HYPERTHERMIA USING MAGNETIC NANOPARTICLES; THE NEXT BIG THING!

1. INTRODUCTION 

The microscale heat transfer finds a lot of interesting applications in the biomedical industry. There is hot research going on in this area, especially associated with drug delivery and cancer therapy. The microscale heat transfer phenomenon through the tissues is an area that needs to be exploited for developing a full-proof system to heat the tumors present in the tissues and provide a feasible solution to cancer therapy.

Hyperthermia therapy (or hyperthermia, or thermotherapy) is a type of medical treatment in which body tissue is exposed to temperatures in the region of 40-45°C. Hyperthermia is usually applied as an adjuvant to Radiotherapy or Chemotherapy, to which it works as a sensitizer, in an effort to treat cancer. Hyperthermia uses higher temperatures than diathermy and lower temperatures than ablation. When combined with radiation therapy, it can be called thermoradiotherapy.

There are three important types of hyperthermia; they are as follows:

• Local hyperthermia heats a very small area and is typically used for cancers near or on the skin or near natural openings in the body (e.g., the mouth). In some instances, the goal is to kill the tumor by heating it, without damaging anything else. The heat may be created with microwave, radiofrequency, ultrasound energy, or using magnetic hyperthermia (also known as magnetic fluid hyperthermia). Depending on the location of the tumor, the heat may be applied to the surface of the body (superficial hyperthermia), inside normal body cavities (intraluminal hyperthermia), or deep in tissue through the use of needles or probes (interstitial hyperthermia). It should not be confused with the ablation of small tumors, where higher temperatures (>55°C) are applied with an aim to kill the tumor cells.

• Regional hyperthermia heats a larger part of the body, such as an entire organ or limb. Usually, the goal is to weaken cancer cells so that they are more likely to be killed by radiation and chemotherapeutic medications. This may use the same techniques as local hyperthermia treatment, or it may rely on blood perfusion. In blood perfusion, the patient's blood is removed from the body, heated up, and returned to blood vessels that lead directly through the desired body part. Normally, chemotherapy drugs are infused at the same time. One specialized type of this approach is continuous hyperthermic peritoneal perfusion (CHPP), which is used to treat difficult cancers within the peritoneal cavity (the abdomen), including primary peritoneal mesothelioma and stomach cancer. Hot chemotherapy drugs are pumped directly into the peritoneal cavity to kill the cancer cells.

• Whole-body hyperthermia heats the entire body to temperatures of about 39 to 43 °C (102 to 109 °F), with some advocating even higher temperatures. It is typically used to treat metastatic cancer (cancer that spreads to many parts of the body). Techniques include infrared hyperthermia domes which include the whole body or the body apart from the head, putting the patient in a very hot room/chamber, or wrapping the patient in hot, wet blankets or a water tubing suit.

Research has shown that hyperthermia is able to damage and kill cancer cells. Localized hyperthermia treatment is a well-established cancer treatment method with a simple basic principle: If a temperature elevation to 40ºC (104ºF) can be maintained for one hour within a cancer tumor, the cancer cells will be destroyed.

The schedule for treatments has varied between study centers. After being heated, cells develop resistance to heat, which persists for about three days and reduces the likelihood that they will die from the direct effects of the heat. Some even suggest a maximum treatment schedule of twice a week. Japanese researchers treated people with "cycles" up to four times a week apart. Radiosensitivity may be achieved with hyperthermia, and using heat with every radiation treatment may drive the treatment schedule. Moderate hyperthermia treatments usually maintain the temperature for approximately an hour.

2. MAGNETIC HYPERTHERMIA

Magnetic hyperthermia is an experimental treatment for cancer, based on the fact that magnetic nanoparticles can transform electromagnetic energy from an external high-frequency field to heat. This is due to the magnetic hysteresis of the material when it is subjected to an alternating magnetic field. The area enclosed by the hysteresis loop represents losses, which are commonly dissipated as thermal energy. In many industrial applications, this heat is undesirable, however, it is the basis for magnetic hyperthermia treatment.

As a result, if magnetic nanoparticles are put inside a tumor and the whole patient is placed in an alternating magnetic field, the temperature of the tumor will rise. This elevation of temperature may enhance tumor oxygenation and radio- and chemosensitivity, hopefully shrinking tumors.

Figure 1: Magnetic Hyperthermia

This experimental cancer treatment has also been investigated for the aid of other ailments, such as bacterial infections. Magnetic hyperthermia is defined by a Specific Absorption Rate (SAR) and it is usually expressed in watts per gram of nanoparticles.

In simple words, the functionalized MNPs are injected into the area close to tumors in the human body and then these drug cargos (MNPs) are moved by an external magnetic field. By changing the intensity of external magnetization, the reversal of the hysteresis takes place within the internal MNPs. This generates heat which is conducted through the tissues in the form of microscale heat conduction. The heat generated will burn the tumor, thereby preventing metastasis. Metastasis refers to the spread of cancer cells from their primary location (the organ in which cancer began) to another region of the body. Cancer cells may spread through the bloodstream, the lymphatic vessels, or locally, and can do so because chemicals that ordinarily keep cells where they belong in the body are absent.

Magnetic particle hyperthermia improves the precision of heating by embedding the heating source (magnetic particles) into the tumor tissue and heating it using an external alternating magnetic field.

The recent success of magnetic hyperthermia in cancer therapy is very promising but the method still needs further improvement before it can become a standard medical procedure. In particular, two main tasks need to be addressed: First, a safe, comfortable, and reproducible application of particles to the tumor region is needed. This includes, besides the realization of a reliable intratumoral injection, the examination of questions concerning antibody targeting and the resulting cellular uptake as well as the toxicity of different formulations or the particles themselves. Second, absorbing materials capable of reaching and maintaining therapeutic temperatures inside tumor tissue need to be improved.

3. MAGNETIC NANOPARTICLES

Magnetic nanoparticles are a class of nanoparticles that can be manipulated using magnetic fields. Such particles commonly consist of two components, a magnetic material, often iron, nickel, and cobalt, and a chemical component that has functionality. The specialty of MNPs is that they can be tailored to be multifunctional material by functionalizing the MNPs with various chemical groups. The MNPs also have the added advantage of excellent affinity to an external magnetic field, which allows it to be moved in any direction by just changing the direction of the externally applied magnetic field.

Magnetic nanoparticles have been examined for use in an experimental cancer treatment called magnetic hyperthermia in which an alternating magnetic field (AMF) is used to heat the nanoparticles. To achieve sufficient magnetic nanoparticle heating, the AMF typically has a frequency between 100–500 kHz, although significant research has been done at lower frequencies as well as frequencies as high as 10 MHz, with the amplitude of the field usually between 8-16kAm−1.

Affinity ligands such as epidermal growth factor (EGF), folic acid, aptamers, lectins, etc. can be attached to the magnetic nanoparticle surface with the use of various chemistries. This enables the targeting of magnetic nanoparticles to specific tissues or cells. This strategy is used in cancer research to target and treat tumors in combination with magnetic hyperthermia or nanoparticle-delivered cancer drugs. Despite research efforts, however, the accumulation of nanoparticles inside cancer tumors of all types is sub-optimal, even with affinity ligands. A broad analysis of nanoparticle delivery to tumors concluded that the median amount of injected dose reaching a solid tumor is only 0.7%.

The challenge of accumulating large amounts of nanoparticles inside of tumors is arguably the biggest obstacle facing nanomedicine in general. While direct

injection is used in some cases, intravenous injection is most often preferred to obtain a good distribution of particles throughout the tumor. Magnetic nanoparticles have a distinct advantage in that they can accumulate in desired regions via magnetically guided delivery, although this technique still needs further development to achieve optimal delivery to solid tumors.

Another potential treatment of cancer includes attaching magnetic nanoparticles to free-floating cancer cells, allowing them to be captured and carried out of the body. The treatment has been tested in the laboratory on mice and the survival studies are analyzed.

Magnetic nanoparticles can be used for the detection of cancer. Blood can be inserted onto a microfluidic chip with magnetic nanoparticles in it. These magnetic nanoparticles are trapped inside due to an externally applied magnetic field as the blood is free to flow through. The magnetic nanoparticles are coated with antibodies targeting cancer cells or proteins. The magnetic nanoparticles can be recovered and the attached cancer-associated molecules can be assayed to test for their existence.

4. PRINCIPLES OF MNP HEATING

If magnetic materials such as dry magnetic nanoparticles are exposed to an external magnetic field, their magnetization undergoes a closed loop during reversal of orientation: the hysteresis loop. This loop is characterized by three material-dependent parameters: saturation magnetization Ms, remanent magnetization (remanence) MR, and coercivity Hc. The area within the loop measures the magnetic energy delivered in the form of heat to the material of the magnetic particles during the reversal of magnetization.

The energy conversion to heat is caused by the coupling of the atomic magnetic moments to the crystal lattice. In macroscopic samples of magnetic materials, magnetic domains which are separated by domain walls usually

exist. In the so-called multi-domain state, reversal of the magnetization direction takes place via domain wall displacement and hysteresis energy is comparatively low.

Figure 2: MNPs Heating Mechanisms

Below a defined particle size, the multi-domain state becomes energetically unfavorable and each particle represents a single magnetic domain. For magnetite, for example, the transition between the states at room temperature occurs at about 30 nm particle diameter. Single domain particles with uniaxial anisotropy may show the highest amount of hysteresis energy that can be expected.

With the field parallel to the aligned particle axes, a rectangular hysteresis loop is observed which gives maximum hysteresis loss Q and specific loss power (SLP):

These losses occur only if the external field exceeds the coercivity field, otherwise, no reversal of the magnetic moments, and consequently no losses occur. The measure ‘coercivity’ contains the contribution of magnetic anisotropy to the magnetic behavior of nanoparticles. This magnetic anisotropy is mainly determined by the effects of crystal anisotropy, shape anisotropy, and surface anisotropy.

Magnetic hysteresis is a non-equilibrium process. This means that after shutting off the external field the macroscopic remanent magnetization will tend to vanish with a typical relaxation time τ due to activation by thermal energy kT (k - Boltzmann constant).

For magnetic single-domain nanoparticles, the energy barrier KV (against reversal of the magnetization) decreases with decreasing particle volume V and the relaxation time is given by

Where K is the magnetic anisotropy and the characteristic flipping time τ0 is of the order of 10-9s. The process is commonly called Neel relaxation. It is the only relaxation process occurring in nanoparticles being immobilized, for instance in tumor tissue.

Particles choose the simplest path to achieve reversal of magnetization with respect to the external magnetic field. In other words, a reversal occurs by the process with the smallest relaxation time constant

The specific heating power (SHP) depends on magnetic properties of applied MNP (which show a strong dependency on particle size and size distribution, besides other materials parameters) and amplitude and frequency of the alternating magnetic field. The measure ‘SHP’ provides the real heating

potential of MNP determined experimentally in an alternating magnetic field by means of caloric measurements – contrary to the calculated SLP on the basis of particle and field parameters. It was shown experimentally and in numerical simulations that certain combinations of particle size, size distribution as well as field frequency, and amplitude lead to the maximum in SHP/SLP. This means that for each applied magnetic field, tailor-made MNP is necessary to obtain maximum SHP or vice versa, the applied field has to be adapted on the magnetic properties of the MNP used. General advice to exploit the heating potential of the particles is to use a field frequency of several hundred kHz in combination with rather a low field amplitude(few kA/m) for superparamagnetic particles and a relatively high field amplitude (a few tens of kA/m) in combination with a frequency of a few hundred kHz for MNP with hysteretic behavior.

5. HEAT TRANSFER IN TUMOUR TISSUE

The magnetic energy supplied by the external alternating magnetic field is converted into heat within the magnetic nanoparticles, which is depleted into the surrounding medium. The attainable temperature in the particle-containing tissue is determined by the balance between heat generation in the particles and the depletion of heat into the tissue. The latter depletion process is mainly due to heat conduction, which depends on the distribution of particles located in the cell plasma or in the interstitial volume between tumor cells. This microscale heat conduction process is very important since the heat should be primarily focused on heating up the tumor cells and tumor tissues. There is a chance of surrounding healthy cells and tissues getting heated up due to the depletion of excess heat via microscale conduction. Though the particle-containing tissue is inhomogeneous (e.g. cell membranes, varying cell size, cell shape, and packing), one spatially constant heat conductivity (nearly that

of water) is assumed in most calculations. Due to the size effect, the normal principles of heat conduction will not work in this tissue domain.

Figure 3: Principle of magnetic mediated hyperthermia. Targeted magnetic nanoparticles delivered to tumor cells are exposed to an alternating magnetic field (AMF). Afterward, AMF energy is converted into heat by the magnetic nanoparticles, which leads to local heating of tumor cells between 41 and 47 ◦C.

There is an influence of the size of the heat generation zone on the spatial dependence of temperature elevation around this zone. Due to the scaling of the heat production with r3, but heat depletion with r2, the decreasing heated volume will become very unfavorable. In particular, a single tumor cell even filled completely with magnetic nanoparticles, would experience a temperature increase only under unrealistically high values of specific heating power. In particular, it was showed that the high efficiency of so-called ‘intracellular’ hyperthermia that is occasionally claimed has no biophysical basis. From the studies, it was found that the cell membranes present have no essential resistance to heat conduction.

On the basis of heat transfer theory at the micro-scale, the balance between generated and dissipated heat inside the tumor and the resulting damaging effects for biological tissue can be examined.

Magnetic particle heating for thermal tumor therapy is based on several loss mechanisms that occur during reversal of magnetization when magnetic nanoparticles are exposed to an external alternating field. Since the extrinsic rotation of particles inside tumor tissue is very improbable due to the fixation of the particles in the tissue, only hysteresis and Neel relaxation contribute to this process. Hysteresis in thermally stable single domain particles principally provides higher reversal losses than Neel relaxation when the critical field amplitude of around twice the coercive field is exceeded.

The magnetically induced heating of objects (tumors) inside a thermal conductible matrix (healthy tissue) requires more than a minimum volume of the tumor for the generation of heat. Taking into account an increasing surface-to-volume ratio for decreasing tumor size, particles with a very high heating power are necessary for the treatment of small tumors. Since there is a maximum obtainable heating power, there is also a limit in treatable tumor size of a few mm.

In principle, magnetic particle hyperthermia has the potential to find its way into standard medical procedures as has already been shown by the first successful and promising clinical trials.

REFERENCES

1. Silvio Dutz, Rudolf Hergt. Magnetic nanoparticle heating and heat transfer on a microscale: Basic principles, realities and physical limitations of hyperthermia for tumor therapy. Int J Hyperthermia 2012.

2. Thiesen B, Jordan A. Clinical applications of magnetic nanoparticles for hyperthermia. Int J Hyperthermia 2008.

3. Dutz S, Hergt R, Murbe J, Topfer J, Muller R, Zeisberger M, et al. Magnetic nanoparticles for biomedical heating applications. Basic principles and limitations of magnetic hyperthermia. Int J Hyperthermia 2006.

4. Gobbo, O.L.; Sjaastad, K.; Radomski, M.W.; Volkov, Y.; Prina-Mello, A. Magnetic nanoparticles in cancer theranostics. Theranostics 2015.

5. Hajba, L.; Guttman, A. The use of magnetic nanoparticles in cancer theranostics: Toward handheld diagnostic devices. Biotechnol. Adv. 2016.

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