BG
B.M.R. Giling
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Synthesis of Holmium-166-alginate microspheres using extrusion dripping and emulsification methods
Including loading efficiency and stability experiments
Master thesis
(2026)
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B.M.R. Giling, A.G. Denkova, Y. Chalashkan, E.J. van den Heuvel, R.M. de Kruijff, T.M. McCoy
Ho-166-alginate microspheres could present a new type of device for the radioembolisation of liver cancer, where targeted radiation therapy is combined with embolisation of tumour blood vessels. Whereas current devices in radioembolisation are permanent, alginate offers a biodegradable device with a cheap and simple production process. The isotope holmium-166 has been of interest in radiotherapy due to its favourable half-life and decay through β-emission. Furthermore, its paramagnetic properties allows visualisation using Magnetic Resonance Imaging (MRI) and its γ-emission allows for imaging using Single Photon Emission Computed Tomography (SPECT). This research investigates the synthesis, loading efficiency and stability of Ho-166-alginate microspheres. For synthesis of alginate microspheres, this research uses the extrusion dripping method and emulsification method. Here, process parameters are investigated to crosslink alginate with Ca2+ and to obtain alginate particles having diameter of around 30 μm. In the extrusion dripping method, increasing pH showed crosslinking of alginate into viscous gel formations or alginate particles having a wrinkled surface. A pH of 4 offered the best conditions to produce spherical alginate particles with smoother surface morphology and smallest particle size. Particle size below 100 μm was not obtained in the extrusion dripping method, but the emulsification method in this research succeeded in particle formation with sizes between 10 to 60 μm. The Ca-alginate microspheres from the emulsification method were further used in an ion-exchange process to replace the Ca2+ in the alginate structure with Ho3+. Using Ho-166, an average loading efficiency of (86.5 ± 1.4)% was found. The obtained Ho-166-alginate microspheres were tested on their radiochemical stability in demiwater and 0.9% NaCl solution. Here, the microspheres in demiwater showed excellent stability, whereas their retention percentage in 0.9% NaCl decreased to ~60% after five minutes. Nevertheless, the retention percentage in 0.9% NaCl further remained stable for up to 24 hours. Further research could include stabilizing the alginate microspheres post-emulsification, as removal of surfactant during washing steps resulted in an increase of particle size. Secondly, investigation on process parameters within the emulsification method could bring the particle size between 20 to 60 μm with a smaller size distribution. Destined for radioembolisation, the Ho-166-alginate microspheres need improved loading efficiency and improved stability in physiological media such as 0.9% NaCl. Literature on Ho-alginate microspheres is very limited as of now, and this research takes a step towards Ho-166-alginate microspheres as radioembolic device for transarterial radioembolisation.
...
Ho-166-alginate microspheres could present a new type of device for the radioembolisation of liver cancer, where targeted radiation therapy is combined with embolisation of tumour blood vessels. Whereas current devices in radioembolisation are permanent, alginate offers a biodegradable device with a cheap and simple production process. The isotope holmium-166 has been of interest in radiotherapy due to its favourable half-life and decay through β-emission. Furthermore, its paramagnetic properties allows visualisation using Magnetic Resonance Imaging (MRI) and its γ-emission allows for imaging using Single Photon Emission Computed Tomography (SPECT). This research investigates the synthesis, loading efficiency and stability of Ho-166-alginate microspheres. For synthesis of alginate microspheres, this research uses the extrusion dripping method and emulsification method. Here, process parameters are investigated to crosslink alginate with Ca2+ and to obtain alginate particles having diameter of around 30 μm. In the extrusion dripping method, increasing pH showed crosslinking of alginate into viscous gel formations or alginate particles having a wrinkled surface. A pH of 4 offered the best conditions to produce spherical alginate particles with smoother surface morphology and smallest particle size. Particle size below 100 μm was not obtained in the extrusion dripping method, but the emulsification method in this research succeeded in particle formation with sizes between 10 to 60 μm. The Ca-alginate microspheres from the emulsification method were further used in an ion-exchange process to replace the Ca2+ in the alginate structure with Ho3+. Using Ho-166, an average loading efficiency of (86.5 ± 1.4)% was found. The obtained Ho-166-alginate microspheres were tested on their radiochemical stability in demiwater and 0.9% NaCl solution. Here, the microspheres in demiwater showed excellent stability, whereas their retention percentage in 0.9% NaCl decreased to ~60% after five minutes. Nevertheless, the retention percentage in 0.9% NaCl further remained stable for up to 24 hours. Further research could include stabilizing the alginate microspheres post-emulsification, as removal of surfactant during washing steps resulted in an increase of particle size. Secondly, investigation on process parameters within the emulsification method could bring the particle size between 20 to 60 μm with a smaller size distribution. Destined for radioembolisation, the Ho-166-alginate microspheres need improved loading efficiency and improved stability in physiological media such as 0.9% NaCl. Literature on Ho-alginate microspheres is very limited as of now, and this research takes a step towards Ho-166-alginate microspheres as radioembolic device for transarterial radioembolisation.
Towards 2040 the global cancer burden could rise to 28.4 million cases. Early diagnosis and treatment leads to a higher number of cancer survivors. 68Ga is a promising radionuclide in radio-imaging, and it is often labelled with a labelling link called DOTA in radiopharmaceuticals. 68Ga can be produced by a 68Ge/68Ga generator. However, the 68Ge supply issue, disposal issue, and an increasing demand in radiotracers for radio-imaging have led to the development of cyclotron production. In this method 68Ga nuclides are produced through proton irradiation of enriched 68Zn solutions. The produced nuclides are extracted from the solutions using a chelator called BPHA. After back extraction, BPHA contamination remains in the final solution and could possibly interfere with the labelling of 68Ga to DOTA. The two objectives of this research were to investigate the effects of BPHA contamination on the labelling of 68Ga to DOTA, and whether the contamination could be washed from the extraction solution. Instant thin layer chromatography, a Wallac gamma counter, and phosphor imaging were used to determine the labelling efficiency in 68Ga solutions with and without BPHA contamination. Experiments have shown that without BPHA contamination an average labelling efficiency of 102.3% ± 2.5% can be calculated from the phosphor imaging, crossing the 100% due to background correction, and an average labelling efficiency of 99.58% ± 0.07% can be calculated from the Wallac gamma counter. In solutions with BPHA contamination this labelling efficiency became 70.8670% ± 41.6798%, showing high error due to major differences in BPHA concentration per extraction solution. In an attempt to remove the BPHA contamination, the extraction solutions were washed with chloroform. The BPHA contamination was measured in UV-Vis absorption, and showed a decrease after one wash. The remaining absorption could be assigned to the solvent. This researched merely addressed the presence of contamination, and did not measure quantitatively. Further research could investigate the quantitative relationship between BPHA contamination concentration and the DOTA-labelling efficiency.
...
Towards 2040 the global cancer burden could rise to 28.4 million cases. Early diagnosis and treatment leads to a higher number of cancer survivors. 68Ga is a promising radionuclide in radio-imaging, and it is often labelled with a labelling link called DOTA in radiopharmaceuticals. 68Ga can be produced by a 68Ge/68Ga generator. However, the 68Ge supply issue, disposal issue, and an increasing demand in radiotracers for radio-imaging have led to the development of cyclotron production. In this method 68Ga nuclides are produced through proton irradiation of enriched 68Zn solutions. The produced nuclides are extracted from the solutions using a chelator called BPHA. After back extraction, BPHA contamination remains in the final solution and could possibly interfere with the labelling of 68Ga to DOTA. The two objectives of this research were to investigate the effects of BPHA contamination on the labelling of 68Ga to DOTA, and whether the contamination could be washed from the extraction solution. Instant thin layer chromatography, a Wallac gamma counter, and phosphor imaging were used to determine the labelling efficiency in 68Ga solutions with and without BPHA contamination. Experiments have shown that without BPHA contamination an average labelling efficiency of 102.3% ± 2.5% can be calculated from the phosphor imaging, crossing the 100% due to background correction, and an average labelling efficiency of 99.58% ± 0.07% can be calculated from the Wallac gamma counter. In solutions with BPHA contamination this labelling efficiency became 70.8670% ± 41.6798%, showing high error due to major differences in BPHA concentration per extraction solution. In an attempt to remove the BPHA contamination, the extraction solutions were washed with chloroform. The BPHA contamination was measured in UV-Vis absorption, and showed a decrease after one wash. The remaining absorption could be assigned to the solvent. This researched merely addressed the presence of contamination, and did not measure quantitatively. Further research could investigate the quantitative relationship between BPHA contamination concentration and the DOTA-labelling efficiency.