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

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.

Matched MeSH terms: Yttrium Radioisotopes*
Dosimetric assessment of Gadolinium-159 for hepatic radioembolization: Tomographic images and Monte Carlo simulation

Musa AS, Abdul Hadi MFR, Hashikin NAA, Ashour NI, Ying CK

Appl Radiat Isot, 2023 Sep;199:110916.
PMID: 37393764 DOI: 10.1016/j.apradiso.2023.110916

A common therapeutic radionuclide used in hepatic radioembolization is yttrium-90 (90Y). However, the absence of gamma emissions makes it difficult to verify the post-treatment distribution of 90Y microspheres. Gadolinium-159 (159Gd) has physical properties that are suitable for therapy and post-treatment imaging in hepatic radioembolization procedures. The current study is innovative for conducting a dosimetric investigation of the use of 159Gd in hepatic radioembolization by simulating tomographic images using the Geant4 application for tomographic emission (GATE) Monte Carlo (MC) simulation. For registration and segmentation, tomographic images of five patients with hepatocellular carcinoma (HCC) who had undergone transarterial radioembolization (TARE) therapy were processed using a 3D slicer. The tomographic images with 159Gd and 90Y separately were simulated using the GATE MC Package. The output of simulation (dose image) was uploaded to 3D slicer to compute the absorbed dose for each organ of interests. 159Gd were able to provide a recommended dose of 120 Gy to the tumour, with normal liver and lungs absorbed doses close to that of 90Y and less than the respective maximum permitted doses of 70 Gy and 30 Gy, respectively. Compared to 90Y, 159Gd requires higher administered activity approximately 4.92 times to achieve a tumour dose of 120 Gy. Thus; this research gives new insights into the use of 159Gd as a theranostic radioisotope, with the potential to be used as a90Y alternative for liver radioembolization.

Matched MeSH terms: Yttrium Radioisotopes/therapeutic use
Systematic investigation on the validity of partition model dosimetry for90Y radioembolization using Monte Carlo simulation

Hashikin NAA, Yeong CH, Guatelli S, Abdullah BJJ, Ng KH, Malaroda A, et al.

Phys Med Biol, 2017 Aug 22;62(18):7342-7356.
PMID: 28686171 DOI: 10.1088/1361-6560/aa7e5b

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. 108track 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.

Matched MeSH terms: Yttrium Radioisotopes/therapeutic use*
Fulltext Preparation and In Vitro Evaluation of Neutron-Activated, Theranostic Samarium-153-Labeled Microspheres for Transarterial Radioembolization of Hepatocellular Carcinoma and Liver Metastasis

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.

Matched MeSH terms: Yttrium Radioisotopes
SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma

Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al.

J Clin Oncol, 2018 07 01;36(19):1913-1921.
PMID: 29498924 DOI: 10.1200/JCO.2017.76.0892

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

Matched MeSH terms: Yttrium Radioisotopes
Fulltext Neutron Activated Samarium-153 Microparticles for Transarterial Radioembolization of Liver Tumour with Post-Procedure Imaging Capabilities

Hashikin NA, Yeong CH, Abdullah BJ, Ng KH, Chung LY, Dahalan R, et al.

PLoS One, 2015;10(9):e0138106.
PMID: 26382059 DOI: 10.1371/journal.pone.0138106

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.

Matched MeSH terms: Yttrium Radioisotopes/therapeutic use
Fulltext Radionuclide therapy of hepatocellular carcinoma

Sundram F

Biomed Imaging Interv J, 2006 Jul;2(3):e40.
PMID: 21614248 MyJurnal DOI: 10.2349/biij.2.3.e40

Hepatocellular carcinoma (HCC) is a malignant tumour of the hepatocyte. It is a common malignancy worldwide and causes almost half a million deaths annually. Asia is a high risk area. Although surgery (hepatectomy or liver transplantation) is the main form of curative treatment, the majority of patients are not eligible for surgery due to extent of tumour and dysfunction of liver. Radiopharmaceuticals used for transarterial treatment of HCC were Yttrium-90 microspheres, Iodine-131 lipiodol, Rhenium-188 lipiodol, and Holmium-166 Chitosan complex. Yittrium-90 microspheres are glass or resin microspheres of mean sphere diameter of 20 to 30 micrometre. The activity administered was about 4 GBq. Reported response rate was about 20%, and median survival was 54 weeks. On inoperable tumours, reported objective response of I-131 lipiodol was 40 to 70%, and median survival was six to nine months. It showed efficacy similar to TACE. In adjuvant treatment following curative resection of HCC, reported three year survival was 86% compared with 46% for the control group. The administered activity in both adjuvant and inoperable HCC was about 2 GBq (55 mCi). Rhenium-188 lipiodol is a new radioconjugate, and using it we treated 70 patients with inoperable HCC. This treatment was a part of a multi-centre trial sponsored by the International Atomic Energy Agency. Partial response was obtained in 17% of cases, while 49% had stable disease at three months, and 34% showed disease progression. In terms of survival, 19% survived one year, 60% for six months, and 90% for three months. The mean activity was about 4.6 GBq (124 mCi). This method was safe and free from adverse effects.

Matched MeSH terms: Yttrium Radioisotopes
Fulltext Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma

Chow PK, Poon DY, Khin MW, Singh H, Han HS, Goh AS, et al.

PLoS One, 2014;9(3):e90909.
PMID: 24614178 DOI: 10.1371/journal.pone.0090909

The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279) was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC) not amenable to curative therapies.

Matched MeSH terms: Yttrium Radioisotopes/therapeutic use