Magnetic nanoparticles mediated cancer hyperthermia

CHAPTER 16

Magnetic nanoparticles mediated cancer hyperthermia Shorif Ahmed1, Bablu Lal Rajak2, Manashjit Gogoi2 and Haladhar Dev Sarma3 1

Department of Nanotechnology, North Eastern Hill University, Meghalaya, India Department of Biomedical Engineering, North-Eastern Hill University, Shillong, India 3 Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India 2

Abbreviations MNPs AMF CNTs LSMO SWNTs MWNTs MFH NIR SPIONs SAR MMS G4@IONPs PAMAM MRI SEM VSM TEM XRD ICP-MS QDs UML PNPs NISV MHT WBH HIFU RFA GO

Magnetic Nanoparticles Applied Magnetic Field Carbon Nanotubes Lanthanum Strontium Manganite Oxide Single Walled Carbon Nanotubes Multi Walled Carbon Nanotubes Magnetic Fluid Hyperthermia Near Infrared Super Paramagnetic Iron Oxide Nanoparticles Specific Absorption Rate Magnetic Mesoporous Silica Nanoparticles Fourth-generation Dendrimer-coated Iron-oxide Nanoparticles Polyamidoamine Magnetic Resonance Imaging Scanning Electron Microscope Vibrating Sample Magnetometer Transmission Electron Microscopy X-ray Diffraction Inductively Coupled Plasma Mass Spectrometry Quantum Dots Ultra-magnetic Liposomes Polymeric Nanoparticles Non-ionic Surfactant Vesicles Magnetic Hyperthermia Treatment Whole Body Hyperthermia High-intensity Focused Ultrasound Radiofrequency Ablation Graphene Oxide

Smart Healthcare for Disease Diagnosis and Prevention DOI: https://doi.org/10.1016/B978-0-12-817913-0.00016-X

r 2020 Elsevier Inc. All rights reserved.

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16.1 Introduction Cancer is one of the most dreadful diseases that have been affecting the human civilization. According to World Health Organization (WHO), close to 8.2 million cancer related deaths has been recorded till 2012 and 18.1 million new cancer cases were estimated by 2018 [1]. This number is expected to increase to 23.6 million by 2030 [2]. Early symptoms of development of cancer are often unnoticeable; and hence, their detection is difficult. Cancer treatments have been accomplished on the basis of pathological and clinical tests done using conventional detection techniques and diagnostic tools. Even after the detection, treatment of cancer has been one of the major challenges in modern medicine due to inadequate delivery of anti-cancer drugs to the tumor sites and their severe side effects in normal tissues [3]. The most common cancer treatments are chemotherapy, radiation therapy and surgery. Chemotherapy is a major therapeutic technique used for the treatment of localized and metastasized cancers. However, the drugs used in chemotherapy are so strong that they can kill any cell in the body, without distinguishing whether it is a cancerous or healthy cell. The inadequacy of treatment is so high that in the past few decades’ deaths due to cancer did not change, even after several new treatment modalities and drugs were discovered. This provides researchers both a threat and an opportunity to develop new therapeutic approach towards cancer diagnosis and treatment. In an approach towards winning over cancer, the emerging branch of nanotechnology namely, cancer nanomedicine is looked at, with high expectations. Cancer nanomedicine provides an improvised therapeutic and diagnostic approach for overcoming multi-drug resistance ability of cancer cells. Moreover, cancer nanomedicine is also expected to overcome the drawbacks of conventional treatments modalities due to poor solubility of hydrophobic anti-cancer drugs, agglomeration, biocompatibility and their bio distribution [4]. Nanotechnology have the potential to increase the selectivity and potency of chemical, physical and biological molecules for eliciting cancer cell death while minimizing collateral toxicity to non-malignant cells [5]. Materials on the nanoscale are increasingly being targeted to cancer cells with great specificity through both active and passive targeting approaches. In cancer nanomedicine, different anticancer drugs and imaging agents are encapsulated and embedded within the biocompatible organic or inorganic shell structures to form a multifunctional system for combined therapy and imaging applications. Among them, super paramagnetic iron oxide nanoparticles (SPIONs) particularly magnetite (Fe3O4) and maghemite (γ-Fe2O3) nanoparticles are used primarily in cancer theranostic applications such as magnetic resonance imaging (MRI), magnetic hyperthermia and magnetic drug targeting (MDT) [3]. Magnetic nanoparticles (MNPs) have been used in disease diagnosis, MRI contrast agents, drug delivery, and hyperthermia. In hyperthermia, the temperature of the

Magnetic nanoparticles mediated cancer hyperthermia

tumor cells/tissue is raised to 42
45  C, which leads to death of cancer cell either by apoptotic or necrotic pathway [6]. MNPs mediated hyperthermia is relatively recent complementary anticancer therapeutic scheme used in synergy with other techniques such as chemotherapy and radiation therapy. In this process, tumors are injected directly with a fluid containing MNPs and then placed in an alternating magnetic field. This results in the generation of heat by the infused MNPs, thereby destroying the tumors. Since the localized MNPs only absorb the magnetic field, the surrounding healthy tissues are not subjected to unnecessary heating and are thus unharmed. This integrated system of self-controlled magnetic hyperthermia therapy holds a great potential in cancer treatment using different types of MNPs. The major significance of MNPs is attributed to the uniformity in magnetic properties of individual particles. In this chapter, different types of MNPs used in magnetic hyperthermia are discussed along with an overview of cancer and its various treatment modalities. In addition, heat generation and heat dissipation mechanisms by the MNPs are also discussed.

16.2 Overview of cancer treatment Cancer is a group of diseases that causes abnormal cell growth in the body and has potential to invade or spread to other parts of the body. Unlike normal cells, cancer cells develop a degree of autonomy from these signals resulting in uncontrolled growth and proliferation. In fact, almost 90% of cancer related deaths are due to tumor spreading to different parts of the body which is called metastasis [7]. About (90
95%)of cancer cases are due to genetic mutations from environmental and lifestyle factors. The common environmental factors that contribute to cancer death include tobacco (25
30%), diet and obesity (30
35%), infections (15
20%), radiation(10%), stress, lack of physical activity and pollution. The remaining (5
10%) is due to inheritance [8]. Among the existing conventional therapies, namely chemotherapy, surgery, radiation, hormonal and immune therapy; chemotherapy is the most common and first line of treatment adopted against cancer. In chemotherapy one or more chemotherapeutic drugs are used as part of the treatment regime. The chemotherapeutic agents act by killing cells that divide rapidly, a critical property of most cancerous cells. Since cancer cells divide much faster than most normal cells, they are more sensitive to chemotherapeutic agents because cell division events are more likely to happen at any time [9]. Chemotherapy is used when there is clear evidence that cancer has spread beyond the original tumor or if there is a reason to suspect there may be undetectable cancer cells in the body [10]. Another preferred therapeutic approach is through surgery. Surgery is most effective local conventional treatment for most of the solid tumors. The aim of surgery is to remove as much tumor as possible without disabling the patient, so that the other treatments have a greater chance of successfully eliminating the remaining tumor cells. The most common surgery is performed on localized cancer tissues in

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lung, breast and skin [11]. Localized treatment approach also involves radiation therapy which delivers high doses of ionizing radiation to damage the tumor cells. Radiation therapy damages the DNA molecules inside the cancer cells and thus inhibits cell division, proliferation and spreading [12]. Radiation is also being delivered in combination with molecular targeted therapy with the aim of further improving the therapeutic ratio of the radiation treatment [13]. Moreover, recent treatment regime also includes hormonal and immunotherapy. In hormonal therapy, hormones are added or removed to slow or stop the growth of rapidly dividing cells [14] and in case of immunotherapy, body’s immune system is boosted to fight cancer. This concept is based on the principle that under an alternating magnetic field (AMF), a ferromagnetic particle can generate heat by hysteresis loss while a super paramagnetic particle generates heat by relaxation of the magnetic moments [3]. The magnetic field has the advantages of not being absorbed by the living tissues and to be able to penetrate deep into those tissues. The important properties of magnetic particles for inducing hyperthermia are: nontoxicity, biocompatibility, injectability, high-level accumulation in the target tumor and effective absorption of the energy of the AMF [9].

16.3 Magnetic nanoparticles in hyperthermia For the first time in 1957 Gilchrist et al. (2003) investigated the application of magnetic materials for hyperthermia by heating various tissue samples with 20
100 nm size particles of γ-Fe2O3 exposed to 1.2 MHz magnetic field [15]. MNPs respond to alternating current magnetic fields and produce an energy transfer effect characterized by magnetic hysteresis producing a localized thermo-ablative effect leading to cellular death in cancerous tissues (Fig. 16.1). In the process of MNPs mediated hyperthermia, the MNPs are administered into and then subjected to an AC magnetic field to generate heat. This heat conducts into the surrounding diseased tissue immediately and the cancer cells get destroyed when the temperature is maintained above the therapeutic threshold of 42  C at least for 30 min or more [16]. In spite of other modalities in hyperthermia, by and large the use of MNPs has more advantage because it ensures heating only at the intended target tissue without harming the healthy ones. Hyperthermia techniques have been devoted from the last 20 years by means of extensive efforts so that they can be successfully used for clinical applications. Hyperthermia treatment is a non-invasive method of increasing tumor temperature to stimulate blood flow, increase oxygenation and render tumor cells more sensitive to radiation. Hyperthermia may make some cancer cells more sensitive to radiation or harm other cancer cells that radiation cannot damage. Hyperthermia is used to treat tumors located within a few centimeters of the surface of the body, such as melanoma or recurrent breast cancer. Hyperthermia

Magnetic nanoparticles mediated cancer hyperthermia

Figure 16.1 The effect of alternating magnetic field on magnetic nanoparticles that produces enough heat to disintegrate cellular integrity of cancer cells which causes their death. Printed with permission from N.D. Thorat, R.A. Bohara, H.M. Yadav, S.A.M. Tofail, Multi-modal MR imaging and magnetic hyperthermia study of gd doped Fe3O4 nanoparticles for integrative cancer therapy, RSC Adv. 6 (97) (2016) 94967
94975.

also can be delivered through a probe, which is useful in treating tumors of the prostate, breast, head and neck, and a variety of other superficial lesions [17].

16.4 Mechanism of heat dissipation by magnetic nanoparticles Heat generation in magnetic particles are caused by changes of the magnetic field. Generally MNPs generate heat either by hysteresis loss or Neel and Brownian relaxations. Heating due to the hysteresis loss is noticeable in particles having size in multidomain nanoparticles. The relative contribution of each process depends strongly on the crystal size and composition of the particles. Nanoparticles with core diameters of less than 20 nm that are used in most magnetic fluid hyperthermia applications are single-domain particles. Magnetic relaxation is governed by a combination of the external rotation (Brownian) and internal (Néel) diffusion of the particle’s magnetic moment, with negligible contribution of hysteresis loss [18]. The heat loss from super paramagnetic nanoparticles is attributed to the relaxation phenomena of magnetic moments. In an external AC magnetic field, energy is

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Brownian relaxation Superparamagnetism Neels relaxation

MNPs Ferromagnetism

Hysteresis loss

Figure 16.2 Schematic representation of various heat-generation and dissipation mechanism of magnetic nanoparticles.

provided to aid the magnetic moments of the particles and this can rotate the particles resulting in overcoming the energy barrier E 5 KV, where K is the anisotropy constant and V is the volume of the magnetic core [3]. Heat dissipation from magnetic particles is caused by the delay in the relaxation of the magnetic moment through either the rotation within the particle (Neel) or the rotation of the particle itself (Brownian), when they are exposed to an external magnetic field with magnetic field reversal times shorter than the magnetic relaxation times of the particles. The Neel and Brownian relaxation time values are crucial because the heating effect depends on the energy delivered per second. Therefore, the AMF frequency must match the calculated relaxation times for an efficient heating to be produced [19]. The factors contributing to heat generation in MNPs are as shown in Fig. 16.2.

16.4.1 Hysteresis loss Hysteresis loss is associated with the phenomenon of hysteresis and is an expression of the fact when ferromagnetic material is involved. In ferromagnetic materials, not all the energy of the magnetic field is returned to the circuit when the external field is removed. A hysteresis loop shows the relationship between the induced magnetic flux density (B) and the magnetizing force (H), losing heat by ferromagnetic materials when placed in an AMF due to the hysteresis loss [20]. Magnetization shows that when MNPs are exposed to an external field, the magnetic moment starts to align in the direction of the field which generally occurs only at high field magnitudes. For the flipping of the magnetization in the particles, the hysteresis should be defeated, as shown in Fig. 16.3; which results in heating of the particles when an alternating field is applied to the amplitude of at least 2 times of the coercivity of the particles. The amount of heat released by the MNPs remains equal to the area of their hysteresis loop [3,21]. The amount of heat released by the ferromagnetic material through hysteresis loss is given by 1H ðmax

A5

μ0 MðHÞdH 2Hmax

ð16:1Þ

Magnetic nanoparticles mediated cancer hyperthermia

Figure 16.3 Hysteresis cycle of a ferromagnetic multi-domain magnetic material with application of time varying magnetic field. Printed with permission from N.D. Thorat, R.A. Bohara, H.M. Yadav, S. A.M. Tofail, Multi-modal MR imaging and magnetic hyperthermia study of gd doped Fe3O4 nanoparticles for integrative cancer therapy, RSC Adv. 6 (97) (2016) 94967
94975.

Then the specific absorption rate (SAR) is SAR 5 Af

ð16:2Þ

where f denotes the frequency of the AC magnetic field, M is magnetization, A is amount of heat release and H applied magnetic field.

16.4.2 Brownian relaxation loss If the magnetic dipole moment aligns with the magnetic field (H) and the particle rotates under an AC field leading to the collisions; these collisions generate heat in the surrounding environment resulting in Brownian Relaxations (τB). Initially, when a magnetic field is applied, nanoparticles align with or against the applied magnetic field. The delay between the magnetic field reversal and the one of magnetic field is called Brownian relaxation. In this context, Brownian relaxation generates heat through friction between MNPs and their surrounding medium. Heat dissipation observed due to the rotational Brownian motion of the particle within the carrier liquid, featuring the rotation of the magnetic particle as a whole because of the twisting force applied on the magnetic dipole moment by the external AC magnetic field [22]. Brownian relaxation is considered to be size and viscosity dependent because, as the size of MNPs increases, the viscosity of the carrier fluid increases too and thus, Brownian relaxation time increases. Brownian relaxation at temperature (T) can be expressed by τB 5

3ηVH KB T

ð16:3Þ

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Figure 16.4 Brownian rotation (the particle as a whole rotates) and Neel rotation of magnetization in a magnetic particle (the particle does not rotate) that are responsible for heat generation. Adapted from N.D. Thorat, R.A. Bohara, H.M. Yadav, S.A.M. Tofail, Multi-modal MR imaging and magnetic hyperthermia study of gd doped Fe3O4 nanoparticles for integrative cancer therapy, RSC Adv. 6 (97) (2016) 94967
94975.

where η is the dynamic viscosity of the carrier liquid and VH is the hydrodynamic radius of the particle, KB is the Boltzmann constant, τ 0 5 1029 (Fig. 16.4).

16.4.3 Neel’s relaxation The energy that is dissipated during relaxation when the magnetic moment returns to its equilibrium orientation is called Neel’s relaxation. When particles are exposed to an AC magnetic field with the time of magnetic reversals less than the magnetic relaxation times of the particles, heat is dissipated as a result of the delay in the relaxation of the magnetic moment [23]. Neel’s spin relaxation can be stated as kV H

TN 5 τ 0 e kB T

ð16:4Þ

Total relaxation can be expressed as τ5

τB τN τB 1 τN

ð16:5Þ

where η denotes the dynamic viscosity of the carrier liquid, VH is the hydrodynamic radius of the particle, and KB is the Boltzmann constant respectively, and τ0 5 1029. Thus by using the harmonic average of both relaxations and their relative contributions depending on the particle diameter, the heat dissipation value is calculated. Degenerated heat can be represented as 00

P 5 μ0 χ f H2

ð16:6Þ

Magnetic nanoparticles mediated cancer hyperthermia

where P denotes the heat dissipation value, μ0 is permeability, χ00 is the AC magnetic susceptibility, f is the frequency of the applied AC magnetic field, and the H is strength of the applied AC magnetic field respectively [3,20]. The relative contribution of heat from Néel and Brownian relaxation losses should be necessarily determined so that the possible minimum and maximum heat could be estimated which is generated during in vivo experiments [18].

16.5 Mathematic model for determination of body heat The investigation of heat transfer and fluid flow in biological processes requires precise mathematical models. During the past 50 years, through development of thermal modeling in biological processes, heat transfer processes have been established that include the impact of fluid flow in human systems due to blood flow [24]. There are several models for determining temperature dispersal in living tissue; but the Penne’s bio-heat transfer equation (PBHTE) has been recognized one of the standard model for predicting temperature distributions in living tissues for more than a half century. The equation was established by conducting a sequence of experiments measuring temperatures of tissue and arterial blood in the resting human forearm. The blood temperature is assumed to be constant arterial blood temperature. The PBHTE is expressed as r:KrT 1 qp 1 qn 2 Wcb ðT 2 Ta Þ 5 ρCp

@T @t

ð16:7Þ

Where T is the local tissue temperature, Ta is the arterial temperature, Cb is the blood specific heat, Cp is the tissue specific heat, W is the local tissue blood perfusion rate, K is the tissue thermal conductivity, ρ is the tissue density, qp is the energy deposition rate, and qn is the metabolism, which is usually very small compared to the external power deposition term. The term Wcb (T-Ta ), which accounts for the effects of blood perfusion, can be the dominant form of energy removal when considering heating processes [19]. Penne’s equation is an approximation equation and does not have a physically consistent theoretical basis; it is surprising that this simple mathematical formulation predicted temperature fields well in many applications. However, several investigators have developed alternative formulations to predict temperatures in living tissues [25]. The temperature distribution in the human tissues is determined by a number of thermo-physical factors such as heat capacity, tissue thermal conductivity, the spatial geometry and heat production due to metabolism [26].

16.6 Different magnetic nanostructures in hyperthermia 16.6.1 Lipid based magnetic nanoparticles The design principles of lipid based nanostructures are based on an array of natural, synthetic or biological materials in order to furnish a conjugated and multifunctional

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response for specific biomedical application. Lipid based structures are one of the most potential candidates for treating cancerous diseases. There are different types of lipid based nanoparticles used in drug delivery systems for anticancer therapeutics. These include liposomes, solid lipid based systems, lipidoid particles, non-ionic surfactant vesicles (NISV) and micelles [27]. Liposomes are biocompatible structures consisting of phospholipid bilayers suspended in aqueous medium. The advantage of lipid based magnetic nanoparticles is being the least toxic for in vivo applications [28]. A large progress has been made in the use of lipid based nano-assemblies designed by conjugating MNPs and magneto liposomes. Different types of cancer therapeutic drugs can be attached to the magneto liposomes via lipid mediated exchange. Solid lipid nanoparticles are able to protect labile anticancer drugs such as camptothecin and doxorubicin and deliver them to the respective site efficiently for performing their committed action [29]. When the MNPs are localized in a tumor area, applying an external alternating magnetic field can generate a significant amount of heat that can kill proximal cancer cells in an effective way. The release of drugs from magneto liposomes can be controlled by AC magnetic heating. This approach opens the door for a combined hyperthermia and drug delivery treatment. Surprisingly, magneto liposomes have only been considered for magnetic hyperthermia in a few studies [27,29]. One particular challenge is to effectively incorporate MNPs into lipid vesicles. Super paramagnetic nanoparticles encapsulated in lipid vesicles was reported for advanced magnetic hyperthermia and biodetection, the obtained temperatures indicate that the therapeutic regime (40
45  C) for hyperthermia treatment can be easily reached with 9.4 nm γ-Fe2O3nanoparticles [30]. Despite the progress, there is still much work required to be performed towards magnetic field sensitivity and responsiveness of magneto liposomes in order to translate into modern medical applications.

16.6.2 Polymer based magnetic nanoparticles Polymeric nanoparticles (PNPs) have gained considerable attention in nanomedicine due to the ability to modify their surface. Nanoparticles which are materialized from polymers are generally inter-connected with novel properties. The importance of these materials lies in idiosyncratic characteristics associated with PNPs. The PNPs based materials are continuously being used in nanocomposites, drug delivery for cancer treatment, and photovoltaic relevance [31]. The distinguishing factors that caused causes PNPs to attain relatively unique properties than their bulk counterparts are linked to their reduced particle size [32]. Due to their unique properties, PNPs are further optimized to achieve desired characteristics for better biocompatibility and bioavailability. Biodegradable PNPs have exhibited therapeutic potential for precise drug delivery applications for the treatment of cancer and advanced diagnosis. Targeted

Magnetic nanoparticles mediated cancer hyperthermia

PNPs have been utilized for efficient transfer of chemotherapeutic drugs to tumor cells with minimum damage to the healthy tissues. They are used for the restricted transportation of numerous sorts of drugs, such as antihypertensive agents, anticancer agents, hormones, immunomodulatory drugs and vitamins. Zhang et al. (2010) reviewed the design of drug transfer systems centered on amphiphilic principles of PNPs for anti-tumor drug carriers [33]. Topete et al. (2014) reported folic acidfunctionalized doxorubicin/super paramagnetic iron oxide nanoparticles-loaded poly lactic-co-glycolic acid)-gold porous shell nanoparticles for directed multimodal chemo and photo-thermal therapy with magnetic and optical resonance imaging in cancer [32,33,34]. Additionally, in vivo hyperthermia experiments carried out on fibrosarcoma tumor bearing mice following intra-tumoral administration of the composite magnetic nanohydrogels showed that NPs mediated hyperthermia was effective in arresting the tumors growth. Significant tumor growth inhibition was observed upon application of double doses of magnetic nano-hydrogel in comparison to the exponential tumor growth in the control [31]. Magneto-thermo responsive smart hydrogels embedded with PEG functionalized Fe3O4 nanostructures are been used as a multimodal system for cancer treatment and bio-imaging. Investigation of PEG coated Fe3O4have been done for its anti-tumor effectiveness using human bladder (T-24) cancer cell lines and its systemic accumulation in lung, liver and heart tissue sections. It is found that more than 40% cells were found to be under apoptotic condition after 24 hr when higher field of 375 Oe was applied externally for an hour. Overall more than 95% cell death was observed in 24 hr due to synergistic behavior of sample under RF field where heat and released doxorubicin both helped treat the cancer cells [35].

16.6.3 Magnetic nano-emulsions Emulsions are dispersions made up of two immiscible liquid phases which are mixed using mechanical shear and surfactant. Nano-emulsions are dispersion of nanoscale particles with droplet sizes on the order of 100 nm obtained by mechanical force which are kinetically stable liquid-in-liquid [36]. Nano-emulsions are finding application in different areas such as drug delivery, pharmaceuticals, food, cosmetics, and as building blocks for advanced material synthesis. Their small size leads to useful properties such as high surface area per unit volume, optically transparent appearance, robust stability, monophasic, and tuneable rheology. The emulsifier also plays important role in stabilizing nano-emulsions through repulsive electro static interactions and steric hindrance resultingin low interfacial tension and reduced repellent force between two liquids. To prepare nano-emulsions, formation methods like high and low energy emulsification are used, including high pressure homogenization, ultrasonication, phase inversion temperature, solvent displacement method and emulsion inversion point [37].

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Ultrasonication and high pressure homogenization are most widely accepted method of nano-emulsion synthesis. Recently, a few novel approaches such as bubble bursting at oil/water interface, evaporative ripening and micro fluidization, have also been developed for the synthesis of nanoemulsions [38]. Magnetic nanoemulsions in the order of 100
200 nm are ideal candidates for multimodal magnetic fluid hyperthermia with a maximum SAR value of 164.4 6 4.3 W/g Fe. Magnetic nanoemulsions have been reported to be used for the target delivery of active ingredient especially in cancer therapy [39]. Nanoemulsions have also been used as ultrasound imaging agents. Gianella et al. (2011) developed a multifunctional nanoemulsion based platform to enable an imaging-guided therapy [40]. Researchers reported oil-in-water nanoemulsions carrying iron oxide nanocrystals for MRI, the fluorescent dye Cy7 for near infrared fluorescent imaging, and the hydrophobic glucocorticoid prednisolone acetate valerate for therapeutic purposes [41].

16.6.4 Carbon based magnetic nanoparticles Carbon has attracted a great deal of interest in the scientific community after the discovery of carbon nanotubes, fullerenes and graphene. Carbon based nanomaterials exhibit unprecedented physical and chemical properties such as high strength, exceptional resistance to corrosion and excellent electrical and thermal conduction and stability. The application of carbon nanotube and graphene based nanomaterials combined with magnetic nanoparticles offers key benefits in the modern biomedicine [42]. Carbon nanotubes (CNTs) are well ordered, hollow graphitic materials with high aspect ratio. The advantage of CNTs over other MNPs is their quasi-onedimensional shape. Their shape renders them more effectiveness in terms of heat generation due to higher coercivity and saturation of magnetization [43]. Owing to the ability to move easily among tissues and parts of body, CNTs are considered as perfect carriers for drugs, nucleic acid and imaging agents for targeted therapy. Magnetic CNTs show a Curie temperature of 43  C and a self-regulating temperature at 42.7 C under clinically applied magnetic field conditions (frequency: 100 kHz, intensity: 200 Oe) and has negligible toxic effect under the concentrations of 6.25 mg/mL to 100 mg/mL [43,44]. Similarly, graphene based MNPs exhibits unique properties such as high chemical and thermal stability, great charge carrier mobility and large surface area, have the potentiality to design a well-organized multifunctional nanocarrier systems. Also properties like negative surface charge and unique sp2carbon structure enables the adsorption of molecules including chemotherapeutic drugs, DNA and RNA which can be precisely accumulated into tumors. A hydrophilic graphene based yolk shell magnetic nanoparticle (GYSMNP) functionalized with copolymer PF-127, have been developed as multifunctional nanocarriers for biomedical applications. Remarkably,

Magnetic nanoparticles mediated cancer hyperthermia

this hybrid nanomaterial also was found to be a competent nano-heater at relatively low concentrations, with exceptional drug loading capacity and controlled drug release triggered by the acidic tumor microenvironment [45]. Some reported examples of carbon based nanoparticles are GO-Fe3O4nanohydrid, Fe3O4@GO nanoplateletsPEG, GOFe3O4-PEGnanocarpets, Fe3O4@graphene yolkshell NPs etc. [46].

16.6.5 Bacteria derived MNPs Magnetotactic bacteria (MTB) are polyphyletic bacteria (organisms derived from more than one common evolutionary ancestor or ancestral group)that orient themselves along the magnetic field lines of earth’s magnetic field. To perform task this bacteria have organelle called magnetosomes that contain magnetic crystals. This bacterium has the ability to biomineralize magnetic nanoparticles (Fe3O4) covered by a lipid bilayer membrane, which allow them to align and direct along the magnetic field lines. The magnetosomes hold great prospective for hyperthermia applications, since they have already been found to possess large SAR values [47]. However, the shape and size of the magnetosomes as well as the type of magnetic material depend on the species of magnetotactic bacteria. In particular, Magnetospirillum gryphiswaldense produces magnetite, Fe3O4, cuboctahedral shaped nanoparticles with an average size diameter of B45 nm. The proteins present in the magnetosome membrane can be used to link bioactive molecules, making the magnetosomes highly biocompatible. Additionally, determination of SAR values at different frequencies and magnetic fields can be easily extracted from M. gryphiswaldense from the hysteresis loops [48,49]. Hergt et al. (2006) reported a maximum SAR value of 960 W/g for magnetosomes with a mean diameter of 30 nm, using 10 kA/m field amplitude and 410kHzfrequency. Alphandéry et al. (2008) determined an SAR of 390 W/g for a chain of magnetosomes of 150 nm mixed in a gel and exposed to an AMF of 32 kA/m and a frequency of 183 kHz [48]. Study indicates that the hyperthermia treatment causes both cell death and inhibition of cell proliferation. Specifically 36% of the treated macrophages remained alive 2 hour after alternating magnetic field exposure, and 24 h later the percentage fell to 22%. However, the heating efficiency obtained for magnetosomes is considerably higher than the one observed for chemically synthesized nanoparticles, regardless of the particle size, ferromagnetic or superparamagnetic regime, or magnetic field amplitude and frequency [50].

16.6.6 Magnetic nanostructures for self-controlled hyperthermia Magnetic nanoparticle (MNP) mediated hyperthermia is considered to be a potential candidate for treating cancer Fe3O4 nanoparticles are extensively used in magnetic nanovesicles. One drawback of these Fe3O4 nanoparticles is their high Curie temperature (Tc; 580  C for Fe3O4 and 477  C for Fe2O3 nanoparticles, respectively).

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Which causes generation of hot spots during hyperthermia that leads to overheating of tissues adjacent to tumor cells. Application of MNPs with a Tc of approximately 44  C can be used to avoid overheating of tissues. At the Tc, nanoparticles lose their magnetism and become paramagnetic and, hence, further heating is not possible. This process is called self-controlled hyperthermia. Kuznetsov et al. reported the potential of Cu
Ni alloy nanoparticles in hyperthermia application [51]. A key advantage of this hyperthermia system is that it is minimally invasive, requiring only a single injection for repeated treatments with automatic temperature control. Self-controlled magnetic hypertherma takes advantages of producing localized heating by subjecting nanomagnetic particles to an alternating magnetic field [4]. MNPs from the perovskite family with a Tc in the range of 42
46  C have been explored for self-controlled hyperthermia. In order to overcome some difficulty, ferromagnetic perovskite-doped transition metal oxides with chemical composition (A (1-x) BxMnO3), where A is lanthanum and B is alkaline earth metal strontium commonly referred to as lanthanum strontium manganite oxide (LSMO) have attracted great attention in biomedicine. This is mainly due to the controllable Curie temperature (TC) in between 283
380 K and large magnetic moment at room temperature [52]. These physical properties of LSMO compounds make them highly suitable as effective heating materials for hyperthermia application. Among the series of LSMO compounds, La0.7Sr0.3MnO3 has a large, considerable magnetic moment (40 emu/g) and zero coercivity (HC 5 0 Oe) at room temperature under a magnetic field of 300
400 Oe. When superparamagnetic Fe3O4 nanoparticles are subjected to an AC magnetic field for hyperthermia applications, because of their high Curie temperature, they can attain temperatures of 100
300  C depending on frequency (f), magnetic field (H) and duration (t). However, the limited studies have paid attention to the MFH properties of La0.7Sr0.3MnO3 MNPs for biomedical applications. The outstanding characteristics of LSMO can allow its use in MFH because of self-controlled heating efficiency without the risk of local overheating and the large magnetic moment may be utilized for marker experiments in biodetection. Oleic acid functionalized LSMO nanoparticles are biocompatible with cell lines, SAR value 62.3 W/g with phosphate buffer saline (PBS)and do not have toxic effects when used in vivo. Specifically, the developed nanoparticles show better colloidal stability, high magnetization, excellent self-heating capacity under an external AC magnetic field and biocompatibility on L929 and HeLa cell lines [53].

16.7 Current status of hyperthermia and combination therapy Even though hyperthermia is currently an experimental therapeutic modality for treating cancer, the use of MNPs as hyperthermia mediators still demand’s for extensive research in areas of synthesis and costeffectiveness, stability, biocompatibility, etc. Magnetic hyperthermia treatment proceeded toward a phase II clinical trial as adjuvant

Magnetic nanoparticles mediated cancer hyperthermia

therapy with conventional radiotherapy, and it has been authorized for cancer treatment since 2011. Current clinical trials carried out by MagForce AG in Germany have shown a 7
8 months increase in the life expectancy of patients with glioblastoma. During the past two decades, however, a significant data base, including both laboratory and clinical study provides motivation for the continued exploration of the role of hyperthermia in cancer therapy [54]. Hyperthermia has been shown to potentiate the cytotoxic effect of ionizing radiation and certain drugs on malignant neoplasms. Although there may not be a universal increased sensitivity of all types of cancer to heat, in comparison with normal cells, leukemias and lymphomas may represent a general group of neoplasms which is unusually sensitive to heat. A combined modality approach reduces the chances that a subpopulation of tumor cells may turn out to be resistant to therapy. Thus, hyperthermia can potentiate the effects of radiation, chemotherapy, and immunotherapy makes its use as part of a multimodality treatment approach attractive. In addition to potentiating the cytotoxic effect of conventional therapeutic modalities, hyperthermia can also modify the effects of certain noncytotoxic drugs on tumor cells.

16.7.1 Hyperthermia and radiotherapy Integration of hyperthermia and radiation therapy offers potential clinical advantages for the treatment of cancer. It has been reported by many clinical trials that hyperthermia therapy has been shown to substantially improve local control of cancer, tumor clinical response, and survival rates when combined with radiation treatments [55]. Hyperthermia may cause increased blood flow and this can result in improvement in tissue oxygenation, which then causes temporary increase in radio-sensitivity of cells. Biologically, hyperthermia has special types of interactions with radiation. Heat primarily has a radio sensitizing effect and this is most prominent with a simultaneous application; however, it affects both tumor and normal tissue [56]. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia influences several molecular parameters involved in sensitizing tumour cells to radiation and can enhance the potential of targeted radiotherapy. There is abundant evidence demonstrating that hyperthermia constitutes a valuable supplement to currently performed radiotherapy improving tumor response in tumor entities such as head and neck or cervix [57].

16.7.2 Hyperthermia and chemotherapy Combination of hyperthermia and chemotherapy is most commonly used procedure where hyperthermia can improve the efficiency of chemotherapy, most importantly

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as a common sensitizing agent, specific delivery of drugs, and impact on drug resistance [57]. Firstly hyperthermia can act as a sensitizing agent, improving the efficacy of drugs in much the same way as it acts as a radio-sensitizer, since the effects caused by chemotherapeutic drugs are similar to those produced by ionizing radiation. Both systemic and localized hyperthermia can be beneficial when applied in combination with chemotherapy. Malignant tumors can be poorly perfused and this can impede chemotherapeutic treatment since drug delivery comes via the blood. One of the primary physiological responses to mild hyperthermia is an increase in perfusion as the body attempts to regulate the temperature of the heated region. Localized hyperthermia is therefore beneficial since it increases the perfusion within the tumor, and therefore also increases the drug uptake relative to the normal tissue [58]. Romanowski et al. (1993), reported that using regional hyperthermia with chemotherapy atleast 20% of patients experienced a complete remission and some remained alive up to 64 months after the combined treatment [59].

16.7.3 Hyperthermia and gene therapy Gene therapy is the kind of treatment in which a cell is introduced with genetic material so that its function could get enhanced or modified. This leads to the protein synthesis, which can directly act as therapeutic agents or interact with other substances exerting a therapeutic effect. For successful cancer treatment, the effect of genetic material inside the body must be restricted to tumor or tumor-associated cells while sparing the normal cells and not eliminating the body’s immune response, which is the critical factor in fighting cancer. Hyperthermia assists in opening up the pores of tumor blood vessels, helps to release liposomes into the tumors, where they deliver their DNA content to tumor cells. It also assists in boosting the immune system to send specialized cells into the tumors so that they get killed. [3]. A stimuli-responsive stem cell-based gene therapy has been developed to enhance the treatment of ovarian cancer. After 24 hours of transfection of adipose-derived mesenchymal stem cells (AD-MSCs) with magnetic core-shell nanoparticles-polyethyleneimine (MCNP-PEI)/ plasmid complexes (50 μg/mL MCNP, 200 ng/mL of plasmid), exposing the cells to an AMF to maintain a temperature of approximately 41  C for one hour. Moreover, mild magnetic hyperthermia resulted in the selective expression of tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) in the engineered MSCs, thereby inducing significant ovarian cancer cell apoptosis and death in vitro and in vivo [58].

16.7.4 Hyperthermia and immunotherapy The combination of immunotherapy with hyperthermia is particularly fascinating concept, as significant clinical effects of hyperthermia have been attributed to the immune system. The accepted observation of the cancer-host immune interface is that tumors

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retain unique antigens that can be recognized by the immune system [60]. After antigen uptake at tumour sites, antigen presenting cells have the ability to create a robust response by entering lymphoid compartments and programming lymphocytes. Studies have demonstrated that extracellular heat shock proteins (HSPs) can activate antitumor immunity during tumor cell necrosis. A model of integrating HSP synthesis mechanism and cell death can expound the HSP involvement in hyperthermia cancer immune therapy and its relation with dead tumor cell. This model is capable of generating maximum HSPs for stimulating anti-tumor immunity, promoting tumor regression, and reducing metastasis [61].

16.7.5 Hyperthermia and ultrasound In cancer treatment, hyperthermia became important as it increased significantly the therapeutic success and clinical management. Ultrasound hyperthermia has become one of the new therapeutic modalities for breast and brain cancer treatment, since ultrasound appears to selectively affect malignant cells. High temperature hyperthermia alone is being used for selective tissue destruction as an alternative to conventional invasive surgery [62]. The degree of thermal destruction of these therapies is strongly reliant on the ability to localize and sustain therapeutic temperature elevations. Owing to the often heterogeneous and dynamic properties of tissues, most notably blood perfusion and the presence of thermally significant blood vessels, therapeutic temperature elevations are difficult to spatially and temporally control during these forms of hyperthermia therapy. However, ultrasound technology has significant advantages that allow for a higher degree of spatial and dynamic control of the heating compared to other commonly utilized heating modalities [63]. In therapeutic focused ultrasound hyperthermia, magnetic nanoparticles engaged as sono-sensitizing materials which provide desired temperature in the focus in a shorter time for hyperthermia application [73]. Pre-clinical study on this combinational therapy regulates the safety and feasibility of using magnetic resonance-guided high-intensity focused ultrasound hyperthermia (MRgHIFU HT) in porcine leg muscles under real-time non-invasive temperature monitoring [64].

16.8 Challenges and future prospect A number of challenges need be overcome before hyperthermia can be considered a standard clinical trial for cancer treatment. It has been confided that MNPs mediated hyperthermia has a lot of technical restrictions for a real clinical application due to the required physical and structural properties, i.e. high magnetic moment, high magnetic susceptibility including magnetic permeability, high heat conduction and dissipation rate, high specific absorption rate (SAR) and capabilities of controlling particle size, shape, and size distributions for in vivo applications [6,7]. For example colloidal

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stability of the MNPs is very crucial for their successful application in the course of in vivo hyperthermia, as they tend to accumulate because of their magnetic nature. So, developments in surface functionalization approaches are much needed to make highly dispersible MNPs for in vivo hyperthermia applications. One possible solution would be to develop MNPs with very high SAR values so that less than a milligram of nanomaterial would be sufficient for magnetic hyperthermia locally in the tumor. However, the controlled Curie temperature is an unsolved problem in magnetic hyperthermia. To develop a Curie temperature tuned smart magnetic particle complexes with chemotherapeutic agent having high heating ability is much in demand for better therapeutic efficacy. Additionally, the targeting of the MNPs on intravenous injection has limited success and this needs further exploration. Uniform heat distribution of particles and toxicity is another major challenge that needs to be addressed. Moreover, large SAR is essential to realize the therapeutic potential, where the applied field amplitude and frequency are limited by practical and clinical considerations. However, many clinical trials were conducted to evaluate the effectiveness of hyperthermia while some trials continue to research hyperthermia in combination with other therapies for the treatment of different cancers. Considering the evolution of science and technology, probably we can assume that, sooner or later, challenges will be overcome. MNPs will then be able to operate simultaneously as heat mediators, contrast agents, drug carriers etc. A multifunctional MNP with appropriate payloads could exploit the tumor vascularity to provide a unique opportunity to improve cancer therapy by integrating tumor imaging, radiotherapy, chemotherapy, immunotherapy, hyperthermia, and gene silencing therapy.

16.9 Conclusion It is evident that MNPs are becoming promising agents for magnetic hyperthermia applications but much more of research towards its efficacy and safety are required before this treatment modality can be clinically adopted. MNPs are seen as potential therapeutic agents towards cancer treatment due to the ever growing demand of new treatment regime. Since last few decades various magnetic materials have been developed for magnetic hyperthermia therapy, still new techniques towards synthesis, their biocompatibility and toxicity, which limits their application are necessary. Finally, it is necessary to develop a magnetic nanoparticle-based hyperthermia system which is stable, has Curie temperature within hyperthermic temperature range, highly biocompatible and distribution of MNPs within the tumor is uniform. As new information about the biology of cancer emerges; treatments will be developed and modified to increase effectiveness, precision, survivability, and quality of life.

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Further reading P.I.P. Soares, I.M.M. Ferreira, R.A.G.B.N. Igreja, C.M.M. Novo, J.P.M.R. Borges, Application of hyperthermia for cancer treatment: recent patents review, Recent Pat. Anticancer Drug Discov. 7 (1) (2012) 64
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