ABSTRACT
The blood−brain barrier is a highly selective semipermeable border that separates blood circulation from the brain and hinders the accumulation of substances in the central nervous system. Hence, a treatment plan aiming to combat neurodegenerative diseases may be restricted. The exploitation of the nose−brain pathway could be a promising bypass method. However, pharmaceutical uptake through the olfactory epithelium is insignificant in terms of treatment, if relying only on fluid dynamic interactions. The main reasons for this are the highly complicated geometry of the nose and the residence time of the substance. The issue can be tackled by using magnetic particles as drug carriers. With the application of an external magnetic field, further control of the particle motion can be achieved, leading to increased uptake. The present work studies this approach computationally by employing magnetite particles with a radius of 7.5 µm while a magnetic field is applied with a permanent neodymium-iron-boron magnet of 9.5×105 A/m magnetization. Through this investigation, the best drug delivery protocol achieved a 2% delivery efficiency. The most significant advantage of this protocol is its straightforward design, which does not require complex equipment, thus rendering the protocol portable and manageable for frequent dosing or at-home administration.
ABSTRACT
Unavoidably, magnetic particle hyperthermia is limited by the unwanted heating of the neighboring healthy tissues, due to the generation of eddy currents. Eddy currents naturally occur, due to the applied alternating magnetic field, which is used to excite the nanoparticles in the tumor and, therefore, restrict treatment efficiency in clinical application. In this work, we present two simply applicable methods for reducing the heating of healthy tissues by simultaneously keeping the heating of cancer tissue, due to magnetic nanoparticles, at an adequate level. The first method involves moving the induction coil relative to the phantom tissue during the exposure. More specifically, the coil is moving symmetrically-left and right relative to the specimen-in a bidirectional fashion. In this case, the impact of the maximum distance (2-8 cm) between the coil and the phantom is investigated. In the second method, the magnetic field is applied intermittently (in an ON/OFF pulsed mode), instead of the continuous field mode usually employed. The parameters of the intermittent field mode, such as the time intervals (ON time and OFF time) and field amplitude, are optimized based on the numerical assessment of temperature increase in healthy tissue and cancer tissue phantoms. Different ON and OFF times were tested in the range of 25-100 s and 50-200 s, respectively, and under variable field amplitudes (45-70 mT). In all the protocols studied here, the main goal is to generate inside the cancer tissue phantom the maximum temperature increase, possible (preferably within the magnetic hyperthermia window of 4-8 °C), while restricting the temperature increase in the healthy tissue phantom to below 4 °C, signifying eddy current mitigation.
ABSTRACT
A magnetic nanocomposite, consisting of Fe3O4 nanoparticles embedded into a Mg/Al layered double hydroxide (LDH) matrix, was developed for cancer multimodal therapy, based on the combination of local magnetic hyperthermia and thermally induced drug delivery. The synthesis procedure involves the sequential hydrolysis of iron salts (Fe2+, Fe3+) and Mg2+/Al3+ nitrates in a carbonate-rich mild alkaline environment followed by the loading of 5-fluorouracil, an anionic anticancer drug, in the interlayer LDH space. Magnetite nanoparticles with a diameter around 30 nm, dispersed in water, constitute the hyperthermia-active phase able to generate a specific loss of power of around 500 W/g-Fe in an alternating current (AC) magnetic field of 24 kA/m and 300 kHz as determined by AC magnetometry and calorimetric measurements. Heat transfer was found to trigger a very rapid release of drug which reached 80% of the loaded mass within 10 min exposure to the applied field. The potential of the Fe3O4/LDH nanocomposites as cancer treatment agents with minimum side-effects, owing to the exclusive presence of inorganic phases, was validated by cell internalization and toxicity assays.
ABSTRACT
Magneto-fluorescent nanocomposites have been recognized as an emerging class of materials displaying great potential for improved magnetic hyperthermia assisted by optical imaging. In this study, we have designed a series of hybrid composites that consist of zinc doped ZnxFe3-xO4 ferrites functionalized by polyethylene-glycol (PEG8000) and an orange-emitting platinum complex [Pt(phen)Cl2]. Experimental and theoretical studies on the optimization of their magnetically-mediated heating properties were conducted. PEG was assembled around particles' surface by two different approaches; in situ and post-PEGylation. PEGylation ensured the optimal distance between the magnetic core and Pt(ii)-complex to maintain significant luminescence in the composite. The successful inclusion of the complex to the organic matrix was confirmed by a variety of spectroscopic techniques. A theoretical model was developed, based on linear response theory, in order to examine the composites' power losses dependence on their properties. Within this model, inter-particle interactions were quantified by inserting a mean dipolar energy term in the estimation of Néel relaxation time, and consequently, the size and concentration that maximize power loss were derived (20 nm and 4 mg mL-1). Moreover, a decrease in the anisotropy of nanoparticles resulted in an increase in specific loss power values. Theoretical estimations are validated by experimental data when heating aqueous dispersions of composites in 24 kA m-1, 765 kHz AMF for various values of concentration and size. Magnetic hyperthermia results showed that the theory-predicted values of optimum concentration and size delivered the maximum-specific loss power which was found equal to 545 W g-1. By the present approach, a quantitative link between the particles' dipolar interactions and their heating properties is established, while opening new perspectives to nanotheranostic applications.
ABSTRACT
Objective: In magnetic particle hyperthermia, a promising least-invasive cancer treatment, malignant regions in proximity with magnetic nanoparticles undergo heat stress, while unavoidably surrounding healthy tissues may also suffer from heat either directly or indirectly by the induced eddy currents, due to the developed electric fields as well. Here, we propose a facile upgrade of a typical magnetic particle hyperthermia protocol, to selectively mitigate eddy currents' heating without compromising the beneficial role of heating in malignant regions.Method: The key idea is to apply the external magnetic field intermittently (in an ON/OFF pulse mode), instead of the continuous field mode typically applied. The parameters of the intermittent field mode, such as time intervals (ON time: 25-100 s, OFF time: 50-200 s, Duty Cycle:16-100%) and field amplitude (30-70 mT) are optimized based on evaluation on healthy tissue and cancer tissue phantoms. The goal is to sustain in cancer tissue phantom the maximum temperature increase (preferably within 4-8°C above body temperature of 37°C), while in the healthy tissue phantom temperature variation is suppressed far below the 4°C dictating the eddy current mitigation.Results: Optimum conditions of intermittent field (ON/OFF: 50/100 in s, Duty Cycle: 33%, magnetic field: 45mT) are then examined in ex-vivo samples verifying the successful suppression of eddy currents. Simultaneously, a well-elaborated theoretical approach provides a rapid calculation of temperature increase and, furthermore, the ability to quickly simulate a variety of duty cycle times and field controls may save experimental time.Conclusion: Eventually, the application of an intermittent field mode in a magnetic particle hyperthermia protocol, succeeds in eddy current mitigation in surrounding tissues and allows for the application of larger field amplitudes that may augment hyperthermia efficiency without objecting typical biomedical applicability field constraints such as Brezovich criterion.
Subject(s)
Hyperthermia, Induced , Humans , Hyperthermia , Magnetic Fields , Magnetics , TemperatureABSTRACT
Attenuation of the unwanted heating of normal tissues due to eddy currents presents a major challenge in magnetic particle hyperthermia for cancer treatment. Eddy currents are a direct consequence of the applied alternating magnetic field, which is used to excite the nanoparticles in the tumor and have been shown to limit treatment efficacy in clinical trials. To overcome these challenges, this paper presents simple, clinically applicable, numerical approaches which reduce the temperature increase due to eddy currents in normal tissue and simultaneously retain magnetic nanoparticles heating efficiency within the tumor. More specifically, two protocols are examined which involve moving the heating source, an electromagnetic coil, relative to a tumor-bearing phantom tissue during the exposure. In the first protocol, the linear motion of the coil on one side with respect to the hypothesized tumor location inside the phantom is simulated. The estimated maximum temperature increase in the healthy tissue and tumor is reduced by 12% and 9%, respectively, compared to a non-moving coil, which is the control protocol. The second technique involves a symmetrical variation of the first one, where the coil is moving left and right of the phantom in a bidirectional fashion. This protocol is considered as the optimum one, since the estimated maximum temperature rise of the healthy tissue and tumor is reduced by 25% and 1%, respectively, compared to the control protocol. Thus, the advantages of a linearly moving coil are assessed through tissue sparing, rendering this technique suitable for magnetic particle hyperthermia treatment.