Improvement of drug delivery by hyperthermia treatment using magnetic cubic cobalt ferrite nanoparticles

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Abstract

In this study, we report a novel synthesis method, characterization and application of a new class of ferromagnetic cubic cobalt ferrite magnetic nanoparticles (MNPs) for hyperthermia therapy and temperature triggered drug release. The MNPs are characterized by XRD, TEM, FESEM, AC magnetic hysteresis and VSM. These MNPs were coated with folic acid and loaded with an anticancer drug. The drug release studies were done at two different temperatures (37 °C and 44 °C) with progress of time. It was found that higher release of drug took place at elevated temperature (44 °C). We have developed a temperature sensitive drug delivery system which releases the heat sensitive drug selectively as the particles are heated up under AC magnetic field and controlled release is possible by changing the external AC magnetic field.

Introduction

In recent years, studies on nanomaterials have drawn immense attention for their high surface to volume ratio and high porosity which make them efficient absorber and can be used in the field of nano-carriers especially in case of drug delivery vehicles [1], [2], [3], [4]. Therefore proper design of smart nano-carrier for drug delivery is a very challenging task to make the drugs to be loaded efficiently [5] and delivered to proper region of interest in the body [2]. In this regard an ideal nano-carrier system should have several suitable properties such as biocompatibility, water solubility, small size for effective cellular uptake and safe excretion from the biological system after functioning [6], [7]. Improved cellular uptake of many nano-carrier systems has been claimed in several studies [1], [2], [8]. People have designed few nano-carriers in which the drug molecules can be loaded efficiently, but some time remaining of drugs inside them become less, as most of the drugs are removed during the carrier surface is made hydrophilic for easy cellular uptake. Elimination of the drug carriers from the biological system after carrying out their diagnostic or therapeutic functions is another important aspect to consider [9]. Though these works have their own importance, nevertheless, this task still remains challenging in most of the nano-carrier systems. Hence, if it is possible to make a good biocompatible and stable nano particle with high cellular uptake which can display some important characteristics in the field of drug delivery by some triggered drug release way, such as heat, may open the new vistas of drug release methodology by using nanoparticles [2], [10], [11], [12].

If such nano-carriers are magnetic in nature then they can be able to serve both as drug carrier and good drug delivery agent as well by magnetically triggered way [3], [13], [14], [15], [16], [17]. Release of drug from such material can also be monitored by magnetically induced heat treatment methodology. It is known that if magnetic particles are kept under alternating current (AC) magnetic field, they are heated up due to the core loss in such nanoparticles and transforms magnetic energy into heat [14], [18], [19]. The heat generated by this method may be utilized to destroy cancer cells in one hand and on the other, can be applied to release drugs from magnetic particles after delivery of the drug loaded particles to the tumor region. In this treatment the AC magnetic field of different range of frequency may also be applied to control the heating effect in the range of 41–45 °C for the magnetic nanoparticles placed in the body as this temperature is ideal to kill cancer cells but keep the normal cells alive [20]. But there are many limitations in use of such magnetic particles such as very poor heating efficiency, internalization of particles with cells, stability, biocompatibility etc. [21]. Major efforts should therefore be given to optimize such nanoparticles’ heating efficiency, by tuning some of the key parameters such as size, shape, magnetic anisotropy, saturation magnetization of the nanoparticles, internalization of the particles with the cells, etc. The usability of iron oxide nanoparticles in this regard is quite higher [8], [17], [22] as iron and their oxides can be metabolized and transported by proteins and it also has the most successful result in the area of nano-medicines [22], [23]. These materials have already been suggested for the use in hyperthermia by applying an AC magnetic field [18]. But, cobalt-iron oxide has not been tested in this field. As cobalt and iron both exist in human body, it would be very interesting to know if it is fruitful in hyperthermia or not. The special advantages of cobalt ferrite MNPs are that their stability is quite higher as Co in +2 state and Fe in +3 state is very stable and aerial oxidation generally does not take place in such materials.

In order to overcome some of limitations, we have synthesized CoFe2O4 nano-cubes and studied their detail AC and DC magnetic properties for the promising hyperthermia treatment and drug delivery applications. Doxorubicin (DOX), a traditional anticancer drug from anthracycline family, which is used to cure a wide range of cancers [24]. However it has serious adverse side effects. Therefore use of such drugs in a low quantity with increase of its efficiency with the help of magnetic hyperthermia is also very challenging job.

Section snippets

Synthesis of particles

The precursor salts ferric chloride (FeCl3, 6H2O) and cobalt chloride (CoCl2·4H2O), ethylene glycol, ethanol, Urea, Triton X-100, oleylamine etc. were procured from Sigma-Aldrich. In a typical synthesis of CoFe2O4 NPs, 3.24 g of FeCl3, 6H2O and 1.4 g of CoCl2, 4H2O were dissolved well in 70 ml ethylene glycol. To make the medium basic, 10 g of Urea in 70 ml ethanol was added to the solution and stirred vigorously at 100 °c temperature until a homogenous solution was obtained. After about 1 h, the

Structural and morphological analysis

Fig. 1(a) depicts the XRD patterns for the synthesized CoFe2O4 MNPs. All the diffraction peaks matches with the JCPDS (card no. 22–1086) of CoFe2O4 MNPs. The crystalline size of the sample is 10.5 nm using the (311) peak, estimated using Scherrer's equation [25]. The FESEM image of the synthesized CoFe2O4 NPs is shown in Fig. 1(b). The individual MNPs are not visible from Fig. 1(b) due to the smaller size of them and low resolution of the instrument. Therefore, the TEM image has been taken and

Conclusion

We have successfully synthesized cubic shaped magnetic nano particles of cobalt ferrite. Structural characterization of these particles shows the pure phase of cobalt ferrite. Magnetic measurements offer about their suitability for the application of drug release using hyperthermia technique which can open new vistas in comparison to the conventional chemotherapy. Temperature dependent drug release studies give us new information about better treatment for cancer by controlled release in a

Acknowledgements

One of the Authors Chaitali Dey would like to thank Centre of Excellence in Systems Biology & Biomedical Engineering, University College of Technology, for providing Research assistantship under CoE-TEQIP-II, University of Calcutta to carry out this work. Arup Ghosh is thankful to SERB, DST, Govt. of India for providing the financial support through National Post-Doctoral Fellowship (PDF/2015/000599). All the authors gratefully acknowledge Centre for Research in Nano science and Nanotechnology

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