Development of yttrium phosphate based porous microspheres for radioembolisation therapy

The principal focus for the materials developed in this thesis was for Radioembolisation therapy applications, particularly tailoring phosphate based glasses (PBG’s) formulations for the treatment of liver cancer. PBG’s have been widely considered in this study due to their fully resorbable, controlled degradation rates and biocompatible properties. Microspheres are gaining attraction as possible advanced materials, owing to their advantages over irregular shaped particles due to its better size, shape, higher surface area and improved flow characteristics. Phosphate glass microspheres containing yttrium oxide (Y2O3) are an area of particular interest in this thesis as Y2O3 has short half-life and been shown to significantly be efficient for improving chemical durability, which in turn is highly beneficial for selective internal radiation therapy (SIRT). Initially, this study investigate the role of yttrium in phosphate-based glasses in the system of 45P2O5–25CaO–(30-x)Na2O–xY2O3 (0≤x≤5) prepared via melt quenching and focuses on their structural characterisation and degradation profiles. The structural analyses were performed using a combination of solid-state nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) analyses. 31P NMR analysis confirmed that depolymerisation of the phosphate network occurred which increased with Y2O3 content as metaphosphate units (Q2) decreased with subsequent increase in pyrophosphate species (Q1). The NMR results correlated well with structural changes observed via FTIR, Raman and XPS analyses. XRD analysis of crystallised glass samples revealed the presence of calcium pyrophosphate (Ca2P2O7) and sodium metaphosphate (NaPO3) phases for all the glass formulations explored. Yttrium-containing phases were found for the formulations comprising 3 and 5 mol% Y2O3. Degradation analyses performed in Phosphate buffer saline (PBS) and Milli-Q water revealed significantly reduced rates with addition of Y2O3 content. The reduction in degradation rate was ascribed to the creation of Y-O-P bonds, which resulted from the octahedral structure of yttrium (YO6) cross-linking phosphate chains, subsequently increasing the chemical durability of the glasses. The ion release profiles also correlated well with degradation profiles. This study also showed successful manufacture of both solid (SGMS) and porous (PGMS) yttrium containing phosphate glass microspheres via flame spheroidisation process within the specific size range 25-45 μm through the modification and optimisation of the manufacturing process. A modified powder feeding and collection system was designed to improve the yield of smaller size range microspheres (in terms of sphericity). Various flow rates of oxygen/acetylene gas, particle to porogen ratio, effect of acid wash, position of the flame were investigated to obtain the maximum yield of smaller sized porous microsphere production. Microspheres generated with higher flow rate (3:3) at 1:0.5 ratio (glass particles: CaCO3) with 5M acetic acid wash were used for the preparation of smaller size porous microspheres based on the findings of the pore distribution, number of pores and sphericity. NMR analysis of SGMS and PGMS indicated that increasing trend of Q1 species (from 35% to 53% for SGMS and 48% to 61% for PGMS) were found with increasing Y2O3 concentration from 0 to 5 mol%, whereas Q2 species decreased from 64 to 47 percent for SGMS and 42 to 29 percent for PGMS. Moreover, a limited amount of Q0 species were found in all of the formulations studied for PGMS. In addition, the dissolution rates of the porous microsphere were higher than the solid microspheres for all glass formulations which were ascribed to the difference in the surface area and porosity between porous and solid microspheres. This study also revealed that the glass formulations remained amorphous with up to 5 mol% Y2O3 addition with further increases in Y2O3 content resulting in significant crystallisation. This phenomenon has been explained by activation energy and crystallisation kinetics of 0 to 5 mol% yttrium containing phosphate based glasses and investigated via Differential Scanning Calorimetry (DSC) using non-isothermal technique at different heating rates (5°C, 10°C, 15°C and 20°C/min). The Moynihan and Kissinger methods were used for the determination of glass transition activation energy (Eg) which decreased from 192 kJ/mol to 118 kJ/mol (Moynihan) and 183 kJ/mol to 113 kJ/mol (Kissinger) with increasing yttrium oxide content. Incorporation of 0 to 5 mol% Y2O3 revealed an approximate decrease of 71 kJ/mol (Ozawa and Augis) for onset crystallisation (Ex) and 26 kJ/mol (Kissinger) for crystallisation peak activation energies (Ec). Avrami index (n) value analysed via Matusita-Sakka equation suggested a one-dimensional crystal growth for the glasses investigated. SEM analysis explored the crystalline morphologies and revealed one-dimensional needle-like crystals. In order to produce porous phosphate microspheres with high yttrium content, a new approach and manufacturing technique was devised in this study in further. In this alternative manufacturing process, different phosphate based glass formulations were mixed with Y2O3 particles at different percentage ratios and fed into the flame. Microspheres of P55-60Y40 (mixture of 60% P55 glass formulations + 40% Y2O3 particles) and P60-60Y40 (mixture of 60% P60 glass formulations + 40% Y2O3 particles) were considered as optimum combinations and ratios as these combinations achieved desired Y2O3 (above 17 mol%) and P2O5 contents (40 mol% or more) confirmed via EDX analysis. XRD analysis revealed that glass-ceramic was formed for high yttrium containing phosphate microspheres instead of glass microspheres. Dissolution profiles of glass-ceramics showed that the higher decrease in particle size was observed for porous glass-ceramic microspheres (PGCMS) in comparison to their respective solid glass-ceramic microspheres (SGCMS). Finally, this study demonstrated successful loading of anticancer drug Doxorubicin (DOX) inside the high yttrium containing porous phosphate glass-ceramic microspheres (P60YPGCMS) via optimisation of drug encapsulation processes. DOX encapsulated microspheres showed a comparatively controlled release behaviour of DOX at low concentrations (2.5 mg/ml) compared to high concentrations (25 mg/ml)