Ferrimagnetic mgfe2o4 nanoparticles for intra arterial hyperthermia agent applications

FERRIMAGNETIC MgFe2O4 NANOPARTICLES FOR INTRA-ARTERIAL HYPERTHERMIA AGENT APPLICATIONS LEE SANGHOON (M Eng.), NUS A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF ENINEERING DEPARTMENT OF ELECTRICAL & COMPUTER ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2012 I Acknowledgment I appreciate to my advisor, Professor Seongtae Bae It is him who led me into the nanomedicine and taught me how to think, talk, write and perform experiments as an engineer as well as scientist I also need to thanks lab member, Minhong Jeun for his support and precious time He always supported and encouraged me, which helped me continuously to focus on research I would like to thanks my parents and younger brother for their endless love, which helped me overcome all the difficulties II Table of Contents Declaration………………………………………………………………… I Acknowledgements………………………………………………………… II Table of Contents…………………………… ………………………… III Summary …………………………….…………………………………… V List of Tables…………………………………….………………… ….VII List of Figures…………………….……….……….……………….….… VIII List of Symbols…………………….…….……………………… … … XI Chapter Introduction 1.1 Background and Motivation ………….….……………….………… 1.2 Research Objectives…………………………………………… …2 1.3 Organization of Thesis………………………………………… …3 Chapter Literature review 2.1 Background of Magnetism 2.1.1 The Classification of Magnetism ………………….………… …4 2.1.2 Soft and Hard Magnetic Materials………………… ……….…6 2.1.3 Magnetic Nanoparticle…………….………………………… …7 2.1.4 Ferrite……… ……… ……………………………………… 10 2.2 Hyperthermia 2.2.1 History of Hyperthermia… …………… ……………….……13 2.2.2 Hyperthermia Methods……………….……… …….……….…14 2.2.3 Side Effects of Hyperthermia …………….……….…….….…14 2.2.4 Future of Hyperthermia………………………………… …….15 2.3 Magnetic Hyperthermia 2.3.1 Magnetic Fluidic Hyperthermia… ……………………… 16 2.3.2 Heating Mechanism…………… …………………… ……17 2.3.3 Specific Loss Power…………… ……………………….…20 2.4 Targeting Liver Tumors with Hyperthermia using Ferrimagnetic Nanoparticle 2.4.1 Liver Cancer…………… ………………………… …………21 2.4.2 Treatment of Liver Cancer…………… ……… …………… 22 III 2.4.3 Arterial Embolization Hyperthermia… …………………………22 2.5 Synthesis of Magnetic nanoparticles…… … ………………………23 2.6 Synthesis of MFe2O4 as hyperthermia agents……………………… …26 Chapter Experiment 3.1 Sol- gel Method… …….… …… ……………… ……… 27 3.2 Preparation Synthesis……………………………………….….…27 3.3 Synthesis Procedures using Modified Sol-gel Method 32 3.4 Characteristics Measurement ………………… …………… ….38 Chapter Results & Discussion 4.1 Ferrimagnetic MFe2O4 (M=Ni, Co and Mg) Nanoparticles 4.1.1 Physical Properties of Ferrimagnetic MFe2O4…………….………….47 4.1.2 AC Magnetically Induced Heating Characteristics of MFe2O4 (M=Ni, Co and Mg)………………………………… 48 4.1.3 The Magnetic Properties of MFe2O4 (M=Ni, Co and Mg)….…50 4.1.4 Biocompatibility………………………………………….……52 4.2 Ferrimagnetic MgFe2O4 Nanoparticles Modified by Modified Sol-gel Method 4.2.1 Ferrimagnetic MgFe2O4 Modified by Calcining Process …… 53 4.2.2 Ferrimagnetic of MgFe2O4 Modified by Sintering Process… 63 4.2.3 Ferrimagnetic of MgFe2O4 Modified by Ball Mill Process ….67 4.2.4 AC magnetically Induced Heating Characteristics in Solid and Liquid States ….…………………………………………… 71 4.2.5 Emulsion Formation with Lipiodol and AC Heating Characteristics in Emulsion states………………… … ……79 Chapter Conclusion & Future work ……………………………… .83 Bibliogrphy………………………….…………………….………… … 86 IV Summary Ferrimagnetic Fe3O4 nanoparticles as a hyperthermia agent for liver cancer have been limited by the large size and low specific loss power (SLP) Accordingly, a new ferrimagnetic nanoparticle agent with a smaller size, a narrower size distribution and a higher SLP, is required for intra-arterial hyperthermia modality In this thesis, ferrimagnetic MFe2O4 (Ni, Co, Mg) nanoparticles were synthesized by conventional sol-gel method to investigate and compare the feasibility for a hyperthermia agent AC magnetically induced heating temperature (TAC,mag) of the synthesized nanoparticles in the size range of 30~40 nm in diameter was measured in solid state at the biologically and physiologically tolerable range of magnetic field (Happ =140 Oe) and frequency (fapp=110 kHz) In addition, MTT assay (methylthiazol tetrazolium bromide test) using normal rat liver epidermal cells, was also investigated for evaluating cytotoxicity In the second part, ferrimagnetic MgFe2O4 nanoparticles that exhibited the fastest frequency response, the highest AC heat power generation and high biocompatibility, were chemically and mechanically modified by a modified sol-gel synthesis process in order to achieve higher SLP for intra-arterial hyperthermia agent applications while maintaining a small size and a narrow size distribution Ferrimagnetic MgFe2O4 nanoparticles were synthesized by controlling calcining temperatures (400 °C, 500 °C and 600 °C) with the fixed sintering temperature (700 °C) Then, Ferrimagnetic MgFe2O4 nanoparticles were synthesized by controlling sintering temperatures (700-900 °C) with the V fixed calcining temperature (600 °C) that exhibited the highest SLP Finally, ball milling process with different ball sizes (diameter : mm, 3mm) was added between the fixed calcining temperature (600 °C) and sintering temperature (850 °C) in order to mechanically modify the nanoparticles The crystal structure, mean particle size, size distribution and magnetic properties of the modified ferrimagnetic MgFe2O4 nanoparticles were measured to investigate the effect of each process on the synthesized nanoparticles In addition, TAC,mag in solid state and a ferrofluid as well as emulsion state where the oleic acid coated nanoparticles were mixed with lipiodol, was also measured to evaluate the feasibility for the clinical use of liver cancer treatment The ferrimagnetic MgFe2O4 nanoparticles modified by calcining temperature of 600 °C, ball milling process (ball diameter: mm) and sintering temperature of 850 °C, had proper size (~40 nm), narrower size distribution (~20 %) and higher SLP (525 W/g) in a ferrofluid In addition, the oleic acid coated ferrimagnetic MgFe2O4 nanoparticles could be well mixed with lipiodol and it exhibited high AC heating characteristics, enabling them to be a suitable agent for the clinical use of liver cancer treatment in intra-arterial hyperthermia modality VI List of Tables Table 2-1 Type of magnetism …………………………………… ……….5 Table 3-1 Name, chemical formula and molecular weight of compounds used in the sol-gel methods………………………………… ……………31 Table 3-2 Name, chemical formula and molecular weight of additional compounds used in the sol-gel methods………………….………………31 Table 3-3 The specification of Al2O3 balls……………………………… 37 Table 4-1 Calculation results of hysteresis loss energy and the real contributions of Phystersis loss to the Ptotal of the sample A, B, C and previous one synthesized by conventional sol-gel method…… ……………………… 60 Table 4-2 Mean size measured by FE-SEM and hydrodynamic diameter and PDI measured by DLS… 77 VII List of Figures Fig 2-1 M–H curves are shown for the ferromagnetic (FM) injected particles, where the response can be either multi-domain (in FM diagram), singledomain (in FM diagram) orsuperparamagnetic (SPM), depending on the size of the particle…………………………………………………………… Fig 2-2 The spinel Structure …………………………………………… 10 Fig 2-3 Arrangements of metal ions in the two octants A and B, showing tetrahedrally (A) and octahefrally (B) coordinated sites ………… …… 11 Fig 2-4 Magnetic structures of normal and inverse spinels (a) normal manganese ferrite, Mn Fe2O4 (b) inverse nickel ferrite, NiFe2O4 (c) normal zinc ferrite, ZnFe2O4 ……… …………………………………… … 12 Fig 2-5 Blood supply to the liver and hepatic tumour The large, blue vessel is the portalvein, and the thin red vessel is the hepatic artery which feeds the tumor… ……………………………………………………… ……….21 Fig 3-1 (a) Sol-gel Systems (b) Three neck round bottom flask and magnetic stirrer bar (c) Corning hot-plate/magnetic stirrer (d)TECPEL digital thermometer (e) Ohaus digital analytical balance…… … 28 Fig 3-2 (a) Natural Convection Oven (b) Mortar and Pestle (c) Crucible (d) Program Muffle Furnaces……………………………………………………29 Fig 3-3 Reactants used in sol-gel method (From left: Iron (III) nitrate nonahydrate, Magnesium acetate tetrahydrate, Cobalt (II) acetate tetrahydrate, Nickel (II) acetate tetrahydrate… … 30 Fig.3-4 Chemicals and synthesis time for the modified sol-gel method… 33 Fig 3-5 Change in calcining temperature of modified sol-gel method… 34 Fig 3-6 Schematic of a ball mill in cataracting motion … 35 Fig 3-7 Change in ball milling process of modified sol-gel method…… 36 Fig 3-8 Change in sintering process of modified sol-gel method…… .37 Fig 3-9 Schematic Diagram of X-Ray Diffractometer ……………… … 38 Fig 3-10 FE-SEM principle ………………… .40 Fig 3-11 Schematic diagram and picture of VSM ……… … .… 43 Fig 3-12 Frequency & Magnetic field tunable AC inductive coil-capacitor VIII system …………………………………………………………………… 44 Fig 3-13 The scattered light falling on the detector and picture of DLS ……………………………………………………………………………… 46 Fig 4-1 Fig 4-1 The sizes and the size distributions of CoFe2O4 (28.7 nm ±6.7 nm), NiFe2O4 (34.3 nm ±9.8 nm), and MgFe2O4 (30.3 nm ±7.2 nm) determined by an FE-SEM…………………………………………………48 Fig 4-2 AC magnetically induced heating characteristics of MFe2O4 (M=Co, Ni, Mg)…………………….……………….……………………… …49 Fig 4-3 The magnetic major/minor systeresis loops of MFe O (M=Co, Ni, Mg)…………………………………… ……………………….50 Fig 4-4 Iinitial M-H curve of MFe2O4 (M=Co, Ni, Mg)……………… …51 Fig 4-5 Cell survival rate of all the ferrimagnetic MFe2O4 (M=Co, Ni, Mg) nanoparticles with normal rat liver epidermal cells…….……………… …53 Fig 4-6 XRD patterns of the sample A(400 °C), B(500 °C) and C (600 °C) fixed sintering temperature at 700 °C……… .55 Fig 4-7 The sizes and the size distributions of the sample A (36 nm ±10 nm), B (37 nm ±11 nm), and C (58 nm ±13 nm) determined by an FE-SEM ……………………………………………………………………………… 56 Fig 4-8 The AC magnetically induced heating characteristics of the sample A, B and C in solid state (60 mg) at the biologically tolerable range of frequency and magnetic field (f appl = 110 kHz, H appl = 140 Oe) …….… 57 Fig 4-9 Magnetic major hysteresis loop of the sample A, B, C…….58 Fig 4-10 (a) Magnetic minor hysteresis loops of the sample A, B and C at the sweeping field of ±140 Oe (b) The initial M-H loops of the sample A, B and C.…………………………….……………………………….……….…… 59 Fig 4-11 (a) The comparison of the Ms and Hc depending on the sample A, B and C (b) Hc depending on the mean particle size of the sample A, B and C………….………………………………………… ………………… 61 Fig 4-12 The AC magnetically induced heating characteristics of the sample A, B and C in liquid state (5mg/ml in toluene) at the biologically tolerable range of frequency and magnetic field (fappl = 110 kHz, Happl = 140 Oe) … 62 Fig 4-13 Spicific loss power (SLP) of the samples in the range of frequency an d magn et i c fi eld (fappl = 110 k Hz, Happ l = 40 Oe) … 63 IX samples are summarized in Table 4-2 As can be seen in table 4-2, the sample K showed the smallest mean size and narrowest size distribution in solid state and exhibited the smallest hydrodynamic diameter and PDI in liquid state This indicated that the smaller size nanoparticle and narrower size distribution thought to be well and separately coated with oleic acid, allowing smaller hydrodynamic diameter and PDI It enables large Prelaxation loss as well as Physteresis loss that resulted from larger DC minor hysteresis loss caused by the well coated and dispersed nanoparticles without magnetic dipole interaction in the response to magnetic field in ferrofluids Table 4-2 Mean size measured by FE-SEM and hydrodynamic diameter and PDI measured by DLS In contrast, sample I which had the largest size and widest size distribution thought to be not well coated due to the agglomeration of the nanoparticle, which resulted in the largest hydrodynamic diameter and PDI It might show less Prelaxation loss and Physteresis loss that resulted from high magnetic dipolar coupling among the agglomerated nanoparticles, precluding magnetic dipole from rotating quickly to the applied magnetic field [86] Therefore, for the heating mechanism in ferrofluids, the smaller particle size and narrower size distribution as well as the coating conditions of nanoparticles could be very important, which means that few dipole interactions resulted from the well 77 CHAPTER RESULTS & DISCUSSION coated nanoparticles and mono-dispersion status are desirable for efficient AC heating generation 4.2.4-4 Specific Loss Power (SLP) Fig 4-22 SLP of the sample I, J, K For the evaluation of AC heating performance of the samples, SLP of the samples were calculated As can be seen in Fig 4-22, even though the sample I showed the highest TAC,mag in solid states, it exhibited the lowest TAC,mag in liquid states This is because that Brownian relaxation time was long due to the large size of hydrodynamic diameter as well as large PDI was high owing to large particle size and wide distribution On the other hand, the sample K showed highest SLP in liquid state because it had the smallest particle size (~40 nm) and the narrowest size distribution (~21%) due to the mechanical modification by ball milling process (3 mm) as well as smallest hydrodynamic 78 CHAPTER RESULTS & DISCUSSION diameter and PDI due to the well coated mono-dispersion condition, leading to the enhancement of Brownian relaxation loss as well as hysteresis loss SLP of the sample K showed the highest SLP (525 W/g), which is higher than that of Fe3O4 nanoparticles (120 W/g) currently used (Size = 25 nm, Happl = 300 Oe, fappl= 120 kHz) [86] 4.2.5 Emulsion Formation with Lipiodol and AC Heating Characteristics in Emulsion States Lipiodol (Andre Guerbet, Aulnay-sous-Bios, France) also known as iodized oil is to function as a contrast agent, as a vehicle for chemotherapeutic agents, and as an embolic agent for Transcatheter arterial chemoembolization (TACE) [87] In the early 1980s, it was found for lipiodol to remain selectively in the neovasculature and extravascular spaces of hepatocellular carcinoma (HCC) when injected into the hepatic artery [88, 89] Thereafter, TACE with lipiodol emulsion and various anticancer drugs has been used as a standard treatment for unresectable or post peratibely recurrent HCC and as alternative to surgery, even for resectable tumors [90, 91] In this part, in order to evaluate the feasibility of ferrimagnetic MgFe2O4 for the clinical use of liver cancer treatment in intra-arterial hyperthermia modality, the oleic acid coated nanoparticles were mixed with lipiodol for the emulsion formation Also, the TAC,mag of the mixed emulsion was measured 4.2.5-1 Pumping Method 79 CHAPTER RESULTS & DISCUSSION Fig 4-23 Emusion formation with lipiodol by pumping method For the emulsion state, pumping method using three way cock and syringes was required As can be seen in Fig 4-23, two syringes were connected by three way cock and the contents were mixed by pumping syringes several times enough to be completely mixed until water in oil formation of the emulsion formed However, it diminished soon due to the differences of specific gravities between the coated nanoparticles and lipiodol For the optimal ratio between the coated nanoparticles and lipiodol for emulsion state, various ratio of lipiodol and the coated nanoparticles (2:1, 6:1 and 30:1) were mixed and observed for 30 minutes and hour 30 minutes, which is shown in Fig 4-24 It indicated that the ratio of 6:1 is proper ratio between the coated nanoparticle and lipiodol sustaining the emulsion formation around one hour However, the concentration and SLP of the coated 80 CHAPTER RESULTS & DISCUSSION nanoparticle should be considered together for the use of exact the ratio in the future Fig 4-24 Emusion formation with lipiodol depending on mixing rate 4.2.5-2 AC Magnetically Induced Heating Characteristic in Emulsion States 81 CHAPTER RESULTS & DISCUSSION Fig 4-25 The AC magnetically induced heating characteristics of the sample A, B and C in (a) solid state (60 mg) and (b) liquid state (5 mg/ml in ethanol) at the biologically tolerable range of frequency and magnetic field (fappl = 110 kHz, Happl = 140 Oe) In order to estimate the heating performance in emulsion state, the TAC,mag of the sample K mixed with lipiodol were measured in emulsion state where the coated nanoparticles were well dispersed (5 mg/ml) As shown in Fig 4-25, AC magnetically heating characteristics of the emulsion state showed slightly lower heating rate verse time This was because the viscosity of lipiodol is quite higher (oil states) than ethanol causing increase in Brownian relaxation time, which reduce Brownian loss However, TAC,mag of both at 2000 seconds were not too different indicating that this emulsion can be suitable for the clinical use of liver cancer treatment in intra-arterial hyperthermia modality 82 CHAPTER RESULTS & DISCUSSION CHAPTER CONCLUSION In the first part, ferrimagnetic MFe2O4 (M=Co, Ni, Mg) nanoparticles were synthesized by the conventional sol-gel method to evaluate the feasibility for intra-arterial hyperthermia agent applications The mean particles size, size distribution and magnetic properties of all samples were investigated The TAC,mag of the samples in the size range of 30~40 nm, was measured in solid state In addition, biocompatibility test using normal rat liver epidermal cells was investigated for evaluating the feasibility of hyperthermia agent applications The ferrimagnetic MgFe2O4 nanoparticles showed the highest TAC,mag due to the softer magnetic properties and exhibited the highest biocompatibility properties among the synthesized ferrimagnetic nanoparticles It demonstrated that ferrimagnetic MgFe2O4 nanoparticles can be suitable for intra-arterial hyperthermia applications In the second part, ferrimagnetic MgFe2O4 nanoparticles were synthesized by the modified sol-gel method in order to enhance the crystal structure, mean particle size, size distribution, and AC heating generation properties for the clinical use of liver cancer treatment in intra-arterial hyperthermia modality Ferrimagnetic MgFe2O4 nanoparticles were synthesized by controlling calcining temperatures (400 °C, 500 °C and 600 °C) with the fixed sintering temperature (700 °C) Even though the sample C (calcining temperature at 600 °C) showed the highest TAC,mag and SLP in solid state and liquid state caused by the improvement of magnetic softness and saturation magnetization leading to the largest hysteresis loss due to few defects and small anisotropy 83 CHAPTER CONCLUSION energy of multi-domains, it showed slightly the larger mean particles size (58 nm) than the ideal size (< 50 nm) as well as wider size distribution (±13 nm) Accordingly, ferrimagnetic MgFe2O4 nanoparticles were synthesized by controlling sintering temperatures (700-900 °C) with the fixed calcining temperature (600 °C) to improve the properties Even though the sample G (sintering temperature at 850 ˚C) was showed the highest rate of temperature rise, the size of the nanoparticle was too high to be used it as a hyperthermia agent (~ 100 nm) Therefore, ball milling process with different ball sizes (5 mm, mm) was added in the processes between the fixed calcining temperature (600 °C) and sintering temperature (850 °C) in order to mechanically modify the properties of the nanoparticles The particle size and size distribution, magnetic properties as well as TAC,mag in solid state and liquid state of the modified nanoparticles were measured and compared Even though the sample K (ball milling process using mm grinding ball) that had proper particle size (~40 nm) and narrower size distribution (~21%), it showed the lowest TAC,mag in solid state, however, it showed the highest TAC,mag and SLP (525 W/g) in liquid state after oleic acid coating This was because the smallest particle size and the narrowest size distribution enabled the enhancement 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U., Chung J W., Park J H., and Kim C Y., J Clin Oncol, 20, 4459 (2002) 91 ... order to achieve higher SLP for intra- arterial hyperthermia agent applications while maintaining a small size and a narrow size distribution Ferrimagnetic MgFe2O4 nanoparticles were synthesized... nanoparticle agent with a smaller size, a narrower size distribution and a higher SLP, is required for intra- arterial hyperthermia modality In this thesis, ferrimagnetic MFe2O4 (Ni, Co, Mg) nanoparticles. .. Biocompatibility………………………………………….……52 4.2 Ferrimagnetic MgFe2O4 Nanoparticles Modified by Modified Sol-gel Method 4.2.1 Ferrimagnetic MgFe2O4 Modified by Calcining Process …… 53 4.2.2 Ferrimagnetic of MgFe2O4 Modified