Development and physicochemical characterization of a biodegradable microspheres formulation loaded with samarium-153 and doxorubicin for chemo-radioembolization of liver tumours.

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are promising treatments for unresectable liver tumours. Some recent studies suggested that combining TACE and TARE in one treatment course might improve treatment efficacy through synergistic cytotoxicity effects. Nonetheless, current formulations do not facilitate a combination of chemo- and radio-embolic agents in one delivery system. Therefore, this study aimed to synthesise a hybrid biodegradable microsphere loaded with both radioactive agent, samarium-153 (153 Sm) and chemotherapeutic drug, doxorubicin (Dox) for potential radio-chemoembolization of advanced liver tumours. 152 Sm and Dox-loaded polyhydroxybutyrate-co-3-hydroxyvalerate (PHBV) microspheres were prepared using water-in-oil-in-water solvent evaporation method. The microspheres were then sent for neutron activation in a neutron flux of 2 × 1012 n/cm2 /s. The physicochemical properties, radioactivity, radionuclide purity, 153 Sm retention efficiency, and Dox release profile of the Dox-153 Sm-PHBV microspheres were analysed. In addition, in vitro cytotoxicity of the formulation was tested using MTT assay on HepG2 cell line at 24 and 72 h. The mean diameter of the Dox-153 Sm-PHBV microspheres was 30.08 ± 2.79 µm. The specific radioactivity was 8.68 ± 0.17 GBq/g, or 177.69 Bq per microsphere. The 153 Sm retention efficiency was more than 99%, tested in phosphate-buffered saline (PBS) and human blood plasma over 26 days. The cumulative release of Dox from the microspheres after 41 days was 65.21 ± 1.96% and 29.96 ± 0.03% in PBS solution of pH 7.4 and pH 5.5, respectively. The Dox-153 Sm-PHBV microspheres achieved a greater in vitro cytotoxicity effect on HepG2 cells (85.73 ± 3.63%) than 153 Sm-PHBV (70.03 ± 5.61%) and Dox-PHBV (74.06 ± 0.78%) microspheres at 300 µg/mL at 72 h. In conclusion, a novel biodegradable microspheres formulation loaded with chemotherapeutic drug (Dox) and radioactive agent (153 Sm) was successfully developed in this study. The formulation fulfilled all the desired physicochemical properties of a chemo-radioembolic agent and achieved better in vitro cytotoxicity on HepG2 cells. Further investigations are needed to evaluate the biosafety, radiation dosimetry, and synergetic anticancer properties of the formulation.

Operational nuclear research reactors in the Asia-Pacific with potential for medical radionuclide production.

Personalised cancer treatment is of growing importance and can be achieved via targeted radionuclide therapy. Radionuclides with theranostic properties are proving to be clinically effective and are widely used because diagnostic imaging and therapy can be accomplished using a single formulation that avoids additional procedures and unnecessary radiation burden to the patient. For diagnostic imaging, single photon emission computed tomography (SPECT) or positron emission tomography (PET) is used to obtain functional information noninvasively by detecting the gamma (γ) rays emitted from the radionuclide. For therapeutics, high linear energy transfer (LET) radiations such as alpha (α), beta (ß - ) or Auger electrons are used to kill cancerous cells in close proximity, whereas sparing the normal tissues surrounding the malignant tumour cells. One of the most important factors that lead to the sustainable development of nuclear medicine is the availability of functional radiopharmaceuticals. Nuclear research reactors play a vital role in the production of medical radionuclides for incorporation into clinical radiopharmaceuticals. The disruption of medical radionuclide supplies in recent years has highlighted the importance of ongoing research reactor operation. This article reviews the current status of operational nuclear research reactors in the Asia-Pacific region that have the potential for medical radionuclide production. It also discusses the different types of nuclear research reactors, their operating power, and the effects of thermal neutron flux in producing desirable radionuclides with high specific activity for clinical applications.

Development of neutron-activated samarium-153-loaded polystyrene microspheres as a potential theranostic agent for hepatic radioembolization.

PURPOSE: Hepatic radioembolization is an effective minimally invasive treatment for primary and metastatic liver cancers. Yttrium-90 [90Y]-labelled resin or glass beads are typically used as the radioembolic agent for this treatment; however, these are not readily available in many countries. In this study, novel samarium-153 oxide-loaded polystyrene ([153Sm]Sm2O3-PS) microspheres were developed as a potential alternative to 90Y microspheres for hepatic radioembolization. METHODS: The [152Sm]Sm2O3-PS microspheres were synthesized using solid-in-oil-in-water solvent evaporation. The microspheres underwent neutron activation using a 1 MW open-pool research reactor to produce radioactive [153Sm]Sm2O3-PS microspheres via 152Sm(n,γ)153Sm reaction. Physicochemical characterization, gamma spectroscopy and in-vitro radionuclide retention efficiency were carried out to evaluate the properties and stability of the microspheres before and after neutron activation. RESULTS: The [153Sm]Sm2O3-PS microspheres achieved specific activity of 5.04 ± 0.52 GBq·g-1 after a 6 h neutron activation. Scanning electron microscopy and particle size analysis showed that the microspheres remained spherical with an average diameter of ~33 µm before and after neutron activation. No long half-life radionuclide and elemental impurities were found in the samples. The radionuclide retention efficiencies of the [153Sm]Sm2O3-PS microspheres at 550 h were 99.64 ± 0.07 and 98.76 ± 1.10% when tested in saline solution and human blood plasma, respectively. CONCLUSIONS: A neutron-activated [153Sm]Sm2O3-PS microsphere formulation was successfully developed for potential application as a theranostic agent for liver radioembolization. The microspheres achieved suitable physical properties for radioembolization and demonstrated high radionuclide retention efficiency in saline solution and human blood plasma.

Neutron-activated theranostic radionuclides for nuclear medicine.

Theranostics in nuclear medicine refers to personalized patient management that involves targeted therapy and diagnostic imaging using a single or combination of radionuclide (s). The radionuclides emit both alpha (α) or beta (ß-) particles and gamma (γ) rays which possess therapeutic and diagnostic capabilities, respectively. However, the production of these radionuclides often faces difficulties due to high cost, complexity of preparation methods and that the products are often sourced far from the healthcare facilities, hence losing activity due to radioactive decay during transportation. Subject to the availability of a nuclear reactor within an accessible distance from healthcare facilities, neutron activation is the most practical and cost-effective route to produce radionuclides suitable for theranostic purposes. Holmium-166 (166Ho), Lutetium-177 (177Lu), Rhenium-186 (186Re), Rhenium-188 (188Re) and Samarium-153 (153Sm) are some of the most promising neutron-activated radionuclides that are currently in clinical practice and undergoing clinical research for theranostic applications. The aim of this paper is to review the physical characteristics, current clinical applications and future prospects of these neutron activated radionuclides in theranostics. The production, physical properties, validated clinical applications and clinical studies for each neutron-activated radionuclide suitable for theranostic use in nuclear medicine are reviewed in this paper.

Systematic investigation on the validity of partition model dosimetry for 90Y radioembolization using Monte Carlo simulation.

We aimed to investigate the validity of the partition model (PM) in estimating the absorbed doses to liver tumour ([Formula: see text]), normal liver tissue ([Formula: see text]) and lungs ([Formula: see text]), when cross-fire irradiations between these compartments are being considered. MIRD-5 phantom incorporated with various treatment parameters, i.e. tumour involvement (TI), tumour-to-normal liver uptake ratio (T/N) and lung shunting (LS), were simulated using the Geant4 Monte Carlo (MC) toolkit. 108 track histories were generated for each combination of the three parameters to obtain the absorbed dose per activity uptake in each compartment ([Formula: see text], [Formula: see text], and [Formula: see text]). The administered activities, A were estimated using PM, so as to achieve either limiting doses to normal liver, [Formula: see text] or lungs, [Formula: see text] (70 or 30 Gy, respectively). Using these administered activities, the activity uptake in each compartment ([Formula: see text], [Formula: see text], and [Formula: see text]) was estimated and multiplied with the absorbed dose per activity uptake attained using the MC simulations, to obtain the actual dose received by each compartment. PM overestimated [Formula: see text] by 11.7% in all cases, due to the escaped particles from the lungs. [Formula: see text] and [Formula: see text] by MC were largely affected by T/N, which were not considered by PM due to cross-fire exclusion at the tumour-normal liver boundary. These have resulted in the overestimation of [Formula: see text] by up to 8% and underestimation of [Formula: see text] by as high as -78%, by PM. When [Formula: see text] was estimated via PM, the MC simulations showed significantly higher [Formula: see text] for cases with higher T/N, and LS ⩽ 10%. All [Formula: see text] and [Formula: see text] by MC were overestimated by PM, thus [Formula: see text] were never exceeded. PM leads to inaccurate dose estimations due to the exclusion of cross-fire irradiation, i.e. between the tumour and normal liver tissue. Caution should be taken for cases with higher TI and T/N, and lower LS, as they contribute to major underestimation of [Formula: see text]. For [Formula: see text], a different correction factor for dose calculation may be used for improved accuracy.

Neutron Activated Samarium-153 Microparticles for Transarterial Radioembolization of Liver Tumour with Post-Procedure Imaging Capabilities.

INTRODUCTION: Samarium-153 (153Sm) styrene divinylbenzene microparticles were developed as a surrogate for Yttrium-90 (90Y) microspheres in liver radioembolization therapy. Unlike the pure beta emitter 90Y, 153Sm possess both therapeutic beta and diagnostic gamma radiations, making it possible for post-procedure imaging following therapy. METHODS: The microparticles were prepared using commercially available cation exchange resin, Amberlite IR-120 H+ (620-830 µm), which were reduced to 20-40 µm via ball mill grinding and sieve separation. The microparticles were labelled with 152Sm via ion exchange process with 152SmCl3, prior to neutron activation to produce radioactive 153Sm through 152Sm(n,γ)153Sm reaction. Therapeutic activity of 3 GBq was referred based on the recommended activity used in 90Y-microspheres therapy. The samples were irradiated in 1.494 x 10(12) n.cm(-2).s(-1) neutron flux for 6 h to achieve the nominal activity of 3.1 GBq.g(-1). Physicochemical characterisation of the microparticles, gamma spectrometry, and in vitro radiolabelling studies were carried out to study the performance and stability of the microparticles. RESULTS: Fourier Transform Infrared (FTIR) spectroscopy of the Amberlite IR-120 resins showed unaffected functional groups, following size reduction of the beads. However, as shown by the electron microscope, the microparticles were irregular in shape. The radioactivity achieved after 6 h neutron activation was 3.104 ± 0.029 GBq. The specific activity per microparticle was 53.855 ± 0.503 Bq. Gamma spectrometry and elemental analysis showed no radioactive impurities in the samples. Radiolabelling efficiencies of 153Sm-Amberlite in distilled water and blood plasma over 48 h were excellent and higher than 95%. CONCLUSION: The laboratory work revealed that the 153Sm-Amberlite microparticles demonstrated superior characteristics for potential use in hepatic radioembolization.

Internal radiation dosimetry of orally administered radiotracers for the assessment of gastrointestinal motility.

Radionuclide imaging using (111)In, (99m)Tc and (153)Sm is commonly undertaken for the clinical investigation of gastric emptying, intestinal motility and whole gut transit. However the documented evidence concerning internal radiation dosimetry for such studies is not readily available. This communication documents the internal radiation dosimetry for whole gastrointestinal transit studies using (111)In, (99m)Tc and (153)Sm labeled formulations. The findings were compared to the diagnostic reference levels recommended by the United Kingdom Administration of Radioactive Substances Advisory Committee, for gastrointestinal transit studies.

Production and first use of 153SmCl3-ion exchange resin capsule formulation for assessing gastrointestinal motility.

We produced an enteric-coated gelatine capsule containing neutron-activated (153)Sm-labelled resin beads for use in gastrointestinal motility studies. In vitro test in simulated gastrointestinal environment and in vivo study on volunteers were performed. Scintigraphic images were acquired from ten volunteers over 24h while blood and urine samples were collected to monitor the presence of (153)Sm. All the capsules remained intact in stomach. This proved to be a safe and practical oral capsule formulation for whole gut transit scintigraphy.

Neutron-activated ¹5³Sm-ion-exchange resin as a tracer for gastrointestinal scintigraphy.

Nuclear medicine techniques are well established for the investigation of gastrointestinal (GI) motility and transit. Ion-exchange resins radiolabelled with 99mTc and ¹¹¹In are widely used as nonabsorbable radiopharmaceutical markers, with ¹¹¹In being preferred for whole-gut transit studies. This radionuclide, however, is not produced in many countries and may be expensive when obtained through international shipment. This study describes the use of neutron-activated ¹5³Sm-resin as an alternative tracer for use in GI scintigraphic investigation. A measure of 50 mg of stable samarium-152 chloride (¹5²SmCl3) was incorporated into 100 mg of cation-exchange resin and irradiated in a neutron flux of 1 × 10¹³ cm⁻² s⁻¹ for 100 s to achieve an activity of 5 MBq after 66 h. Aliquots of ¹¹¹In-radiolabelled resin (5 MBq) were prepared for comparison of labelling and stability. Radiolabelling efficiencies were obtained by washing resin with distilled water, and the activity lost was measured. The radiolabelled resins were immersed in simulated gastric and intestinal fluid environments, and the retention of ¹5³Sm³âº and ¹¹¹In³âº was measured over a 24 h period. At 66 h after production, 91.15 ± 12.42% of ¹5³Sm was bound to the resin after washing in distilled water, whereas radiolabelling with ¹¹¹In achieved 99.96 ± 0.02% efficiency. Both radiolabelled resins demonstrated almost 100% stability in simulated intestinal fluid and >90% stability in artificial gastric juice over 24 h. The performance of neutron-activated ¹5³Sm-resin is similar to that of ¹¹¹In-resin and can be used as an alternative tracer for GI transit studies when In is not available.