Nanoparticles-based magnetic and photo induced hyperthermia for cancer treatment

Highlights

• Mechanisms of magnetic and photo-induced hyperthermia for designing relevant nanomaterials.

• Comprehensive comparison between both modalities and requirement for clinical translation.

• Illustrations of different nanoparticles for both modalities of therapy.

• Advocate the combining two modalities as a novel avenue for research.

Abstract

Nanoscience provides several modalities to combat cancer disease effectively. Magnetic hyperthermia and photothermal therapy techniques are central research themes among various groups in the world by utilizing magnetic and optical characteristics of distinct or composite nanoentities. This review provides the current research on both the techniques and their successes towards clinical translation. This review discusses about the various heating mechanisms involved in magnetic and photo-induced hyperthermia. We have evaluated potential functional nanoparticles with excellent properties capable of providing innovative future solutions to current problems associated with these therapies. Several factors (extracellular and intracellular) have been covered and explained which may affect such thermal treatments. We have provided some instrumental and technical details of both the techniques that are important for consideration in using these modalities of treatments. A direct comparison of these two techniques and a further need of the combined therapy (magnetic hyperthermia plus photothermal therapy) was highlighted as a new pathway for cancer treatments.

Introduction

Temperature is one of the basic variables in science and with the latest advancements in nanothermometry nowadays it can be measured with submicrometric spatial resolution [1]. The resolution in temperature measurements expands the applications and control of temperature changes in biological systems leading to a detailed determination of their dynamics and viability for a wide range of organic systems from cells, tissues to organisms [2]. The use of heat for the purpose of therapy is an old fashion methodology in ancient history which had a rise of popularity through the 19^th century as a treatment against cancer, being optimized in 21^st century, but still remained unaccomplished due to the lack of measuring methodologies [3]. In recent decades of “the nanoscale era”, the research activities in terms of scientific/technological output using thermal treatments have led to renewed interest in thermal therapy, especially on the magnetic-thermal therapy and photo-induced thermal therapy [4]. Novel techniques for controlled and localized heat generation, monitoring it, and transferring localized heat to the biological targets are being proposed purposely and specified. The understanding of different mechanisms causing temperature induced cell killing, cell-modification and the capability to produce heat in the vicinity of cells is very important. The type of nanoscale materials used to generate heat from external force such as magnetic field, infrared (IR) radiation, X-rays etc., are the main focus of research in the field [5]. The basic mechanism of thermal therapy is sometime controversial due to a lack of comprehensive understanding of the local effects caused by the temperature elevation on individual cells in most of the given bio-specimen [6]. All thermal treatments are based on driving part of the body or the whole above its normal temperature for a defined period of time. Temperature rise at cellular level causes changes in tissue elasticity, blood flow rate, protein synthesis, dissociation and inactivity of cells from minutes to several hours or days. The essential points in using thermal treatment are: the amount of localized temperature rise in biosystems and the duration of treatment in external field force. The magnitude of the temperature gradient is the primary factor that classifies thermal treatments and their macroscopic effects on cancer cells/tumors in three major categories:

• Diathermic treatment: It is based on heating tissues and organs from the standard body temperature up to 41 °C. These processes increase blood flow and cause a rise in the diffusion rates of “bio-liquids” across cell membranes but generally preserve the cellular homeostasis [6].

• Hyperthermia Treatment (HT): It is required the local generation of temperature in the range from 41 to 48 °C which is generally described as clinically relevant [7]. A comprehensive understanding of the biomechanisms acting at the cellular level in this range of temperature is still far from completion. In this temperature range, because of protein denaturation, aggregation and the synthesis of heat-shock proteins, long time treatments may lead to long term cell inactivation and change in the rates of several biochemical reactions. Hyperthermia treatments commonly used in combination with other cancer treatments such as chemotherapy or radiation therapy which are applied after due to increased susceptibility to the treatments of the heat stressed cells [8].

• Irreversible thermal treatment: It includes all treatments that increase the tumor temperature above 48 °C for a relatively short time. At this temperature range the effect on cells/tissues is drastic and non-reversible [9]. Irreversible thermal treatments can be very efficient in the ablation of tumors but sometimes they may cause secondary damages to DNA and proteins of healthy cells. So far that irreversible thermal treatments are not generally used for cancer treatment but primarily only in urology and cardiology as option to the traditional surgery [10].

Besides direct thermal-induced therapy, there are several other techniques and methodologies which contribute to the efficiency of hyperthermia as a therapeutic tool against cancer diseases such as oxygenation, pH-maintenance, photodynamic therapy, heat released chemotherapy, etc. [7]. Compared with others, thermal therapy is less invasive, and it increases the efficacy of traditional treatments by reducing side effects. Using a sufficiently accurate control, thermal therapy has been used for localized heating of cancer cells with minimal effect on normal cells [12]. Heating on superficial tumors can be done using radio frequencies, microwave irradiation, ultrasound techniques or with IR laser sources [13]. Depending on the depth and size of cancerous tissue, several parameters in instrumental setup can be varied in order to get a more effective treatment. Figs. 1a &1b explain the fundamental experimental arrangements of the magnetic hyperthermia treatment (MHT) as well as the photothermal treatment (PTT) and they can be combined together (Fig. 1c) for more effective treatments [14].

In difference with micro or bulk counterparts, materials synthesized and engineered on nanoscale usually have novel characteristics which may be favorable in biological systems for interaction with cell surface and intercellular structures. Nowadays the nanoscale materials have become strong candidates for medical treatments as carriers for drugs, therapy and for the detection of diseases. In cancer or tumor treatment, nanoparticles (NPs) have recently been considered as a promising new approach [15]. Nanomedicine requires a multidisciplinary attitude and its understanding requiring knowledge of ethical, physical, chemical, physiological and biological aspects. Nanotechnology promises to revolutionize the area of cancer/tumor treatment with a wide spectrum of nanostructures including polymers, dendrimers, lipids, organometallic, carbon based materials, several inorganic nanomaterials (iron oxide, Au, Ag, semiconductor quantum dots (QDs) contributing to development of treatments with different physical process and mechanisms of action [15]. An approach to the selection of nanomaterials should consider biodistribution, toxicity (short and long term), size control, surface chemistry, their behavior in biological systems and the use of nanomaterials with their unique properties can open a new set of opportunity for medicine. Here, NPs can have therapeutic as well as diagnostic properties to be designed to carry a large therapeutic “payload^” [4]. They can also be modified with targeting ligands which yield high affinity and specificity for target cells to deliver highly active chemotherapy and hyperthermia with cellular precision. The complex structure of NPs can be made to accommodate multiple active molecules simultaneously allowing combinatorial cancer therapy with different drugs [16] and biomimetic NPs can bypass cellular membranes as well as overcome drug resistance mechanism [17,18]. Currently, NPs and nanoparticulate formulations have been integrated into cancer therapeutics and ongoing clinical trials with improved efficacy and reduced toxicity [19].

Thermal treatments mediated with nanomaterials can be classified through the process used to generate the therapeutic effect a slight activated in the photothermal and photodynamic therapies or magnetically induced for the magnetothermal therapy [18,20]. Magnetothermal therapy is based on different mechanisms including hysteresis loss, Neel relaxation and Brown relaxation to convert the energy of an external magnetic field into heat. A typical method of delivering the NPs to the tumor site is the direct injection in the tumor area followed by diffusion in the damaged tissues [21]. The first clinical results in the field of MHT were obtained by Jordan et al [22] against brain tumor using superparamagnetic iron-oxide coated by aminosilane. A benefit of using magnetic nanostructures for MHT is the simultaneously use of either being contrast agent in magnetic resonance imaging (MRI) or acting as heat source when exposed to specific frequencies. On the negative side, MHT may cause protein denaturation, DNA damage, signaling interruption, cell growth inhibition and apoptosis [23].

PTT, or optical hyperthermia, uses the energy of laser to trigger the action of either photothermal conversion agents or specific physical phenomena to generate heat causing thermal ablation of cancer cells [24]. A field of PTT study has expanded since the beginning of the millennia with the development of easily producible Au nanostructures (e.g., rods, cubes) [25], and nowadays it is extended to nanostructures with a variety of different elements or materials. Nanomaterials used in PTT are generally characterized by a great efficiency in photothermal conversion for wavelength in the near infrared (NIR) to exploit the optical window of living tissues [26]. In addition, the materials also need to have high performance, especially when applied to in vivo, a low toxicity and tumor targeting properties. NIR lasers are the main energy source for PTT which can penetrate through the tissues and be converted into heat by the nanomaterials (Fig. 1). Using laser directly to ablate tumor tissues would require high energy settings causing unintended damage to normal tissues. The introduction of a photothermal conversion agents allows the use of low energy laser able to penetrate healthy tissues without causing heat damages [16]. Several necessary characteristics are important for such agents including photostability, biocompatibility, large absorption coefficient and NIR absorption. Metals have different optical properties from standard dielectric materials (based on oxides, fluorides, nitrides etc.) and among them nanostructured Au is the most promising photothermal metallic agent. Here, the heating mainly involves surface plasmon generation or localized surface plasmon resonance from the interaction of light with metals. One of the traditional draw backs of PTT was the necessity of the laser to be able to penetrate the healthy tissues without damaging them or loosing too much power (due to scattering). This limitation has been recently overcome by moving the light source inside the patient with the use of fiber optic waveguides. With a powerful laser source, the output, however, was relatively weak limited from fraction of watt to few watts for direct laser ablation or even lower for longer time when used for particles mediated hyperthermia [28].

The difference between MHT and PTT is the attainable tissue penetration. PTT is only able to treat tumors seated at the surface or a few millimeters below the tissue level because of limited tissue penetration of light [29] while MHT can treat tumors seated at any depth thanks to the large tissue penetration ability of the magnetic field [30]. Moreover, the contactless use of alternating AC magnetic field enables a controllable remote treatment to eliminate tumors that are inaccessible by PTT. The continuous effort of working on the subject of cancer treatments using thermal approach has been linked specially with the synthesis of nanomaterials focusing on high degree of shape-size tunability, surface modifications and bioconjugations with NPs. At the moment, a very few clinical centers use MHT/PTT for anticancer therapy, but there are a large number of particles and protocols in pre-clinical or in the process of being approved in Europe and USA for clinical use [31,32]. The pursuit of innovative, multifunctional, more efficient and safer treatments is a major challenge in preclinical NP-mediated thermotherapeutic research, and it is important to search for “dual” materials to act as both magnetic and photothermal agents. In this review, we are aiming to provide comprehensive information about magnetic and photothermal hyperthermia including the processes involved in their mechanisms, on the factors affecting the efficiency, the biological interactions as well as details on the instrumentations used for the therapies. We also review both the therapies at clinical levels and the combined therapy showing the research work on this hot topic.