes both recent entrants and pioneers in the field.

The benefits of heat as a therapeutic agent have been recognised since antiquity, yet our clinical application of this tool continues to evolve with advances in technology and science. It may be said that a history of the practice of heat therapy, or hyperthermia encapsulates the story of the evolution of our understanding of science and medicine. The tools for clinical hyperthermia have advanced from hot pokers to radio-frequency ablation devices; hot-water pads to microwave antenna arrays and high-intensity focused ultrasound; and, most recently we attempt to exploit our control of manufacturing at the atomic scale to produce virus-sized devices that can convert external energy into heat for targeted therapy and drug delivery.

Harnessing nanometre-scale engineered materials as devices to focus or convert external coherent or incoherent energy into heat with ever-increasing precision within a patient is a poignant example of our continuing evolution to both understand the physical world and to exert our will upon it. It is also a story of the development of truly multi-disciplinary science. Few areas of human endeavour demand integrating clinical practice with expertise in materials science and chemistry, electrical and mechanical engineering, physics, and biology. If, however, ‘nanomedicine’ is to become a clinical reality we must learn to navigate in unfamiliar territory. Charting a course through the frontier of nanotechnology to enable effective treatment of disease with reduced morbidity is the research focus of the contributing authors in this special issue. Indeed, it was this vision that provided the motivation to first explore magnetic iron oxide nanoparticle hyperthermia with electromagnetic (radio-frequency or RF) radiation.

Perhaps the first publication that systematically describes the concept of hyperthermia with magnetic iron oxide nanoparticles using RF, is appropriately coauthored by surgeons and electronics engineers who were motivated to develop a new modality to ‘destroy metastases in lymph nodes missed at operation’ in order to reduce mortality in the ‘immediate post-operative period’ in patients with colorectal carcinomas [1]. They report results of heating experiments with Fe₂O₃ (maghemite) particles in silico and ex vivo (beef livers) exposed to alternating magnetic fields having a frequency of about 1.2 MHz. The surgeon Robert Gilchrist presented these results at a meeting of the American Surgical Association in Chicago, Illinois, in May of 1957 and subsequently published the findings in the Annals of Surgery in October of that year [1]. In addition to the heating experiments, they report results of histological examination of tissues obtained from dogs following injections into the subserosa, subcutaneous, and subperitoneal tissues [1]. In this early study, no heating experiments were conducted in live animals because the authors believed their magnetic field coils produced unsafe high voltage fields. They also concluded that the alcohol thermometers available to them as an alternative to metallic thermocouples were too large and unsuitable to perform reliable in situ thermometry while conducting hyperthermia in a live animal. Finally, they considered the heating performance and size (0.02–0.1 µm) of their particles to be inadequate to provide sufficient heating at realistically achievable intra-tissue concentrations. Thus, in this first work published over 50 years ago, Gilchrist et al. accurately identify and describe the challenges to translating this version of ‘nano-thermal medicine’ to the clinic. Given its age, how then can we consider this concept to be a ‘frontier’ in biology and medicine?

Since the early demonstration by Gilchrist et al., advances in materials and electronics engineering, thermometry and biology have produced new tools and refined methods to control heating in living cells and animals, and to measure the response that such heating generates. Also, the recent clinical application of this technology by MagForce for glioblastoma multiforme establishes a place for this technology in the clinic for treating human disease. There is thus every indication that hyperthermia with nanoscale devices is ready to advance further into the realm of biology and medicine, opening new frontiers in our study of biological response to heat and its application for therapy.

In the first review paper of this issue, Kozissnik et al. [2] provide a description of the concept and technology of magnetic nanoparticle hyperthermia. They take the reader through a tour of the development of the science and applications and highlight the areas that remain challenging, providing opportunities for further exploration. Echoing the early efforts of Gilchrist, they emphasise the need to identify appropriate magnetic field conditions that will enable differential heat deposition, suitable magnetic nanoparticle constructs that provide therapeutic heating for achievable concentrations in tissue, and accurate measurement of nanoparticle heating. In a modern departure, they identify the potential to achieve therapeutic results with molecular targeting of the nanoparticles. Such ‘smart’ nanoparticles can be systemically delivered to minimise intervention, but with the added challenge that insufficient material will accumulate for hyperthermia. They propose, citing their work and the work of others, that energy delivered by cell-targeted nanoparticles may affect the fate of cells or intracellular components without the need to achieve a macroscopic (measurable) temperature rise in tissue. Following this introductory review, contributions by other authors provide detailed and focused discussion of the various aspects of iron oxide nanoparticle hyperthermia.

Our understanding of the properties and mechanisms that lead to heating by magnetic nanostructured materials in alternating magnetic fields is summarised in a review by Dennis and Ivkov [3]. Linear response theory, one of the earliest models used to develop concepts of heating, was initially useful but possesses significant limitations that no longer provide a meaningful interpretation of the underlying physical mechanisms without significant modification. Furthermore, advances in other fields such as geology provide additional and more appropriate models for calculating the responsiveness of magnetic nanoparticles to linearly oscillating fields. Dennis and Ivkov highlight the anisotropic energy of magnetic materials as being the significant contributor to clinically relevant heating. The anisotropic energy, in turn is sensitive to interactions of each magnetic nanocrystal with other crystals via collective magnetic interactions. Reviewed are recently published results that describe the influence of collective associations, their impact on heating behaviour, and methods to control these interactions to produce clinically suitable magnetic constructs for hyperthermia. This latter aspect of magnetic nanoparticles presents an exciting and dynamic development for medicine.

In an original research contribution, LeBrun et al. [4] demonstrate the capability provided by numerical methods to calculate heating by nanoparticles in mouse models of human prostate cancer (PC3). They describe results obtained from algorithms developed to efficiently convert microCT images of nanoparticle distribution within the tumour, and by using the loss power of the nanoparticles (specific absorption rate or SAR) they demonstrate that significant heat can be generated within the tumour. This original research contribution highlights the importance that both nanoparticle distribution within the tumour and the intrinsic heating capability of the particles interact to produce effective therapy. It also provides a demonstration of the potential to develop efficient algorithms that can be used to simulate heating from imaging data. Such tools are critical for successful clinical applications because they will provide the basis for image-guided treatment planning, a necessary component to establish prescriptive treatment paradigms in the clinic.

Thermometry in the presence of alternating magnetic fields presents unique challenges. Gilchrist et al. [1] identify this as one of their challenges. At heart is the nature of the interaction of electromagnetic fields with matter. Oscillating magnetic fields generate eddy currents (Faraday’s law of induction) leading to Joule heating in electrically conducting bodies. Accurate thermometry with metal-based thermocouples is impossible for hyperthermia with magnetic fields. Heat is the therapeutic agent, and the nanoparticles are its carrier. Thus, the potency or amount of heat generated by the nanoparticles becomes a critical parameter to be measured. In their review, Andreu et al. [5] highlight the necessity to accurately determine this heating capability, and the success and limitations of various methods developed for this purpose. In an original research contribution, Rodriguez et al. [6] describe experiments in which infrared thermography is used to characterise heating and thermal evolution when mice are injected with magnetic nanoparticles and subsequently exposed to inhomogeneous magnetic fields. In this contribution, the challenges identified by Gilchrist are illustrated and the nature of complex interactions of magnetic fields with both tissue and magnetic nanoparticles within tissues are demonstrated.

In the next two review papers by Salas and Morales [7] and Gruettner et al. [8], we revisit nanoparticle synthesis and recent advancements. Salas and Morales highlight the influence that the magnetic structure of iron oxide nanoparticles, their coating, and colloid stability has to determine heating and performance in vivo. Gruettner et al. summarise advances in synthesis to manufacture nanoparticles with desired heating properties, and focus on methods recently developed to achieve desired coating and functionality for molecular targeting. Systemic delivery of molecular targeted magnetic iron oxide nanoparticles, followed by demonstrated selective heating of tumours has been performed by few laboratories. The challenges presented by this approach, and opportunities provided by recently developed site-directed chemistries are summarised.

Questions of the fundamental nature of heating and heat transfer at dimensions relevant to cells, and their implications for hyperthermia resurface in a review by Dutz and Hergt [9]. A recurring theme in this issue is the fundamental nature of heating by magnetic nanoparticles, and the realities imposed by laws of heat transfer. To achieve clinically relevant hyperthermia, a sufficient amount of magnetic material must be appropriately concentrated and distributed within the tumour. Gilchrist understood this, and identified it as a challenge that necessitated further development. Dutz and Hergt summarise the basics of physics of nanoparticle heating with a focus on microscale heating and heat transfer. The question of treating metastatic disease with nanoparticle hyperthermia is addressed here, but from a different perspective than by Gruettner et al. [8] who focus on targeting. For readers interested in these topics, this review provides a complementary treatment to the preceding contribution, and also an interesting comparison with Kozissnik et al. [2] who propose ‘magnetically mediated energy delivery’.

The topic of nanoparticle synthesis is revisited by Alphandery et al. [10] who review the literature that explores controlled nanoparticle synthesis by magnetotactic bacteria, i.e. ‘magnetosomes’. Magnetotactic bacteria represent several species of soil and marine bacteria that have evolved mechanisms to manufacture precisely controlled magnetic iron oxide crystals for orientation using the Earth’s magnetic field, similar to a compass. Harnessing this biological synthesis route has yielded benefits for magnetic nanoparticle hyperthermia that are summarised by one of the pioneers in this field.

The nature of the interaction of electromagnetic fields with living cells continues to motivate new areas of research across multiple disciplines. Despite our deep understanding of electromagnetic energy provided by Maxwell’s equations, we still find surprises in cellular responses to EM field exposure. Perhaps, this is because we have available new tools and our understanding of cellular processes is evolving as suggested by Goya et al. [11]. After a brief summary of the fundamental nature of interactions of electromagnetic fields with living cells to orient the reader, Goya et al. focus discussion on interaction of electromagnetic fields particularly on cell culture models and the need to enhance power deposition for cancer therapy. Described are results suggesting alternative cell pathways affected by nanoparticle interactions with EM fields, including non-thermal effects. It provides a complementary perspective to the reviews by Kozissnik et al. [2] and Dutz and Hergt [8]. Petryk et al. [12] describe experiments comparing the effects of microwave (EM only) heating with magnetic iron oxide nanoparticle heating in a murine model of mammary carcinoma. The results are suggestive that magnetic nanoparticle-mediated hyperthermia may deposit heat into the tumour in a manner that produces a different response than heat by an external EM energy source alone.

One of the pioneers who has developed in vivo models of magnetic iron oxide nanoparticle hyperthermia, Ingrid Hilger, provides an update of the progress with magnetic nanoparticle hyperthermia in animal models of cancer [13]. This is followed by an original research contribution by Oliveira et al. [14] who demonstrate effective heating of rat bladder with dosimetry. This contribution emphasises the potential utility of nanoparticle hyperthermia to exploit non-localised effects, i.e. not targeted to specific cells. Such an approach avoids issues with targeting nanoparticle heat deposition, opening the possibility to explore novel directions for therapeutic applications.

In the final contribution, Petryk et al. [15] highlight potential future clinical benefits of magnetic nanoparticle hyperthermia as a concomitant or adjuvant therapy with chemotherapeutic agents. This is a rapidly developing area of nanotechnology in medicine because it offers potential to overcome limitations of using magnetic nanoparticle hyperthermia as a single agent. Furthermore, ample clinical data support the use of hyperthermia (applied by multiple technologies) as concomitant therapy with radiation or chemotherapy agents.

It is my hope that readers of this special issue will be inspired and challenged to explore new avenues for research in this dynamic and rapidly evolving field.

Declaration of interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.