Elsevier

Journal of Controlled Release

Volume 235, 10 August 2016, Pages 205-221
Journal of Controlled Release

Review article
Nanotechnology in hyperthermia cancer therapy: From fundamental principles to advanced applications

https://doi.org/10.1016/j.jconrel.2016.05.062Get rights and content

Abstract

In this work, we present an in-depth review of recent breakthroughs in nanotechnology for hyperthermia cancer therapy. Conventional hyperthermia methods do not thermally discriminate between the target and the surrounding normal tissues, and this non-selective tissue heating can lead to serious side effects. Nanotechnology is expected to have great potential to revolutionize current hyperthermia methods. To find an appropriate place in cancer treatment, all nanotechnology-based hyperthermia methods and their risks/benefits must be thoroughly understood. In this review paper, we extensively examine and compare four modern nanotechnology-based hyperthermia methods. For each method, the possible physical mechanisms of heat generation and enhancement due to the presence of nanoparticles are explained, and recent in vitro and in vivo studies are reviewed and discussed. Nano-Photo-Thermal Therapy (NPTT) and Nano-Magnetic Hyperthermia (NMH) are reviewed as the two first exciting approaches for targeted hyperthermia. The third novel hyperthermia method, Nano-Radio-Frequency Ablation (NaRFA) is discussed together with the thermal effects of novel nanoparticles in the presence of radiofrequency waves. Finally, Nano-Ultrasound Hyperthermia (NUH) is described as the fourth modern method for cancer hyperthermia.

Graphical abstract

Nanoparticles are concentrated inside the tumor and can absorb the energy originated from various external sources to enhance the effects of hyperthermia.

Abbreviations

NPTT: Nano-Photo-Thermal Therapy

NMH: Nano-Magnetic Hyperthermia

NaRFA: Nano-Radio-Frequency Ablation

NUH: Nano-Ultrasound Hyperthermia.

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Introduction

Cancer is one of the major causes of mortality worldwide. Several current methods used to treat cancers can be classified into conventional and modern methods (Fig. 1). Surgery, radiation therapy, and chemotherapy are considered the main conventional methods for cancer treatment but suffer from many limitations. Despite the recent technical advancements in these methods, the need for an efficient method for cancer therapy still remains [1].

Hyperthermia has been recently introduced as an adjuvant therapy for cancer and holds great promise for combating this disease. Hyperthermia is defined as a treatment in which the target tissue is exposed to high temperatures that either destroy the tissues directly (thermal ablation with temperatures above 47 °C) or render the cancer cells more susceptible to other treatment modalities (thermal sensitization in the temperature ranges of 41–45 °C). This elevation in the temperature of the tissue changes the vascular permeability, increases blood flow and eventually leads to tumor oxygenation. Thus, hyperthermia mitigates tissue hypoxia and could be concomitantly applied with radiation or anti-cancer drugs to intensify their cytotoxic effects on the tumor [2], [3], [4], [5], [6], [7]. Many clinical experiments conducted on breast, cervix, bladder, brain, head and neck tumors have demonstrated that the addition of hyperthermia to radiotherapy or chemotherapy significantly improves tumor control and patient survival rates [8], [9], [10], [11], [12].

Selection of an appropriate means for heat delivery to the tumor is an important and challenging issue in hyperthermia. Different energy sources are currently used to heat the tumor and include microwave, radiofrequency, laser and ultrasound sources. Conventional hyperthermia generates a temperature gradient with a maximum on the body's surface that instantaneously decreases with distance from the external source (outside-in hyperthermia). In this type of hyperthermia, the majority of energy is dissipated in the healthy tissues situated along the path of external radiation. As a result, no thermal discrimination occurs between the targeted tissue and the surrounding normal tissues, and this non-selectivity in tissue heating can lead to serious side effects [13]. These drawbacks must be addressed to develop an efficient hyperthermia method. Continuing efforts to develop more effective hyperthermia methods have led to the application of nanoparticles as hyperthermia agents.

Nanotechnology has been introduced into the biomedical applications with the expectation of revolutionizing current diagnostic and treatment techniques [14], [15], [16], [17], [18], [19], [20]. Nanoparticles can absorb energy originated from an external source and enhance the effects of hyperthermia (Fig. 2). In fact, nanoparticles play the role of the primary source of heat and reverse the direction of heat loss (inside-out hyperthermia). In this type of hyperthermia, nanoparticles focus the energy from the external source on the tumor to induce localized thermal destruction while minimizing the adverse effects on collateral tissues [2], [21], [22].

Beyond their ability to deliver therapeutic activities, nanoparticles have the potential for use as contrast agents for various medical imaging modalities [23], [24], [25], [26], [27]. Therefore, nanoparticle-mediated hyperthermia can simultaneously realize both diagnosis and therapy. Additionally, chemotherapy delivery might also be feasible if nanoparticles are attached to an anti-cancer drug [28], [29], [30]. Herein, we review novel hyperthermia methods based on new and emerging nanomaterials

(Fig. 3). Moreover, the potential mechanisms and applications of nanoparticles in promoting the efficacy of conventional hyperthermia methods are extensively discussed.

Section snippets

Nano-photo-thermal therapy (NPTT)

In the NPTT method, selective tumor killing is induced by specific targeting of a nano-photosensitizer towards the cancer cells and subsequent exposure to laser light (Fig. 4). The introduction of nanoparticles, such as gold nanoparticles (AuNPs), into the tissue changes the photothermal properties of the medium and increases the local conversion of optical energy into heat, and in this way, localized hyperthermia is induced [31], [32]. In addition to AuNPs, certain other nanostructures that

Nano-magnetic hyperthermia (NMH)

The major problem of conventional hyperthermia is inhomogeneity in the heat distribution profile, which might cause unwanted hot spots in collateral tissues that could damage healthy cells. Moreover, this inhomogeneity could create unheated regions inside the tumor, allowing it to eventually relapse [82], [83], [84]. As a result, to obtain the highest therapeutic ratio, thermal differentiation between tumor and healthy tissues must be achieved.

Based on the hyperthermic effects of magnetic

Nano-Radio-Frequency Ablation (NaRFA)

Application of non-ionizing radiofrequency (RF) waves is one of the more common thermal therapy approaches in clinical oncology. Non-ionizing radiation can be used as an adjuvant therapy to enhance the toxic effects of chemotherapy and radiotherapy on cancer cells. Moreover, thermal ablation of unresectable tumors, such as hepatocellular carcinoma and colorectal metastases, is possible through RF radiation [122], [123].

As stated previously, near infrared (NIR) light can be used to heat cancer

Nano-ultrasound hyperthermia (NUH)

Ultrasound is as an external source of energy that can be used to heat cancer cells and offers selected intrinsic advantages over other heating sources. Heat induced by ultrasound can be remotely focused at any depth of the body. As a result, localized heating of the tumor with reduced thermal damage to the surrounding healthy tissues is achievable via ultrasound [142].

High intensity focused ultrasound, referred to as HIFU (0.1–1 kW/cm2), is a non-invasive treatment modality that has been used

Combination of hyperthermia and other cancer therapies

It has been demonstrated that the combination of hyperthermia and chemotherapy results in supra-synergistic effects in cancer therapy [137], [155]. Nanoparticles can be utilized as carriers to selectively deliver chemotherapeutic agents to the tumor. Additionally, thermo-chemotherapy may be feasible if drug loaded nanoparticles are exposed with a hyperthermia energy source. Heat deposition due to application of nanotechnology based hyperthermia approaches (such as NPTT, NMH, NaRFA, and NUH) may

Further discussion

A wide range of radiation sources is able to generate the necessary heat for hyperthermia and destruction of cancer cells. Radiofrequency, microwave, infrared and acoustic waves are examples of energy sources currently applied in hyperthermia. Each of these mentioned sources of energy has its own heat generation principles, advantages and limitations.

It is well known that the penetration depth of electromagnetic waves inversely depends on frequency. Accordingly, RF waves with frequencies of

Conclusion

Nanotechnology-based hyperthermia methods have recently yielded significant breakthroughs, but it is clear that these methods and their risks must be thoroughly understood if they are to be correctly developed. In this review paper, we presented an overview of various nanotechnology-based hyperthermia methods and comparisons from different points of view. For selection of a good approach, many factors must be considered, such as SAR, depth of the tumor, penetration depth of external energy into

Acknowledgements

The authors appreciate all support received from the Science and Research Branch of Islamic Azad University (IAU), Tehran, Iran (Project No. ab-01).

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