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  1. Wong, Y. H., Kasbollah, A., Md. Shah M. N., Abdullah, B. J. J., Yeong, Chai Hong
    MyJurnal
    Introduction: Constipation is affecting a quarter of human population at any one time in all age groups. However, a proper gamma scintigraphic study of whole GI transit is rarely performed in Malaysia due to the lack of suitable radiopharmaceutical. Hence, this study was taken to develop a suitable radiotracer formulation for gamma scintigraphy study of whole gastric-intestinal transit. Methods: The biocompatible polystyrene (PS) incorporated with 152Sm2O3 (5%, w/v) will be used to synthesize the radiotracer. The 152Sm-labelled PS particles was neutron activated to 153Sm in a nuclear reactor for 5 minutes. Characterization of the physicochemical properties, gamma spectrometry and in-vitro radiolabeling studies in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were carried out to study the properties and stability of the radiotracer before and after neutron activation. Results: Scanning electron microscope (SEM) and particle size analysis showed that size, shape and surface morphology of the particles remained after neutron activation. The synthesized 153Sm-labelled PS radiotracer (100 mg) particles achieved an activity of 3.7 MBq after 46 hrs. As indicated by the gamma spectrometry result, there is no long half-life radioimpuirties present in the samples. The 153Sm-labelled PS particles achieved radiolabeling efficiency of more than 95% in both SGF and SIF over 72 hrs. Conclusions: A 153Sm-labelled radiotracer particles formulation has been successfully developed from biocompatible PS. The proposed formulation has the advantage of cheaper, easier to be produced and reduced radiation exposure to staff. Further studies are required to validate the in-vivo performance of 153Sm-labelled formulation for assessing GI motility and transit in clinical use.
  2. Tan, H. Y., Wong, Y. H., Kasbollah A., Md. Shah M. N., Abdullah B. J. J., Yeong, Chai Hong
    MyJurnal
    Introduction: Hepatic radioembolization is a minimally invasive procedure involving intrarterial administration of radioembolic microspheres for the treatment of liver tumours. In this study, a biocompatible polystyrene (PS) microspheres formulation containing radioactive Samarium-153 (153Sm) was synthesized and tested. The 153Sm emits both diagnostic gamma energy and therapeutic beta radiation, renders the synthesized microspheres an ideal theranostic radioembolic agent for hepatic radioembolization. Methods: First, the 152Sm2O3 (20 – 50%, w/v) was encapsulated in PS microspheres using solid-in-oil-in-water solvent evaporation method. The 152Sm-labelled PS microspheres were then activated to 153Sm (Eβmax = 807.6 keV, half-life = 46.3 hours) via 152Sm (n,γ) 153Sm reaction in a nuclear reactor with a neutron flux of 2.0 x 1012 n.cm-2.s-1. Physicochemical characterization, gamma spectroscopy and in-vitro radiolabeling studies were carried out to study the properties and stability of the microspheres before and after neutron activation. Results: The 153Sm -labelled PS microspheres achieved a nominal activity of 4.0 GBq.g-1 after 6 hours of neutron activation. Scanning electron microscope (SEM) and particle size analysis show that the microspheres remained spherical with diameters within 15 – 60 μm after neutron activation. No long half-life radioimpurities were found in the samples as revealed by the gamma spectroscopy results. The 153Sm-labelled PS microspheres achieved radiolabeling efficiency of more than 95% in saline and blood plasma over 480 hours. Conclusion: A biocompatible 153Sm-radiolabelled PS microspheres formulation has been successfully developed. The formulation achieved desirable properties for theranostic treatment of liver tumours. The formulation is relatively cheaper, easier to be produced and more readily available.
  3. Wong YH, Kasbollah A, Abdullah BJJ, Yeong CH
    Pharmaceutics, 2023 Mar 08;15(3).
    PMID: 36986738 DOI: 10.3390/pharmaceutics15030877
    Radioembolization shows great potential as a treatment for intermediate- and advanced-stage liver cancer. However, the choices of radioembolic agents are currently limited, and hence the treatment is relatively costly compared to other approaches. In this study, a facile preparation method was developed to produce samarium carbonate-polymethacrylate [152Sm2(CO3)3-PMA] microspheres as neutron activatable radioembolic microspheres for hepatic radioembolization. The developed microspheres emits both therapeutic beta and diagnostic gamma radiations for post-procedural imaging. The 152Sm2(CO3)3-PMA microspheres were produced from commercially available PMA microspheres through the in situ formation of 152Sm2(CO3)3 within the pores of the PMA microspheres. Physicochemical characterization, gamma spectrometry and radionuclide retention assay were performed to evaluate the performance and stability of the developed microspheres. The mean diameter of the developed microspheres was determined as 29.30 ± 0.18 µm. The scanning electron microscopic images show that the spherical and smooth morphology of the microspheres remained after neutron activation. The 153Sm was successful incorporated into the microspheres with no elemental and radionuclide impurities produced after neutron activation, as indicated by the energy dispersive X-ray analysis and gamma spectrometry. Fourier transform infrared spectroscopy confirmed that there was no alteration to the chemical groups of the microspheres after neutron activation. After 18 h of neutron activation, the microspheres produced an activity of 4.40 ± 0.08 GBq.g-1. The retention of 153Sm on the microspheres was greatly improved to greater than 98% over 120 h when compared to conventionally radiolabeling method at ~85%. The 153Sm2(CO3)3-PMA microspheres achieved suitable physicochemical properties as theragnostic agent for hepatic radioembolization and demonstrated high radionuclide purity and 153Sm retention efficiency in human blood plasma.
  4. Tarafder MT, Kasbollah A, Saravanan N, Crouse KA, Ali AM, Tin Oo K
    J. Biochem. Mol. Biol. Biophys., 2002 Apr;6(2):85-91.
    PMID: 12186762
    Eight selective nitrogen-sulfur donor ligands have been synthesized from the condensation of S-methyldithiocarbazate (SMDTC) with aldehydes and ketones with a view to evaluating their antimicrobial and cytotoxic activities, and also to correlate the biological properties with the structure of the ligands. The compounds were all characterized by elemental analyses and other physicochemical techniques. SMDTC and the Schiff bases were screened for antimicrobial and cytotoxic activities. SMDTC showed very large inhibition zones (24-44 mm) against bacteria and fungi with a minimum inhibitory concentration (MIC) of 390-25,000 and 1562-6250 microg ml(-1), against different bacteria and fungi, respectively. Streptomycin and nystatin were used as the internal standards against bacteria and fungi, respectively. SMDTC along with its Schiff bases with pyridine-2-carboxaldehyde, acetylacetone and 2,3-butanedione were strongly antifungal and the MIC values were comparable to nystatin. Most of the Schiff bases were strongly cytotoxic. In particular, those with pyridine-2-carboxaldehyde and 2,3-butanedione have CD(50) values of 5.5, 1.9-2.0 microg ml(-1), respectively, against leukemic cells, while against colon cancer cells, the values were 3.7 and 2.0 microg ml(-1), respectively. The glyoxal Schiff base was strongly active only against leukemic cell with CD(50) value of 4.0 microg ml(-1). The present findings have been compared with standard drugs.
  5. Wong YH, Tan HY, Kasbollah A, Abdullah BJJ, Yeong CH
    Pharmaceutics, 2019 Nov 12;11(11).
    PMID: 31718079 DOI: 10.3390/pharmaceutics11110596
    INTRODUCTION: Transarterial radioembolization (TARE) has been proven as an effective treatment for unresectable liver tumor. In this study, neutron activated, 153Sm-labeled microspheres were developed as an alternative to 90Y-labeled microspheres for hepatic radioembolization. 153Sm has a theranostic advantage as it emits both therapeutic beta and diagnostic gamma radiations simultaneously, in comparison to the pure beta emitter, 90Y.

    METHODS: Negatively charged acrylic microspheres were labeled with 152Sm ions through electrostatic interactions. In another formulation, the Sm-labeled microsphere was treated with sodium carbonate solution to form the insoluble 152Sm carbonate (152SmC) salt within the porous structures of the microspheres. Both formulations were neutron-activated in a research reactor. Physicochemical characterization, gamma spectrometry, and radiolabel stability tests were carried out to study the performance and stability of the microspheres.

    RESULTS: The Sm- and SmC-labeled microspheres remained spherical and smooth, with a mean size of 35 µm before and after neutron activation. Fourier transform infrared (FTIR) spectroscopy indicated that the functional groups of the microspheres remained unaffected after neutron activation. The 153Sm- and 153SmC-labeled microspheres achieved activity of 2.53 ± 0.08 and 2.40 ± 0.13 GBq·g-1, respectively, immediate after 6 h neutron activation in the neutron flux of 2.0 × 1012 n·cm-2·s-1. Energy-dispersive X-ray (EDX) and gamma spectrometry showed that no elemental and radioactive impurities were present in the microspheres after neutron activation. The retention efficiency of 153Sm in the 153SmC-labeled microspheres was excellent (~99% in distilled water and saline; ~97% in human blood plasma), which was higher than the 153Sm-labeled microspheres (~95% and ~85%, respectively).

    CONCLUSION: 153SmC-labeled microspheres have demonstrated excellent properties for potential application as theranostic agents for hepatic radioembolization.

  6. Tan HY, Wong YH, Kasbollah A, Md Shah MN, Perkins AC, Yeong CH
    Nucl Med Commun, 2023 Apr 01;44(4):227-243.
    PMID: 36808108 DOI: 10.1097/MNM.0000000000001665
    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 (β - ) 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.
  7. Wong YH, Tan HY, Kasbollah A, Abdullah BJJ, Acharya RU, Yeong CH
    World J Exp Med, 2020 Mar 30;10(2):10-25.
    PMID: 32266125 DOI: 10.5493/wjem.v10.i2.10
    BACKGROUND: Liver cancer is the 6th most common cancer in the world and the 4th most common death from cancer worldwide. Hepatic radioembolization is a minimally invasive treatment involving intraarterial administration of radioembolic microspheres.

    AIM: To develop a neutron-activated, biodegradable and theranostics samarium-153 acetylacetonate (153SmAcAc)-poly-L-lactic acid (PLLA) microsphere for intraarterial radioembolization of hepatic tumors.

    METHODS: Microspheres with different concentrations of 152SmAcAc (i.e., 100%, 150%, 175% and 200% w/w) were prepared by solvent evaporation method. The microspheres were then activated using a nuclear reactor in a neutron flux of 2 × 1012 n/cm2/s1, converting 152Sm to Samarium-153 (153Sm) via152Sm (n, γ) 153Sm reaction. The SmAcAc-PLLA microspheres before and after neutron activation were characterized using scanning electron microscope, energy dispersive X-ray spectroscopy, particle size analysis, Fourier transform infrared spectroscopy, thermo-gravimetric analysis and gamma spectroscopy. The in-vitro radiolabeling efficiency was also tested in both 0.9% sodium chloride solution and human blood plasma over a duration of 550 h.

    RESULTS: The SmAcAc-PLLA microspheres with different SmAcAc contents remained spherical before and after neutron activation. The mean diameter of the microspheres was about 35 µm. Specific activity achieved for 153SmAcAc-PLLA microspheres with 100%, 150%, 175% and 200% (w/w) SmAcAc after 3 h neutron activation were 1.7 ± 0.05, 2.5 ± 0.05, 2.7 ± 0.07, and 2.8 ± 0.09 GBq/g, respectively. The activity of per microspheres were determined as 48.36 ± 1.33, 74.10 ± 1.65, 97.87 ± 2.48, and 109.83 ± 3.71 Bq for 153SmAcAc-PLLA microspheres with 100%, 150%, 175% and 200% (w/w) SmAcAc. The energy dispersive X-ray and gamma spectrometry showed that no elemental and radioactive impurities present in the microspheres after neutron activation. Retention efficiency of 153Sm in the SmAcAc-PLLA microspheres was excellent (approximately 99%) in both 0.9% sodium chloride solution and human blood plasma over a duration of 550 h.

    CONCLUSION: The 153SmAcAc-PLLA microsphere is potentially useful for hepatic radioembolization due to their biodegradability, favorable physicochemical characteristics and excellent radiolabeling efficiency. The synthesis of the formulation does not involve ionizing radiation and hence reducing the complication and cost of production.

  8. Tan HY, Yeong CH, Wong YH, McKenzie M, Kasbollah A, Md Shah MN, et al.
    Nucl Med Biol, 2020;90-91:55-68.
    PMID: 33039974 DOI: 10.1016/j.nucmedbio.2020.09.005
    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 (β-) 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.
  9. De Silva L, Fu JY, Htar TT, Muniyandy S, Kasbollah A, Wan Kamal WHB, et al.
    Int J Nanomedicine, 2019;14:1101-1117.
    PMID: 30863048 DOI: 10.2147/IJN.S184912
    Background and purpose: Niosomes are nonionic surfactant-based vesicles that exhibit certain unique features which make them favorable nanocarriers for sustained drug delivery in cancer therapy. Biodistribution studies are critical in assessing if a nanocarrier system has preferential accumulation in a tumor by enhanced permeability and retention effect. Radiolabeling of nanocarriers with radioisotopes such as Technetium-99m (99mTc) will allow for the tracking of the nanocarrier noninvasively via nuclear imaging. The purpose of this study was to formulate, characterize, and optimize 99mTc-labeled niosomes.

    Methods: Niosomes were prepared from a mixture of sorbitan monostearate 60, cholesterol, and synthesized D-α-tocopherol polyethylene glycol 1000 succinate-diethylenetriaminepentaacetic acid (synthesis confirmed by 1H and 13C nuclear magnetic resonance spectroscopy). Niosomes were radiolabeled by surface chelation with reduced 99mTc. Parameters affecting the radiolabeling efficiency such as concentration of stannous chloride (SnCl2·H2O), pH, and incubation time were evaluated. In vitro stability of radiolabeled niosomes was studied in 0.9% saline and human serum at 37°C for up to 8 hours.

    Results: Niosomes had an average particle size of 110.2±0.7 nm, polydispersity index of 0.229±0.008, and zeta potential of -64.8±1.2 mV. Experimental data revealed that 30 µg/mL of SnCl2·H2O was the optimal concentration of reducing agent required for the radiolabeling process. The pH and incubation time required to obtain high radiolabeling efficiency was pH 5 and 15 minutes, respectively. 99mTc-labeled niosomes exhibited high radiolabeling efficiency (>90%) and showed good in vitro stability for up to 8 hours.

    Conclusion: To our knowledge, this is the first study published on the surface chelation of niosomes with 99mTc. The formulated 99mTc-labeled niosomes possessed high radiolabeling efficacy, good stability in vitro, and show good promise for potential use in nuclear imaging in the future.

  10. De Silva L, Fu JY, Htar TT, Wan Kamal WHB, Kasbollah A, Muniyandy S, et al.
    Front Pharmacol, 2021;12:778396.
    PMID: 35069200 DOI: 10.3389/fphar.2021.778396
    The purpose of this work was to study the biodistribution of niosomes in tumor-implanted BALB/c mice using gamma scintigraphy. Niosomes were first formulated and characterized, then radiolabeled with Technetium-99 m (99mTc). The biodistribution of 99mTc-labeled niosomes was evaluated in tumor-bearing mice through intravenous injection and imaged with gamma scintigraphy. The labeled complexes possessed high radiolabeling efficiency (98.08%) and were stable in vitro (>80% after 8 h). Scintigraphic imaging showed negligible accumulation in the stomach and thyroid, indicating minimal leaching of the radiolabel in vivo. Radioactivity was found mainly in the liver, spleen and kidneys. Tumor-to-muscle ratio indicated a higher specificity of the formulation for the tumor area. Overall, the formulated niosomes are stable both in vitro and in vivo, and show preferential tumor accumulation.
  11. Alregib AH, Tan HY, Wong YH, Kasbollah A, Wong EH, Abdullah BJJ, et al.
    J Labelled Comp Radiopharm, 2023 Aug;66(10):308-320.
    PMID: 37287213 DOI: 10.1002/jlcr.4046
    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.
  12. Tan HY, Wong YH, Kasbollah A, Md Shah MN, Abdullah BJJ, Perkins AC, et al.
    Nucl Med Commun, 2022 Apr 01;43(4):410-422.
    PMID: 35045548 DOI: 10.1097/MNM.0000000000001529
    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.

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