Synthesis of Doped Lanthanum Strontium Manganite Nanoparticles for Magnetic Hyperthermia Applications

Abstract

Cancer is a disease in which abnormal cells divide in an uncontrolled manner and invade nearby tissues. These cells can spread across the body through the blood and lymph systems. It starts when cells grow out of control and crowd out normal cells. According to the world health organization (WHO), cancer is a second leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Globally, one in every six deaths is caused by cancer. In many developing countries, more than quarter of deaths are attributed to cancer. Advanced technologies are required in many cases and ongoing research initiatives are not sufficient for the complete understanding of the disease and its control. Technological advances and ever increasing understanding of cancer make this field one of the most rapidly evolving areas of modern medicine. According to American Cancer Society (ACS), treatments of cancer differ considerably depending upon the site and stage of the tumour. It includes surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, etc. Hyperthermia is one of the earliest known therapies for cancer. From 1800’s, hyperthermia is used for the treatment of cancer. In hyperthermia a part of the human body such as certain organ or tissue or the whole body is heated between 41 °C to 45 °C for specific time. Traditionally, hyperthermia has been acknowledged for its curative capabilities for the treatment of malignancies. Hyperthermia is in general used in combination with other cancer treatments such as chemotherapy or radiotherapy. An alternating magnetic field is used in the localized cancer therapy known as magnetic hyperthermia. In this therapy magnetic nanoparticles injected into the tumour region are excited by external AC magnetic field causing them to produce heat. An applied magnetic field on magnetic nanoparticles focuses directly on tumour-specific region causing controlled targeted heating of tumor cells while sparing the normal cells. The malignant cells stop functioning when the tumour tissue temperature reaches ~ 42 °C. Hysteresis loss and relaxation losses are two primary ways by which magnetic nanoparticles generate heat when subject to an alternating magnetic field. Large magnetic nanoparticles with several magnetic domains have hysteresis losses. When such particles are exposed to an alternating magnetic field, the magnetic moments' orientations will continuously line-up with the direction of the magnetic field. During magnetization and demagnetization cycle part of the magnetic energy gets converted into heat. The number of magnetic domains will decrease with decreasing nanoparticle size. When single domain these particles behave as superparamagnetic. These single domain magnetic nanoparticles produce heat by Brownian and Néel relaxation. The frictional heat produced by the physical rotation of particles inside a supporting liquid medium as they seek to realign themselves with the shifting magnetic field direction is referred as “Brownian relaxation”. The moment rotates while the particle itself remains fixed, than the particle has undergone Néel relaxation. In this case thermal energy is dissipated by the rearrangement of atomic magnetic dipole moments within the crystal. xviii Generally, maghemite (γ-Fe2O3) and magnetite (Fe3O4) nanoparticles are used in magnetic hyperthermia studies because of their good biocompatibility. However, high Curie temperatures (TC ˃ 500 °C) is the major limitation of these magnetic nanoparticles. Because of high TC, when these magnetic nanoparticles are subjected to an alternating magnetic field, they continue to produce heat even after reaching hyperthermia temperature (42-45 °C). Rising temperature can overheat the surrounding healthy tissues. In order to overcome this problem, magnetic nanoparticles with TC close to the hyperthermia temperature (45 C) is required. Amongst numerous magnetic nanostructures, perovskite-doped transition metal oxides with chemical composition La1-xSrxMnO3 possess controllable TC in the range of 10–107 C. Thus, lanthanum strontium manganite (LSMO) nanoparticles can be used in magnetic hyperthermia therapy with self-controlled heating. The characteristic behavior and transitions in these compositions also depend on the degree of the lattice distortion in the crystal with varying concentrations of Sr2+, which leads to changes in the structural and magnetic properties of LSMO. This thesis aimed at developing LSMO nanoparticle based magnetic fluids that possess Curie temperature close to the hyperthermia temperature and hence can be utilized for self-controlled magnetic hyperthermia. Chapter 1 briefly describes cancer along with their types. This chapter also provides an insight on statistical data of various cancer types and corresponding mortality in both genders. Chapter 1 presents an overview of various cancer treatments and list their limitations. In this chapter an alternate treatment approach called “hyperthermia” is described along with its merits over conventional treatment modalities. It also deals with different hyperthermia treatments with a focus on magnetic hyperthermia therapy. Various magnetic nanoparticle candidates for magnetic hyperthermia are also reviewed here. This chapter stress upon need of magnetic nanoparticles with tunable Curie temperature for self-controlled magnetic hyperthermia. Amongst various magnetic nanoparticles it was found that La1-xSrxMnO3 manganite nanoparticles possesses interesting magnetic properties which can be tuned by controlling doping at A and B sites in the perovskite structure of LSMO. This chapter concludes with a summary on structure and magnetic properties of LSMO nanoparticles. Chapter 2 describes detailed literature review on undoped and doped lanthanum strontium magnetite (La1-xSrxMnO3) nanoparticles. Various techniques used for the synthesis of LSMO nanoparticles have been compared in this chapter. Effect of strontium doping (x) on crystal structure and its effect on magnetic properties of La1-xSrxMnO3 nanoparticles have also been reviewed. Literature on doped La1-xSrxMnO3 nanoparticles is also presented with respect to their structural and magnetic properties. Preparation of La1-xSrxMnO3 magnetic nanoparticle based fluids with different surfactants is also presented. An overview of existing literature on the evaluation of magnetic hyperthermia performance of undoped and doped La1-xSrxMnO3 nanoparticles as a function of magnetic field strength, frequency and nanoparticle concentration is also summarized in this chapter. Chapter 3 describes detailed experimental protocols followed for the preparation of undoped and Nd, Al, Ca doped lanthanum strontium manganite (La1-xSrxMnO3) xix nanoparticles. This chapter also includes characterization of nanoparticles by various techniques. X-ray diffraction with Rietveld refinement is used to understand the effect of doping and other synthesis parameters on their structural properties. Vibrating sample magnetometer (VSM) was used to determine magnetic properties (saturation magnetization, coercivity, remanence, Curie temperature, etc.) of undoped and doped LSMO nanoparticles. Magnetization curves are fitted with modified Langevin function. Morphology and chemical composition of undoped and doped LSMO nanoparticles were determined by scanning electron microscopy equipped with energy dispersive spectroscopy (EDS). Detailed discussion on effect of synthesis parameters and degree of doping on structural and magnetic properties of LSMO nanoparticles is discussed and optimum sample composition(s) and synthesis protocols have been developed for magnetic hyperthermia applications of these nanoparticles. La1-xSrxMnO3 (x = 0.1 – 0.4) nanoparticles are synthesized by sol-gel auto combustion method. Amongst synthesized nanoparticles, La0.6Sr0.4MnO3 has optimum magnetic properties with constant Curie temperature (~80 °C). To further, understand the role of reaction pH on the crystal structure of La0.6Sr0.4MnO3 nanoparticles and its effect on their magnetic properties, LSMO nanoparticles are synthesized at 10-13 pH. Amongst the synthesized La0.6Sr0.4MnO3 nanoparticles the one synthesized at pH=11 exhibits highest magnetization. However, their Curie temperature is higher than the hyperthermia temperature. To further tune the hyperthermia temperature of LSMO nanoparticles, they are co-doped with Nd at A-site (La). With the Nd-doping, TC of the nanoparticles decreases from 89 °C to 64 °C. However, saturation magnetization of Nd-doped LSMO nanoparticles also decreased simultaneously from 50 emu/g to 28 emu/g. To further tune the magnetic properties, Ca and Al were also doped in LSMO nanoparticles at B-site. Ca doping had drastically reduced the magnetization (0.25 emu/g) of nanoparticles and hence not useful for hyperthermia applications. With Al doping, TC of the nanoparticles reduced from 60 °C to -20 °C. To balance the saturation magnetization and Curie temperature of the nanoparticles Nd and Al are co-doped in La0.6Sr0.4MnO3 nanoparticles. Simultaneous, doping at A-site with Nd and B-site with Al yields nanoparticles with Curie temperature (46 °T) close to the hyperthermia temperature and magnetization (35.39 emu/g), which is good enough to work in hyperthermia applications. Chapter 4 presents detailed discussion on the development of synthesis protocols for undoped and doped La0.6Sr0.4MnO3 nanoparticles based magnetic fluids. LSMO nanoparticles are coated with a fine layer of polyvinylpyrrolidone (PVP) and dispersed in water. Magnetic hyperthermia experiments were carried out on aqueous dispersions of PVP-coated LSMO nanoparticle as a function of magnetic field frequency, field strength and nanoparticle concentration. Magnetic hyperthermia performance of undoped and doped LSMO nanoparticles are determined by measuring specific loss power (SLP) and intrinsic loss power (ILP) of nanoparticles. Nanoparticles synthesized at pH = 11 exhibits highest SLP value at 10.04 W/g. To further enhance SLP value of LSMO nanoparticles and minimize their TC, they are co-doped with Nd. Amongst the Nd-doped samples, highest SLP value (12.53 W/g) is recorded at 580.6 kHz, frequency, 10 mT field for nanoparticle concentration of 50 mg/mL. xx Irrespective of doping, SLP of nanoparticles increases with increase in magnetic field frequency and magnetic field strength and it decreases with increasing nanoparticles concentration. ILP values of nanoparticles are independent of experimental conditions. Optimized sample compositions and their preparation conditions have been established for LSMO nanoparticles which are suitable for self-controlled magnetic hyperthermia therapy of cancer. Chapter 5 summarizes the important findings of this research work. This thesis ends with discussion on scope for future work.