Principles of Magnetic Hyperthermia: A Focus on Using Multifunctional Hybrid Magnetic Nanoparticles

Hyperthermia is a noninvasive method that uses heat for cancer therapy where high temperatures have a damaging effect on tumor cells. However, large amounts of heat need to be delivered, which could have negative effects on healthy tissues. Thus, to minimize the negative side effects on healthy cells, a large amount of heat must be delivered only to the tumor cells. Magnetic hyperthermia (MH) uses magnetic nanoparticles particles (MNPs) that are exposed to alternating magnetic field (AMF) to generate heat in local regions (tissues or cells). This cancer therapy method has several advantages, such as (a) it is noninvasive, thus requiring surgery, and (b) it is local, and thus does not damage health cells. However, there are several issues that need to achieved: (a) the MNPs should be biocompatible, biodegradable, with good colloidal stability (b) the MNPs should be successfully delivered to the tumor cells, (c) the MNPs should be used with small amounts and thus MNPs with large heat generation capabilities are required, (d) the AMF used to heat the MNPs should meet safety conditions with limited frequency and amplitude ranges, (e) the changes of temperature should be traced at the cellular level with accurate and noninvasive techniques, (f) factors affecting heat transport from the MNPs to the cells must be understood, and (g) the effect of temperature on the biological mechanisms of cells should be clearly understood. Thus, in this multidisciplinary field, research is needed to investigate these issues. In this report, we shed some light on the principles of heat generation by MNPs in AMF, the limitations and challenges of MH, and the applications of MH using multifunctional hybrid MNPs.

Download Full-text

Optimization Study on Specific Loss Power in Superparamagnetic Hyperthermia with Magnetite Nanoparticles for High Efficiency in Alternative Cancer Therapy

Nanomaterials ◽

10.3390/nano11010040 ◽

2020 ◽

Vol 11 (1) ◽

pp. 40

Author(s):

Costica Caizer

Keyword(s):

Magnetic Field ◽

Magnetic Nanoparticles ◽

Cancer Therapy ◽

Tumor Cells ◽

Heating Temperature ◽

Magnetic Hyperthermia ◽

Optimal Conditions ◽

Specific Loss ◽

Specific Loss Power ◽

The Magnetic Field

The cancer therapy with the lowest possible toxicity is today an issue that raises major difficulties in treating malignant tumors because chemo- and radiotherapy currently used in this field have a high degree of toxicity and in many cases are ineffective. Therefore, alternative solutions are rapidly being sought in cancer therapy, in order to increase efficacy and a reduce or even eliminate toxicity to the body. One of the alternative methods that researchers believe may be the method of the future in cancer therapy is superparamagnetic hyperthermia (SPMHT), because it can be effective in completely destroying tumors while maintaining low toxicity or even without toxicity on the healthy tissues. Superparamagnetic hyperthermia uses the natural thermal effect in the destruction of cancer cells, obtained as a result of the phenomenon of superparamagnetic relaxation of the magnetic nanoparticles (SPMNPs) introduced into the tumor; SPMNPs can heat the cancer cells to 42–43 °C under the action of an external alternating magnetic field with frequency in the range of hundreds of kHz. However, the effectiveness of this alternative method depends very much on finding the optimal conditions in which this method must be applied during the treatment of cancer. In addition to the type of magnetic nanoparticles and the biocompatibility with the biological tissue or nanoparticles biofunctionalization that must be appropriate for the intended purpose a key parameter is the size of the nanoparticles. Also, establishing the appropriate parameters for the external alternating magnetic field (AMF), respectively the amplitude and frequency of the magnetic field are very important in the efficiency and effectiveness of the magnetic hyperthermia method. This paper presents a 3D computational study on specific loss power (Ps) and heating temperature (ΔT) which allows establishing the optimal conditions that lead to efficient heating of Fe3O4 nanoparticles, which were found to be the most suitable for use in superparamagnetic hyperthermia (SPMHT), as a non-invasive and alternative technique to chemo- and radiotherapy. The size (diameter) of the nanoparticles (D), the amplitude of the magnetic field (H) and the frequency (f) of AMF were established in order to obtain maximum efficiency in SPMHT and rapid heating of magnetic nanoparticles at the required temperature of 42–43 °C for irreversible destruction of tumors, without affecting healthy tissues. Also, an analysis on the amplitude of the AMF is presented, and how its amplitude influences the power loss and, implicitly, the heating temperature, observables necessary in SPMHT for the efficient destruction of tumor cells. Following our 3D study, we found for Fe3O4 nanoparticles the optimal diameter of ~16 nm, the optimal range for the amplitude of the magnetic field of 10–25 kA/m and the optimal frequency within the biologically permissible limit in the range of 200–500 kHz. Under the optimal conditions determined for the nanoparticle diameter of 16.3 nm, the magnetic field of 15 kA/m and the frequency of 334 kHz, the magnetite nanoparticles can be quickly heated to obtain the maximum hyperthermic effect on the tumor cells: in only 4.1–4.3 s the temperature reaches 42–43 °C, required in magnetic hyperthermia, with major benefits in practical application in vitro and in vivo, and later in clinical trials.

Download Full-text

Enhanced Cytotoxic Effect of TAT–PLGA-Embedded DOXO Carried by Biomimetic Magnetic Nanoparticles upon Combination with Magnetic Hyperthermia and Photothermia

Pharmaceutics ◽

10.3390/pharmaceutics13081168 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1168

Author(s):

Ylenia Jabalera ◽

Alberto Sola-Leyva ◽

Salvatore Calogero Gaglio ◽

María P. Carrasco-Jiménez ◽

Guillermo R. Iglesias ◽

...

Keyword(s):

Magnetic Nanoparticles ◽

Laser Irradiation ◽

Tumor Cells ◽

Drug Transport ◽

Cytotoxic Effect ◽

Near Infrared ◽

Magnetic Hyperthermia ◽

Thermal Therapy ◽

Tat Peptide

The synergy between directed chemotherapy and thermal therapy (both magnetic hyperthermia and photothermia) mediated by a nanoassembly composed of functionalized biomimetic magnetic nanoparticles (BMNPs) with the chemotherapeutic drug doxorubicin (DOXO) covered by the polymer poly(lactic-co-glycolic acid) (PLGA), decorated with TAT peptide (here referred to as TAT–PLGA(DOXO-BMNPs)) is explored in the present study. The rationale behind this nanoassembly lies in an optimization of the nanoformulation DOXO-BMNPs, already demonstrated to be more efficient against tumor cells, both in vitro and in vivo, than systemic traditional therapies. By embedding DOXO-BMNPs into PLGA, which is further functionalized with the cell-penetrating TAT peptide, the resulting nanoassembly is able to mediate drug transport (using DOXO as a drug model) and behaves as a hyperthermic agent (induced by an alternating magnetic field (AMF) or by laser irradiation with a laser power density of 2 W/cm2). Our results obtained using the HepG2 cell line show that there is a synergy between chemotherapy and thermal therapy that results in a stronger cytotoxic effect when compared to that caused by the soluble DOXO. This is probably due to the enhanced DOXO release occurring upon the application of the thermal therapy, as well as the induced local temperature rise mediated by BMNPs in the nanoassembly following exposition to AMF or to near-infrared (NIR) laser irradiation. These results represent a proof of concept demonstrating that TAT–PLGA(DOXO-BMNPs) can be used to efficiently combine therapies against tumor cells, which is a step forward in the transition from systemic to local treatments.

Download Full-text

Agglomeration of magnetic nanoparticles and its effects on magnetic hyperthermia

Current Directions in Biomedical Engineering ◽

10.1515/cdbme-2017-0096 ◽

2017 ◽

Vol 3 (2) ◽

pp. 457-460 ◽

Cited By ~ 8

Author(s):

Ulrich Engelmann ◽

Eva Miriam Buhl ◽

Martin Baumann ◽

Thomas Schmitz-Rode ◽

Ioana Slabu

Keyword(s):

Magnetic Nanoparticles ◽

Local Heating ◽

Magnetic Hyperthermia ◽

Cellular Level ◽

Tumor Site ◽

Tumor Treatment ◽

Tumor Cell Death ◽

Magnetic Fluid Hyperthermia ◽

Heating Efficiency ◽

Intracellular Compartments

AbstractMagnetic fluid hyperthermia (MFH) is a promising approach for organ-confined tumor treatment. In MFH, magnetic nanoparticles (MNP) are magnetically targeted at the tumor site and heated in an alternating magnetic field. The heat produced by the MNP is used to cause tumor cell death. At the tumor site, MNP bind to the cell membrane and form agglomerates before they are internalized into the intracellular compartments. Intracellular immobilization and the formation of agglomerates influence heating properties of MNP making it difficult to control the local heating inside the tumor. In this study, we investigated MNP agglomerated samples for their heating efficiency. We found an increase in heating of 22 % upon agglomeration. If MNP are additionally immobilized, however, the heating decreases by 30 %. Consequently, due to the binding of bigger MNP agglomerates at cellular level, heating efficiency inside tumors is assumed to decrease.

Download Full-text

Bifunctional magnetic nanoparticles for early detection and magnetic hyperthermia cancer therapy

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.lb335 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Sivasai Balivada ◽

Raja Shekar Rachakatla ◽

Hongwang wang ◽

Thilani N. Samarakoon ◽

Raj Kumar Dani ◽

...

Keyword(s):

Magnetic Nanoparticles ◽

Cancer Therapy ◽

Early Detection ◽

Magnetic Hyperthermia

Download Full-text

Size Dependent Heat Generation of Magnetic Nanoparticles Under AC Magnetic Field for Cancer Therapy

Basic and Applied Aspects ◽

10.1007/978-90-481-3892-0_68 ◽

2010 ◽

pp. 415-421 ◽

Cited By ~ 3

Author(s):

Jun Motoyama ◽

Toshiyuki Hakata ◽

Ryuji Kato ◽

Noriyuki Yamashita ◽

Tomio Morino ◽

...

Keyword(s):

Magnetic Field ◽

Magnetic Nanoparticles ◽

Cancer Therapy ◽

Heat Generation ◽

Ac Magnetic Field ◽

Size Dependent

Download Full-text

Tumor-Derived Exosomes in Immunosuppression and Immunotherapy

Journal of Immunology Research ◽

10.1155/2020/6272498 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Wioletta Olejarz ◽

Agnieszka Dominiak ◽

Aleksandra Żołnierzak ◽

Grażyna Kubiak-Tomaszewska ◽

Tomasz Lorenc

Keyword(s):

Cell Proliferation ◽

Cancer Therapy ◽

Tumor Cells ◽

Immune Cells ◽

Immune Cell ◽

Nk Cell ◽

Immune Surveillance ◽

Cell Activity ◽

Factors Affecting ◽

Promising Area

Tumor-derived exosomes (TEX) are involved in cancer development, metastasis, and disease progression. They can modulate angiogenesis to elevate the malignant degree of tumor cells. TEX carry immunosuppressive factors affecting the antitumor activities of immune cells. Tumor cells as well as immune cells secrete immunologically active exosomes which affect intercellular communication, antigen presentation, activation of immune cells, and immune surveillance. Cell proliferation and immune response suppression create a favorable microenvironment for tumor. TEX can inhibit immune cell proliferation, induce apoptosis of activated CD8+ Teffs, suppress NK cell activity, interfere with monocyte differentiation, and promote Treg as well as MDSC expansion. Exosomes of microenvironment cells may also contribute to the development of drug resistance in cancer therapy. An important role of TEX in modulating the sensitivity of tumor cells to immunotherapy is a promising area of research to make the cancer therapy more successful.

Download Full-text

The Treatment of Heterotopic Human Colon Xenograft Tumors in Mice with 5-Fluorouracil Attached to Magnetic Nanoparticles in Combination with Magnetic Hyperthermia Is More Efficient than Either Therapy Alone

Cancers ◽

10.3390/cancers12092562 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2562

Author(s):

Mohammad Dabaghi ◽

Rainer Quaas ◽

Ingrid Hilger

Keyword(s):

Colorectal Cancer ◽

Magnetic Nanoparticles ◽

Tumor Cells ◽

Tumor Model ◽

Magnetic Hyperthermia ◽

Target Cells ◽

Αvβ3 Integrin ◽

Tumor Vascularity ◽

Chemotherapeutic Treatment ◽

Therapy Sessions

Magnetic nanoparticles (MNPs) have shown promising features to be utilized in combinatorial magnetic hyperthermia and chemotherapy. Here, we assessed if a thermo-chemotherapeutic approach consisting of the intratumoral application of functionalized chitosan-coated MNPs (CS-MNPs) with 5-fluorouracil (5FU) and magnetic hyperthermia prospectively improves the treatment of colorectal cancer. With utilization of a human colorectal cancer (HT29) heterotopic tumor model in mice, we showed that the thermo-chemotherapeutic treatment is more efficient in inactivating colon cancer than either tumor treatments alone (i.e., magnetic hyperthermia vs. the presence of 5FU attached to MNPs). In particular, the thermo-chemotherapeutic treatment significantly (p < 0.01) impacts tumor volume and tumor cell proliferation (Ki67 expression, p < 0.001) compared to the single therapy modalities. The thermo-chemotherapeutic treatment: (a) affects DNA replication and repair as measured by H2AX and phosphorylated H2AX expression (p < 0.05 to 0.001), (b) it does not distinctly induce apoptosis nor necroptosis in target cells, since expression of p53, PARP cleaved-PARP, caspases and phosphorylated-RIP3 was non-conspicuous, (c) it renders tumor cells surviving therapy more sensitive to further therapy sessions as indicated by an increased expression of p53, reduced expression of NF-κB and HSPs, albeit by tendency with p > 0.05), and (d) that it impacts tumor vascularity (reduced expression of CD31 and αvβ3 integrin (p < 0.01 to 0.001) and consequently nutrient supply to tumors. We further hypothesize that tumor cells die, at least in parts, via a ROS dependent mechanism called oxeiptosis. Taken together, a very effective elimination of colon cancers seems to be feasible by utilization of repeated thermo-chemotherapeutic therapy sessions in the long-term.

Download Full-text

Understanding MNPs Behaviour in Response to AMF in Biological Milieus and the Effects at the Cellular Level: Implications for a Rational Design That Drives Magnetic Hyperthermia Therapy toward Clinical Implementation

Cancers ◽

10.3390/cancers13184583 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4583

Author(s):

David Egea-Benavente ◽

Jesús G. Ovejero ◽

María del Puerto Morales ◽

Domingo F. Barber

Keyword(s):

Magnetic Nanoparticles ◽

Rational Design ◽

Molecular Mechanisms ◽

Biological Effects ◽

Basic Research ◽

Magnetic Hyperthermia ◽

Cellular Level ◽

Target Area ◽

Clinical Implementation ◽

Promising Alternative

Hyperthermia has emerged as a promising alternative to conventional cancer therapies and in fact, traditional hyperthermia is now commonly used in combination with chemotherapy or surgery during cancer treatment. Nevertheless, non-specific application of hyperthermia generates various undesirable side-effects, such that nano-magnetic hyperthermia has arisen a possible solution to this problem. This technique to induce hyperthermia is based on the intrinsic capacity of magnetic nanoparticles to accumulate in a given target area and to respond to alternating magnetic fields (AMFs) by releasing heat, based on different principles of physics. Unfortunately, the clinical implementation of nano-magnetic hyperthermia has not been fluid and few clinical trials have been carried out. In this review, we want to demonstrate the need for more systematic and basic research in this area, as many of the sub-cellular and molecular mechanisms associated with this approach remain unclear. As such, we shall consider here the biological effects that occur and why this theoretically well-designed nano-system fails in physiological conditions. Moreover, we will offer some guidelines that may help establish successful strategies through the rational design of magnetic nanoparticles for magnetic hyperthermia.

Download Full-text

Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

Current Medicinal Chemistry ◽

10.2174/0929867325666180719145819 ◽

2020 ◽

Vol 27 (13) ◽

pp. 2118-2132 ◽

Cited By ~ 5

Author(s):

Aysegul Hanikoglu ◽

Hakan Ozben ◽

Ferhat Hanikoglu ◽

Tomris Ozben

Keyword(s):

Oxidative Stress ◽

Drug Resistance ◽

Side Effects ◽

Cancer Therapy ◽

Tumor Cells ◽

Anticancer Drugs ◽

Chemotherapeutic Agents ◽

Oxidation Reactions ◽

Hybrid Compounds ◽

Induced Apoptosis

: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

Download Full-text

Transferrin-Conjugated Nanocarriers as Active-Targeted Drug Delivery Platforms for Cancer Therapy

Current Pharmaceutical Design ◽

10.2174/1381612822666161026162347 ◽

2017 ◽

Vol 23 (3) ◽

pp. 454-466 ◽

Cited By ~ 16

Author(s):

Daniele R. Nogueira-Librelotto ◽

Cristiane F. Codevilla ◽

Ammad Farooqi ◽

Clarice M. B. Rolim

Keyword(s):

Drug Delivery ◽

Cancer Therapy ◽

Tumor Cells ◽

Therapeutic Benefit ◽

Active Targeting ◽

Future Research ◽

Passive Targeting ◽

The Right ◽

Review Current ◽

Target Effects

A lot of effort has been devoted to achieving active targeting for cancer therapy in order to reach the right cells. Hence, increasingly it is being realized that active-targeted nanocarriers notably reduce off-target effects, mainly because of targeted localization in tumors and active cellular uptake. In this context, by taking advantage of the overexpression of transferrin receptors on the surface of tumor cells, transferrin-conjugated nanodevices have been designed, in hope that the biomarker grafting would help to maximize the therapeutic benefit and to minimize the side effects. Notably, active targeting nanoparticles have shown improved therapeutic performances in different tumor models as compared to their passive targeting counterparts. In this review, current development of nano-based devices conjugated with transferrin for active tumor-targeting drug delivery are highlighted and discussed. The main objective of this review is to provide a summary of the vast types of nanomaterials that have been used to deliver different chemotherapeutics into tumor cells, and to ultimately evaluate the progression on the strategies for cancer therapy in view of the future research.

Download Full-text