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.

Facile Preparation of Samarium Carbonate-Polymethacrylate Microspheres as a Neutron-Activatable Radioembolic Agent for Hepatic Radioembolization.

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.

Evaluation of Therapeutic Efficacy and Imaging Capabilities of 153Sm2O3-Loaded Polystyrene Microspheres for Intra-Tumoural Radionuclide Therapy of Liver Cancer Using Sprague-Dawley Rat Model.

Introduction: Neutron-activated samarium-153-oxide-loaded polystyrene ([153Sm]Sm2O3-PS) microspheres has been developed in previous study as a potential theranostic agent for hepatic radioembolization. In this study, the therapeutic efficacy and diagnostic imaging capabilities of the formulation was assessed using liver cancer Sprague-Dawley (SD) rat model. Methods: Twelve male SD rats (150-200 g) that implanted with N1-S1 hepatoma cell line orthotopically were divided into two groups (study versus control) to monitor the tumour growth along 60 days of treatment. The study group received an intra-tumoural injection of approximately 37 MBq of [153Sm]Sm2O3-PS microspheres, while control group received an intra-tumoural injection of 0.1 mL of saline solution. A clinical single photon emission computed tomography/computed tomography (SPECT/CT) system was used to scan the rats at Day 5 post-injection to investigate the diagnostic imaging capabilities of the microspheres. All rats were monitored for change in tumour volume using a portable ultrasound system throughout the study period. Histopathological examination (HPE) was performed after the rats were euthanized at Day 60. Results: At Day 60, no tumour was observed on the ultrasound images of all rats in the study group. In contrast, the tumour volumes in the control group were 24-fold larger compared to baseline. Statistically significant difference was observed in tumour volumes between the study and control groups (p < 0.05). The SPECT/CT images clearly displayed the location of [153Sm]Sm2O3-PS in the liver tumour of all rats at Day 5 post-injection. Additionally, the [153Sm]Sm2O3-PS microspheres was visible on the CT images and this has added to the benefits of 153Sm as a CT contrast agent. The HPE results showed that the [153Sm]Sm2O3-PS microspheres remained concentrated at the injection site with no tumour cells observed in the study group. Conclusions: Neutron-activated [153Sm]Sm2O3-PS microspheres demonstrated excellent therapeutic and diagnostic imaging capabilities for theranostic treatment of liver cancer in a SD rat model. Further studies with different animal and tumour models are planned to validate this finding.

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.

Laser-heated needle for biopsy tract ablation: In vivo study of rabbit liver biopsy.

PURPOSE: To investigate the efficacy of a newly-developed laser-heated core biopsy needle in the thermal ablation of biopsy tract to reduce hemorrhage after biopsy using in vivo rabbit's liver model. MATERIALS AND METHODS: Five male New Zealand White rabbits weighed between 1.5 and 4.0 kg were anesthetized and their livers were exposed. 18 liver biopsies were performed under control group (without tract ablation, n = 9) and study group (with tract ablation, n = 9) settings. The needle insertion depth (~3 cm) and rate of retraction (~3 mm/s) were fixed in all the experiments. For tract ablation, three different needle temperatures (100, 120 and 150 °C) were compared. The blood loss at each biopsy site was measured by weighing the gauze pads before and after blood absorption. The rabbits were euthanized immediately and the liver specimens were stained with hematoxylin-eosin (H&E) for further histopathological examination (HPE). RESULTS: The average blood loss in the study group was reduced significantly (p < 0.05) compared to the control group. The highest percentage of bleeding reduction was observed at the needle temperature of 150 °C (93.8%), followed by 120 °C (85.8%) and 100 °C (84.2%). The HPE results show that the laser-heated core biopsy needle was able to cause lateral coagulative necrosis up to 14 mm diameter along the ablation tract. CONCLUSION: The laser-heated core biopsy needle reduced hemorrhage up to 93.8% and induced homogenous coagulative necrosis along the ablation tract in the rabbits' livers. This could potentially reduce the risk of tumor seeding in clinical settings.

Comparison of deep and moderate neuromuscular blockade in microwave ablation of liver tumours: a randomized-controlled clinical trial.

Microwave ablation (MWA) is gaining popularity for the treatment of small primary hepatocellular carcinoma and metastatic lesions especially if patients are not candidates for surgical resection. Deep neuromuscular blockade (DMB) is perceived to improve surgical working conditions compared to moderate neuromuscular blockade (MMB) but no studies have examined the same benefits in MWA of liver tumours. This study aimed to compare the clinical outcomes of DMB and MMB in MWA of liver tumours in terms of liver excursion, performance scores by the interventional radiologists and patients, requirements of additional muscle relaxants and complications. 50 patients were recruited and 45 patients (22 in MMB group, 23 in DMB group) completed the study. The mean liver excursion for the MMB group (1.42 ± 1.83 mm) was significantly higher than the DMB group (0.26 ± 0.38 mm) (p = 0.001). The mean Leiden-Surgical Rating Scale (L-SRS) rated by the two interventional radiologists were 4.5 ± 0.59 and 3.6 ± 0.85 for the DMB and MMB groups, respectively (p = 0.01). There was also statistically significant difference on patient satisfaction scores (0-10: Extremely Dissatisfied-Extremely Satisfied) between DMB (8.74 ± 1.1) and MMB (7.86 ± 1.25) groups (p = 0.01). 5 patients from MMB group and none from DMB group required bolus relaxant during the MWA procedure. Adverse events were also noted to be more severe in the MMB group. In conclusion, DMB significantly reduced liver excursion and movement leading to improved accuracy, safety and success in ablating liver tumour.

Neutron-activated biodegradable samarium-153 acetylacetonate-poly-L-lactic acid microspheres for intraarterial radioembolization of hepatic tumors.

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) via 152Sm (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.

Preparation and In Vitro Evaluation of Neutron-Activated, Theranostic Samarium-153-Labeled Microspheres for Transarterial Radioembolization of Hepatocellular Carcinoma and Liver Metastasis.

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.

Experimental assessment on feasibility of computed tomography-based thermometry for radiofrequency ablation on tissue equivalent polyacrylamide phantom.

Purpose: This study aimed to evaluate the effects of various computed tomography (CT) acquisition parameters and metal artifacts on CT number measurement for CT thermometry during CT-guided thermal ablation. Methods: The effects of tube voltage (100-140 kVp), tube current (20-250 mAs), pitch (0.6-1.5) and gantry rotation time (0.5, 1.0 s) as well as metal artifacts from a radiofrequency ablation (RFA) needle on CT number were evaluated using liver tissue equivalent polyacrylamide (PAA) phantom. The correlation between CT number and temperature from 37 to 80 °C was studied on PAA phantom using optimum CT acquisition parameters. Results: No statistical significant difference (p > 0.05) was found on CT numbers under the variation of different acquisition parameters for the same temperature setting. On the other hand, the RFA needle has induced metal artifacts on the CT images of up to 8 mm. The CT numbers decreased linearly when the phantom temperature increased from 37 to 80 °C. A linear regression analysis on the CT numbers and temperature suggested that the CT thermal sensitivity was -0.521 ± 0.061 HU/°C (R2 = 0.998). Conclusion: CT thermometry is feasible for temperature assessment during RFA with the current CT technology, which produced a high CT number reproducibility and stable measurement at different CT acquisition parameters. Despite being affected by metal artifacts, the CT-based thermometry could be further developed as a tissue temperature monitoring tool during CT-guided thermal ablation.

Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine.

Recent studies suggest that the main driving force behind the therapeutic activity observed in mesenchymal stem cells (MSCs) are the paracrine factors secreted by these cells. These biomolecules also trigger antiapoptotic events to prevent further degeneration of the diseased organ through paracrine signalling mechanisms. In comparison with the normal physiological conditions, an increased paracrine gradient is observed within the peripheral system of diseased organs that enhances the migration of tissue-specific MSCs towards the site of infection or injury to promote healing. Thus, upon administration of conditioned media derived from mesenchymal stem cell cultures (MSC-CM) could contribute in maintaining the increased paracrine factor gradient between the diseased organ and the stem cell niche in order to speed up the process of recovery. Based on the principle of the paracrine signalling mechanism, MSC-CM, also referred as the secretome of the MSCs, is a rich source of the paracrine factors and are being studied extensively for a wide range of regenerative therapies such as myocardial infarction, stroke, bone regeneration, hair growth, and wound healing. This article highlights the current technological applications and advances of MSC-CM with the aim to appraise its future potential as a regenerative therapeutic agent.

Effect of Aging on NK Cell Population and Their Proliferation at Ex Vivo Culture Condition.

Age-associated changes in natural killer (NK) cell population, phenotype, and functions are directly attributed to the risk of several diseases and infections. It is predicted to be the major cause of the increase in mortality. Based on the surface density of CD56, NK cells are subdivided into two types, such as CD56bright and CD56dim cells, which represent cytokine production and cytotoxicity. In our study, we have examined the age-associated changes in the NK cell population and their subsets at different age groups of males and females (at a range from 41 to 80 years). We found that the total lymphocyte count significantly dropped upon aging in both genders. Although, the level of total immune cells also dropped on aging, and surprisingly the total NK cell population was remarkably increased with the majority of NK cells being CD56dim. Subsequently, we evaluated the proliferation potential of NK cells and our results showed that the NK cell proliferation ability declines with age. Overall, our findings prove that there is an increase in the circulating NK cell population upon aging. However, the proliferation rate upon aging declines when compared to the young age group (<41 yrs).

Automated diagnosis of focal liver lesions using bidirectional empirical mode decomposition features.

Liver is the heaviest internal organ of the human body and performs many vital functions. Prolonged cirrhosis and fatty liver disease may lead to the formation of benign or malignant lesions in this organ, and an early and reliable evaluation of these conditions can improve treatment outcomes. Ultrasound imaging is a safe, non-invasive, and cost-effective way of diagnosing liver lesions. However, this technique has limited performance in determining the nature of the lesions. This study initiates a computer-aided diagnosis (CAD) system to aid radiologists in an objective and more reliable interpretation of ultrasound images of liver lesions. In this work, we have employed radon transform and bi-directional empirical mode decomposition (BEMD) to extract features from the focal liver lesions. After which, the extracted features were subjected to particle swarm optimization (PSO) technique for the selection of a set of optimized features for classification. Our automated CAD system can differentiate normal, malignant, and benign liver lesions using machine learning algorithms. It was trained using 78 normal, 26 benign and 36 malignant focal lesions of the liver. The accuracy, sensitivity, and specificity of lesion classification were 92.95%, 90.80%, and 97.44%, respectively. The proposed CAD system is fully automatic as no segmentation of region-of-interest (ROI) is required.

Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions.

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm.Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin.Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73-83. ©2017 AACR.

Optimal approach for complete liver tumor ablation using radiofrequency ablation: a simulation study.

PURPOSE: To investigate the effect of radiofrequency ablation (RFA) electrode trajectory on complete tumor ablation using computational simulation. MATERIAL AND METHODS: The RFA of a spherical tumor of 2.0 cm diameter along with 0.5 cm clinical safety margin was simulated using Finite Element Analysis software. A total of 86 points inside one-eighth of the tumor volume along the axial, sagittal and coronal planes were selected as the target sites for electrode-tip placement. The angle of the electrode insertion in both craniocaudal and orbital planes ranged from -90° to +90° with 30° increment. The RFA electrode was simulated to pass through the target site at different angles in combination of both craniocaudal and orbital planes before being advanced to the edge of the tumor. RESULTS: Complete tumor ablation was observed whenever the electrode-tip penetrated through the epicenter of the tumor regardless of the angles of electrode insertion in both craniocaudal and orbital planes. Complete tumor ablation can also be achieved by placing the electrode-tip at several optimal sites and angles. CONCLUSIONS: Identification of the tumor epicenter on the central slice of the axial images is essential to enhance the success rate of complete tumor ablation during RFA procedures.

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.

Magnetic resonance guided focused ultrasound for treatment of bone tumors.

AIMS: Magnetic resonance guided focused ultrasound (MRgFUS) is a new modality in the management of primary and secondary bone tumors. We aimed to investigate the safety, efficacy, and feasibility of using MRgFUS for the treatment of (1) benign bone tumors with the intent of complete tumor ablation, (2) primary malignant bone tumors with the intent to assess its effectiveness in causing tumor necrosis, and (3) metastatic bone disease with the intent of pain relief. METHOD: Twenty-four patients with benign bone tumors, primary malignant bone tumors, and metastatic bone disease were treated with one session of MRgFUS. Contrast-enhanced (CE) magnetic resonance imaging (MRI) was carried out post-procedure to assess and quantify the area of ablation. Those with malignant primary tumors had the tumors resected 2 weeks after the treatment and the ablated areas were examined histopathologically (HPE). The other patients were followed up for 3 months to assess for the side effects and pain scores. RESULTS: Significant volume of ablation was noted on CE MRI after the treatment. Benign bone tumors were ablated with minimal adverse effects. Metastatic bone disease was successfully treated with significant decrease in pain scores. Ablated primary malignant tumors showed significant coagulative necrosis on MRI and the HPE showed 100% necrosis. Pain scores significantly decreased 3 months after the procedure. Only two patients had superficial skin blistering and three patients had increase in pain scores immediately after treatment. CONCLUSION: MRgFUS is effective, safe, and noninvasive procedure that can be an adjunct in the management of primary and metastatic bone tumors.

Low-melting-point polymeric nanoshells for thermal-triggered drug release under hyperthermia condition.

PURPOSE: The aim of this paper was to synthesise core-shell nanostructures comprised of mesoporous silica core and a low melting-point polyethylene glycol (PEG) nanoshell with a sharp gel-liquid phase transition for rapid drug release at hyperthermia temperature range. MATERIALS AND METHODS: The phase transition behaviours of PEGs with molecular weights of 1000, 1500, and 2000 Da were analysed using differential scanning calorimetry (DSC) to determine the optimal formulation with phase transition in the hyperthermia range. The 'graft-to' method was employed to synthesise core-shell nanostructures using the selected PEG formulation. The drug loading and release behaviours of these nanocarriers were examined by ultra-violet visible spectroscopy (UV-Vis) using doxorubicin as a model drug. Magnetic resonance-guided focused ultrasound (MRgFUS) was also applied as a typical thermal modality to evaluate the rate of drug release from the core-shell nanostructures. RESULTS: The PEG molecular weight of 1500 Da presented the optimal phase transition temperature for thermal-triggered release under hyperthermia conditions. Drug release measurements at different temperatures using UV-Vis methods showed a 20.2 ± 4.3% leakage in aqueous solution at 37 °C after 30 min, while this value was significantly increased to 68.2 ± 3.7% at 50 °C. A 45.5 ± 3.1% drug release was also obtained after sonication of the drug-loaded nanoparticles for 5 × 20 s using MRgFUS. CONCLUSION: Although the ratio of drug leakage at physiological temperatures was relatively high, the sharp transition temperature, high loading efficiency, and fast drug release at hyperthermia temperature range could make these core-shell nanoparticles prominent for enhancing the efficacy of various hyperthermia modalities in the treatment of cancer tumours.

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.

Triggering Mechanisms of Thermosensitive Nanoparticles Under Hyperthermia Condition.

Nanoparticle-based hyperthermia is an effective therapeutic approach that allows time- and site-specific treatment with minimized off-site effects. The recent advances in materials science have led to design a diversity of thermosensitive nanostructures that exhibit different mechanisms of thermal response to the external stimuli. This article aims to provide an extensive review of the various triggering mechanisms in the nanostructures used as adjuvants to hyperthermia modalities. Understanding the differences between various mechanisms of thermal response in these nanostructures could help researchers in the selection of appropriate materials for each experimental and clinical condition as well as to address the current shortcomings of these mechanisms with improved material design.

A new mechanism of thermal sensitivity for rapid drug release and low systemic toxicity in hyperthermia and thermal ablation temperature ranges.

PURPOSE: The aim of this paper was to introduce a new mechanism of thermal sensitivity in nanocarriers that results in a relatively low drug release at physiological temperature and rapid release of the encapsulated drug at hyperthermia and thermal ablation temperature range (40-60 °C). MATERIALS AND METHODS: The nanocarriers were synthesised by coating mesoporous silica nanoparticles with a thin layer of polyacrylamide. The low gelation temperature of the protective shell provides preferred routes for drug diffusion when the nanocarriers are heated within the hyperthermia temperature range. In order to determine the gelation point of polyacrylamide shell, differential scanning calorimetry was used. Various chemical, morphological, thermal, as well as drug loading capacities of these nanocarriers were characterised and their drug release behaviour was examined using magnetic resonance -guided focused ultrasound (MRgFUS). RESULTS: Drug release measurements at different temperatures using doxorubicin showed 11.5 ± 2.4% leakage in aqueous solution at 37 °C after 30 min, while this value was significantly increased to 67.6 ± 2.5% at 60 °C. A 39.2 ± 2.2% release of doxorubicin was also obtained due to the sonication of drug-loaded nanoparticles for 5 × 20 s using MRgFUS. CONCLUSION: The nanocarriers developed do not exhibit a sharp transition temperature. However, a relatively high loading efficiency as well as rapid drug release at thermal ablation temperature range makes these nanostructures promising candidates for application as adjuvants to various thermal modalities such as radiofrequency and high intensity focused ultrasound.