Simulating physiological conditions to evaluate nanoparticles for magnetic fluid hyperthermia (MFH) therapy applications

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Abstract

Magnetite nanoparticles with high self-heating capacity and low toxicity characteristics are a promising candidate for cancer hyperthermia treatment. In order to achieve minimum dosage to a patient, magnetic nanoparticles with high heating capacity are needed. In addition, the influence of physiological factors on the heat capacity of a material should be investigated in order to determine the feasibility. In this study, magnetite nanoparticles coated with lauric acid were prepared by co-precipitation of Fe3+:Fe2+ in a ratio of 2:1, 5:3, 3:2, and 4:3, and the pH was controlled using NaOH. Structural and magnetization characterization by means of X-ray diffractometry (XRD) and a superconducting quantum interference device (SQUID) revealed that the main species was Fe3O4 and further showed that most of the nanoparticles exhibited superparamagnetic properties. All of the magnetic nanoparticles showed a specific absorption rate (SAR) increase that was linear with the magnetic field strength and frequency of the alternating magnetic field. Among all, the magnetic nanoparticles prepared in a 3:2 ratio showed the highest SAR. To further test the influence of physiological factors on the 3:2 ratio magnetic nanoparticles, we simulated the environment with protein (bovine serum albumin, BSA), blood sugar (dextrose), electrolytes (commercial norm-saline) and viscosity (glycerol) to examine the heating capacity under these conditions. Our results showed that the SAR value was unaffected by the protein and blood sugar environments. On the other hand, the SAR value was significantly reduced in the electrolyte environment, due to precipitation and aggregation with sodium ions. For the simulated viscous environment with glycerol, the result showed that the SAR values reduced with increasing glycerol concentration. We have further tested the heating capacity contribution from the Néel mechanism by trapping the magnetic nanoparticles in a solid form of polydimethylsiloxane (PDMS) to eliminate the heating pathway due to a Brownian motion. We measured the heating capability and determined that 47% of the total heat generated by the magnetic nanoparticles was from the Néel mechanism contribution. For evaluating magnetic nanoparticles, this method provides a fast and low cost method for determining qualitative and quantitative information measurement for the effect of physiological interference and could greatly reduce the cost and time by in vitro or animal test.

Introduction

Superparamagnetic iron oxide nanoparticles have been applied in many areas of biomedicine, such as DNA separation [1], drug targeting [2], immune detection [3], and contrast enhancement in magnetic resonance imaging [4]. In addition, some studies have shown that the self-heating characteristics of magnetic nanoparticles under an alternating magnetic field cannot only kill tumor cells [5], [6] and increase the efficacy of chemotherapy [7], but also induce immunological antitumor activity [8]. Accordingly, magnetic nanoparticle hyperthermia is thought to be a promising cancer treatment [9].

Previous studies have shown that the heating capacity of magnetic nanoparticles can be influenced by many factors. For example, Hergt et al. observed that the heating effect of magnetic particles depended strongly on the particle size [10]. The magnetic anisotropy constant can influence the heating mechanism of magnetic nanoparticles [11], and high saturation magnetization was shown to achieve higher temperatures under the same heating conditions [12]. In addition, the specific absorption rate (SAR) values of some magnetic nanoparticles increased with increasing frequency and amplitude of the alternating magnetic field [11], [13]. The viscosity of the sample was shown to reduce the heating contribution from the Brownian mechanism [11]. Also, the heating capacity of magnetic nanoparticles was influenced by different surfactant coating [14]. Among the factors mentioned above, the surfactant is a component which is in direct contact with the surrounding environment.

For biomedical applications, biocompatible surfactants, such as dextran [5], starch, chitosan [14], cationic liposomes [15], polyethylene-imine (PEI) [16], poly(ethylene oxide) (PEO) [17], folic acid, and poly(ethylene glycol) (PEG) [18] have been used to coat magnetic nanoparticles. Before measuring the heating capacity of magnetic nanoparticles coated by a biocompatible surfactant for in vitro or in vivo testing, it is necessary to mix the nanoparticles into a medium or inject them into an organism. However, the result of such studies showed that aggregation occurred with time, as magnetic nanoparticles coated by PEI, PVA or A-PVA (vinyl alcohol/vinyl amine copolymer) were added to Dulbecco's modified Eagle's medium (DMEM) or RPMI medium [19]. The agglomeration rate of magnetic nanoparticles coated by PVA or A-PVA was influenced in the DMEM and RPMI with or without serum. [20]. In addition, non-dispersed magnetic nanoparticles generated low SAR (specific adsorption rate) values [21].

Jordan et al. [22] showed that combining magnetic nanoparticle thermotherapy with radiation treatment for treating prostate tumors was more effective than treatment by radiation treatment alone. Further, the results suggested that cancer cells with DNA damage by radiation treatment lost their repair function due to magnetic nanoparticle thermotherapy. In addition, Hilger et al. [23] showed that when cancer cells were heated to the thermoablative temperature using magnetic nanoparticles, cell survival was influenced significantly when DNA damage was over 50%. Based on these studies, magnetic nanoparticles with high heating capacity may provide a more effective treatment option for cancer cells.

To provide the most effective thermotherapy, it is critical to synthesize magnetic nanoparticles that posses high heating capacity under actual physiological conditions. However, the methods used to evaluate the heating capacity of the magnetic nanoparticles and to determine the impact of various factors through in vitro and/or in vivo testing are slow and expensive, especially if many biocompatible surfactants are used. Accordingly, in our study, magnetic nanoparticles coated by lauric acid were used as a thermoseed to investigate the influence of simulated physiological environments, such as protein, glucose, electrolytes and viscosity, on heating capacity.

Our results showed that magnetic nanoparticles coated with lauric acid were sensitive to electrolyte and viscosity. In further tests using solid polydimethylsiloxane (PDMS) as a matrix for immobilizing the magnetic nanoparticles, we were able to determine the relative contributions to the heating capacity by the Néel and Brownian mechanisms. The methods described in this report provide a quick and simple way to evaluate the quality and performance of magnetic nanoparticles in relevant physiological environments.

Section snippets

Materials and methods

FeCl3·6H2O, FeCl2·4H2O, NaOH, acetone, ethanol (all purchased from Merck) and lauric acid (purchased from J.T.Baker) which was used for the synthesis of magnetic nanoparticle. BSA, glycerol (both purchased from Sigma), norm-saline injection (purchased from Taiwan Otsuka Pharmaceutical), dextrose (purchased from Cerestar Deutschland GMBH) were used for simulating physiological factors. PDMS (purchased from DOW-Corning, part No. Sylgard 184) was used for testing heating mechanism. In the process

Characterization of magnetic nanoparticles

The XRD spectra from four magnetic nanoparticle samples with different Fe3+:Fe2+ ratios are shown in Fig. 2. The XRD spectra for all of the samples exhibited the characteristic peaks of Fe3O4 (comparison with reference value from JCPDS No. 82–1533). Also, Yamaura et al. showed that Fe3O4 is black in color and Fe2O3 is brown in color under sunlight [27]. Therefore, based on the XRD results and the black color of our samples, we conclude that Fe3O4 is the dominant species for all four samples.

Conclusion

The results of our study show that lauric acid-coated magnetic nanoparticles synthesized using a ratio of Fe3+:Fe2+=3:2, had a higher heating capacity 16.5 W/g when tested under the conditions of 0.1 g/mL, 215 kHz and 3.8 kA/m than particles synthesized at an Fe3+:Fe2+ ratio of 2:1, 5:3 or 4:3. The majority species was Fe3O4. If we normalize the SAR value of 16.5 W/g to a frequency of 1 MHz and an amplitude of 100 Oe [21], magnetic nanoparticles synthesized at an Fe3+:Fe2+ ratio of 3:2 could generate

Acknowledgements

The author would like to thank the financial support from the National Science Council (NSC97-2113-M-110-007-MY2) and Center for Nanoscience and Nanotechnology, National Sun Yat-Sen University, Taiwan. Also, the author would like to thank the Joint Laboratories of Center for Nanoscience and Nanotechnology, National Sun Yat-Sen University, Taiwan for magnetic measurements obtained from SQUID (MPMS XL-7), and the members of Low temperature laboratory, National Sun Yat-Sen University for technical

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