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Embolotherapy is a minimally invasive transcatheter technique aiming at reduction or complete obstruction of the blood flow by infusion of micro-sized particles in order to induce tumor regression. A major drawback of the current commercially available and clinically used microspheres is that they cannot be detected in vivo with medical imaging techniques, impeding intra- and post-procedural feedback. It can be expected that real-time monitoring of microsphere infusion and post-procedural imaging will result in better predictability and higher efficacy of the treatment. In this study, a novel microsphere formulation has been developed that can be visualized with fluoroscopy, X-ray computed tomography (CT) and magnetic resonance imaging (MRI). The microspheres were prepared with the JetCutter technique and consist of alginate (matrix-forming polymer), holmium (cross-linking and MRI contrast agent), lipiodol (radiopaque contrast agent) and Pluronic F-68 (surfactant). The mean size (±SEM) of the hydrated holmium-lipiodol-alginate microspheres (Ho-lip-ams) was 570±12 μm with a holmium content of 0.38±0.01% (w/w). Stability studies showed that the microspheres remained intact during incubation for two weeks in fetal calf serum (FCS) at 37 °C. The inclusion of lipiodol in the microspheres rendered excellent visualization capabilities for fluoroscopy and CT, whereas the holmium ions, which keep the alginate network together, also allow MR imaging. In this study it was shown that single sphere detection was possible by fluoroscopy, CT and MRI. The Ho-lip-ams were visualized in real-time, during infusion in a porcine kidney using fluoroscopy, and post-procedural, the deposition of the microspheres was examined with fluoroscopy, (cone beam rotational) CT and MRI. The different imaging modalities showed similar deposition patterns of the microspheres within the organ. The combination of intra-procedural visualization, multimodality imaging for patient follow-up and the possibility of quantification offers a new and promising method for more safe, efficient and successful embolization treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To present a new method, S0 estimation of the free induction decay combined with a single spin echo measurement (SOFIDSE), that enables simultaneous measurements of R2*, R2, and R2' in order to quantify the local concentration of holmium microspheres (Ho-MS) for radioembolization., Theory and Methods: SOFIDSE estimates R2* and the signal magnitude at time point 0, S0, from a multigradient echo readout of the free induction decay and subsequently estimates R2 using S0 and a single spin echo, from which R2' is deducted. The method was evaluated by comparing SOFIDSE R2 values with values obtained from shifted spin echo (SSE) measurements on a phantom setup containing Ho-MS and from dual spin echo measurements on a healthy volunteer., Results: On average, SOFIDSE showed a small overestimation of R2 values compared with SSE independent of the microsphere concentration. R2' values determined by subtraction of either SOFIDSE R2 or SSE R2 from R2* showed excellent agreement (correlation coefficient = 1; P = 9 · 10(-11)). The Ho-MS-induced R2' values obtained by SOFIDSE were insensitive to the R2 value of the tissue in which they resided., Conclusion: SOFIDSE enables quantification of Ho-MS, in media with spatially or temporally varying R2 values, in a single acquisition., (© 2014 Wiley Periodicals, Inc.)

Purpose: To assess the radiation exposure to individuals coming from patients after treatment with holmium-166 ((166)Ho) microspheres., Materials and Methods: Holmium-166 radioembolization (RE) with escalating whole-liver doses of 20 Gy, 40 Gy, 60 Gy, and 80 Gy was administered to 15 patients. Exposure rates (μSv/h) from patients were measured at 1.0 m distance from a lateral and frontal position at 0, 3, 6, 24, and 48 hours after infusion. The total effective dose equivalent (TEDE) to a maximally exposed contact was calculated in accordance with guidelines of the U.S. Nuclear Regulatory Commission (NRC). Results were extrapolated to a whole-liver dose of 60 Gy used in future treatments., Results: The median exposure rate at discharge, 48 hours after infusion, measured from a lateral position was 26 μSv/h (range, 7-45 μSv/h). Extrapolated to a whole-liver dose of 60 Gy, none of the exposure rates for the NRC contact scenario, at any time, frontal or lateral, would lead to a TEDE > 5 mSv; all patients may be released directly after treatment. Release after 6 hours is possible without contact restrictions for patients who received up to 7 GBq., Conclusions: The TEDE to a contact of patients treated with (166)Ho RE would not exceed the NRC limit of 5 mSv. Contact restrictions 6 hours after treatment are unnecessary for infused activities < 7 GBq., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation pneumonitis is a rare but serious complication of radioembolic therapy of liver tumours. Estimation of the mean absorbed dose to the lungs based on pretreatment diagnostic (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) imaging should prevent this, with administered activities adjusted accordingly. The accuracy of (99m)Tc-MAA-based lung absorbed dose estimates was evaluated and compared to absorbed dose estimates based on pretreatment diagnostic (166)Ho-microsphere imaging and to the actual lung absorbed doses after (166)Ho radioembolization., Methods: This prospective clinical study included 14 patients with chemorefractory, unresectable liver metastases treated with (166)Ho radioembolization. (99m)Tc-MAA-based and (166)Ho-microsphere-based estimation of lung absorbed doses was performed on pretreatment diagnostic planar scintigraphic and SPECT/CT images. The clinical analysis was preceded by an anthropomorphic torso phantom study with simulated lung shunt fractions of 0 to 30 % to determine the accuracy of the image-based lung absorbed dose estimates after (166)Ho radioembolization., Results: In the phantom study, (166)Ho SPECT/CT-based lung absorbed dose estimates were more accurate (absolute error range 0.1 to -4.4 Gy) than (166)Ho planar scintigraphy-based lung absorbed dose estimates (absolute error range 9.5 to 12.1 Gy). Clinically, the actual median lung absorbed dose was 0.02 Gy (range 0.0 to 0.7 Gy) based on posttreatment (166)Ho-microsphere SPECT/CT imaging. Lung absorbed doses estimated on the basis of pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging (median 0.02 Gy, range 0.0 to 0.4 Gy) were significantly better predictors of the actual lung absorbed doses than doses estimated on the basis of (166)Ho-microsphere planar scintigraphy (median 10.4 Gy, range 4.0 to 17.3 Gy; p < 0.001), (99m)Tc-MAA SPECT/CT imaging (median 2.5 Gy, range 1.2 to 12.3 Gy; p < 0.001), and (99m)Tc-MAA planar scintigraphy (median 5.5 Gy, range 2.3 to 18.2 Gy; p < 0.001)., Conclusion: In clinical practice, lung absorbed doses are significantly overestimated by pretreatment diagnostic (99m)Tc-MAA imaging. Pretreatment diagnostic (166)Ho-microsphere SPECT/CT imaging accurately predicts lung absorbed doses after (166)Ho radioembolization.

Unlabelled: (166)Ho-poly(l-lactic acid) microspheres allow for quantitative imaging with MR imaging or SPECT for microsphere biodistribution assessment after radioembolization. The purpose of this study was to evaluate SPECT- and MR imaging-based dosimetry in the first patients treated with (166)Ho radioembolization., Methods: Fifteen patients with unresectable, chemorefractory liver metastases of any origin were enrolled in this phase 1 study and were treated with (166)Ho radioembolization according to a dose escalation protocol (20-80 Gy). The contours of all liver segments and all discernible tumors were manually delineated on T2-weighted posttreatment MR images and registered to the posttreatment SPECT images (n = 9) or SPECT/CT images (n = 6) and MR imaging-based R2* maps (n = 14). Dosimetry was based on SPECT (n = 15) and MR imaging (n = 9) for all volumes of interest, tumor-to-nontumor (T/N) activity concentration ratios were calculated, and correlation and agreement of MR imaging- and SPECT-based measurements were evaluated., Results: The median overall T/N ratio was 1.4 based on SPECT (range, 0.9-2.8) and 1.4 based on MR imaging (range, 1.1-3.1). In 6 of 15 patients (40%), all tumors had received an activity concentration equal to or higher than the normal liver (T/N ratio ≥ 1). Analysis of SPECT and MR imaging measurements for dose to liver segments yielded a high correlation (R(2) = 0.91) and a moderate agreement (mean bias, 3.7 Gy; 95% limits of agreement, -11.2 to 18.7)., Conclusion: With the use of (166)Ho-microspheres, in vivo dosimetry is feasible on the basis of both SPECT and MR imaging, which enables personalized treatment by selective targeting of inadequately treated tumors.

Purpose: Quantitative imaging of the radionuclide distribution is of increasing interest for microsphere radioembolization (RE) of liver malignancies, to aid treatment planning and dosimetry. For this purpose, holmium-166 ((166)Ho) microspheres have been developed, which can be visualized with a gamma camera. The objective of this work is to develop and evaluate a new reconstruction method for quantitative (166)Ho SPECT, including Monte Carlo-based modeling of photon contributions from the full energy spectrum., Methods: A fast Monte Carlo (MC) simulator was developed for simulation of (166)Ho projection images and incorporated in a statistical reconstruction algorithm (SPECT-fMC). Photon scatter and attenuation for all photons sampled from the full (166)Ho energy spectrum were modeled during reconstruction by Monte Carlo simulations. The energy- and distance-dependent collimator-detector response was modeled using precalculated convolution kernels. Phantom experiments were performed to quantitatively evaluate image contrast, image noise, count errors, and activity recovery coefficients (ARCs) of SPECT-fMC in comparison with those of an energy window-based method for correction of down-scattered high-energy photons (SPECT-DSW) and a previously presented hybrid method that combines MC simulation of photopeak scatter with energy window-based estimation of down-scattered high-energy contributions (SPECT-ppMC+DSW). Additionally, the impact of SPECT-fMC on whole-body recovered activities (A(est)) and estimated radiation absorbed doses was evaluated using clinical SPECT data of six (166)Ho RE patients., Results: At the same noise level, SPECT-fMC images showed substantially higher contrast than SPECT-DSW and SPECT-ppMC+DSW in spheres ≥ 17 mm in diameter. The count error was reduced from 29% (SPECT-DSW) and 25% (SPECT-ppMC+DSW) to 12% (SPECT-fMC). ARCs in five spherical volumes of 1.96-106.21 ml were improved from 32%-63% (SPECT-DSW) and 50%-80% (SPECT-ppMC+DSW) to 76%-103% (SPECT-fMC). Furthermore, SPECT-fMC recovered whole-body activities were most accurate (A(est) = 1.06 × A - 5.90 MBq, R(2) = 0.97) and SPECT-fMC tumor absorbed doses were significantly higher than with SPECT-DSW (p = 0.031) and SPECT-ppMC+DSW (p = 0.031)., Conclusions: The quantitative accuracy of (166)Ho SPECT is improved by Monte Carlo-based modeling of the image degrading factors. Consequently, the proposed reconstruction method enables accurate estimation of the radiation absorbed dose in clinical practice.

Purpose: Holmium-166 acetylacetonate microspheres ((166)Ho-AcAc-MS) are proposed as an intratumoral radioablation device. This article presents a pilot study in housecats with unresectable liver cancer. Feasibility and tolerability of intratumoral administrations of (166)Ho-AcAc-MS was investigated., Methods and Materials: Three cats with unresectable liver tumors of different histotype were included. One cat had hepatocellular carcinoma (HCC), one had cholangiocarcinoma (CC), and one had a malignant epithelial liver tumor (MELT) of unspecified histotype. (166)Ho-AcAc-MS were injected percutaneously under ultrasound guidance into the tumors. Followup consisted of physical examinations and hematologic and biochemical analyses., Results: (166)Ho-AcAc-MS were administered to three liver tumor-bearing cats. The treatment was well tolerated and the clinical condition, that is body weight, alertness, mobility, and coat condition of the animals improved markedly. Most biochemical and hematologic parameters normalized shortly after treatment. Life of all cats was extended and associated with a good quality of life. The HCC cat that received 33-Gy tumor-absorbed dose was euthanized 6 months after the first administration owing to disease progression. The MELT cat received 99-Gy tumor dose and was euthanized 3 months posttreatment owing to bacterial meningitis. The CC cat received 333Gy and succumbed 4 months after the first treatment owing to the formation of a pulmonary embolism., Conclusions: Percutaneous intratumoral injection of radioactive (166)Ho-AcAc-MS is feasible in liver tumor-bearing cats. The findings of this pilot study indicate that (166)Ho-AcAc-MS may constitute safe brachytherapeutic microspheres and warrant studies to confirm the clinical utility of this novel brachytherapy device., (Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To demonstrate the feasibility of MRI-based assessment of the intrahepatic Ho-PLLA-MS biodistribution after radioembolisation in order to estimate the absorbed radiation dose., Methods: Fifteen patients were treated with holmium-166 ((166)Ho) poly(L-lactic acid)-loaded microspheres (Ho-PLLA-MS, mean 484 mg; range 408-593 mg) in a phase I study. Multi-echo gradient-echo MR images were acquired from which R (2) maps were constructed. The amount of Ho-PLLA-MS in the liver was determined by using the relaxivity r (2) of the Ho-PLLA-MS and compared with the administered amount. Quantitative single photon emission computed tomography (SPECT) was used for comparison with MRI regarding the whole liver absorbed radiation dose., Results: R (2) maps visualised the deposition of Ho-PLLA-MS with great detail. The mean total amount of Ho-PLLA-MS detected in the liver based on MRI was 431 mg (range 236-666 mg) or 89 ± 19 % of the delivered amount (correlation coefficient r = 0.7; P < 0.01). A good correlation was found between the whole liver mean absorbed radiation dose as assessed by MRI and SPECT (correlation coefficient r = 0.927; P < 0.001)., Conclusion: MRI-based dosimetry for holmium-166 radioembolisation is feasible. Biodistribution is visualised with great detail and quantitative measurements are possible.

Purpose: The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres ((166)HoAcAcMS). This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI., Methods: (166)HoAcAcMS were administered intratumorally in orthotopic renal tumors (Balb/C mice). Post administration CT, SPECT and MRI was performed. At several time points (2 h, 1, 2, 3, 7 and 14 days) after MS administration, tumors were measured and histologically analyzed. Holmium accumulation in organs was measured using inductively coupled plasma mass spectrometry., Results: (166)HoAcAcMS were successfully administered to tumor bearing mice. A striking near-complete tumor-control was observed in (166)HoAcAcMS treated mice (0.10±0.01 cm(3) vs. 4.15±0.3 cm(3) for control tumors). Focal necrosis and inflammation was present from 24 h following treatment. Renal parenchyma outside the radiated region showed no histological alterations. Post administration CT, MRI and SPECT imaging revealed clear deposits of (166)HoAcAcMS in the kidney., Conclusions: Intratumorally administered (166)HoAcAcMS has great potential as a new local treatment of renal tumors for surgically unfit patients. In addition to strong cancer control, it provides powerful multimodality imaging opportunities.

Background: The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases., Methods: Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784., Findings: 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity., Interpretation: (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: To investigate the potential of magnetic resonance imaging (MRI) for accurate assessment of the three-dimensional (166)Ho activity distribution to estimate radiation-absorbed dose distributions in (166)Ho-loaded poly (L-lactic acid) microsphere ((166)Ho-PLLA-MS) liver radioembolization., Methods and Materials: MRI, computed tomography (CT), and single photon emission CT (SPECT) experiments were conducted on an anthropomorphic gel phantom with tumor-simulating gel samples and on an excised human tumor-bearing liver, both containing known amounts of (166)Ho-PLLA-MS. Three-dimensional radiation-absorbed dose distributions were estimated at the voxel level by convolving the (166)Ho activity distribution, derived from quantitative MRI data, with a (166)Ho dose point-kernel generated by MCNP (Monte Carlo N-Particle transport code) and from Medical Internal Radiation Dose Pamphlet 17. MRI-based radiation-absorbed dose distributions were qualitatively compared with CT and autoradiography images and quantitatively compared with SPECT-based dose distributions. Both MRI- and SPECT-based activity estimations were validated against dose calibrator measurements., Results: Evaluation on an anthropomorphic phantom showed that MRI enables accurate assessment of local (166)Ho-PLLA-MS mass and activity distributions, as supported by a regression coefficient of 1.05 and a correlation coefficient of 0.99, relating local MRI-based mass and activity calculations to reference values obtained with a dose calibrator. Estimated MRI-based radiation-absorbed dose distributions of (166)Ho-PLLA-MS in an ex vivo human liver visually showed high correspondence to SPECT-based radiation-absorbed dose distributions. Quantitative analysis revealed that the differences in local and total amounts of (166)Ho-PLLA-MS estimated by MRI, SPECT, and the dose calibrator were within 10%. Excellent agreement was observed between MRI- and SPECT-based dose-volume histograms., Conclusions: Quantitative MRI was demonstrated to provide accurate three-dimensional (166)Ho-PLLA-MS activity distributions, enabling localized intrahepatic radiation-absorbed dose estimation by convolution with a (166)Ho dose point-kernel for liver radioembolization treatment optimization and evaluation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The clinical application of holmium acetylacetonate microspheres (HoAcAcMS) for the intratumoral radionuclide treatment of solid malignancies requires a thorough understanding of their stability. Therefore, an in vitro and an in vivo stability study with HoAcAcMS was conducted., Methods: HoAcAcMS, before and after neutron irradiation, were incubated in a phosphate buffer at 37°C for 6 months. The in vitro release of holmium in this buffer after 6 months was 0.5%. Elemental analysis, scanning electron microscopy, infrared spectroscopy and time of flight secondary ion mass spectrometry were performed on the HoAcAcMS., Results: After 4 days in buffer the acetylacetonate ligands were replaced by phosphate, without altering the particle size and surface morphology. HoAcAcMS before and after neutron irradiation were administered intratumorally in VX2 tumor-bearing rabbits. No holmium was detected in the faeces, urine, femur and blood. Histological examination of the tumor revealed clusters of intact microspheres amidst necrotic tissue after 30 days., Conclusion: HoAcAcMS are stable both in vitro and in vivo and are suitable for intratumoral radionuclide treatment.

Purpose: The present study introduces the preparation and in vitro characterization of a nanoparticle device comprising holmium acetylacetonate for radioablation of unresectable solid malignancies., Methods: HoAcAc nanoparticles were prepared by dissolving holmium acetylacetonate in chloroform, followed by emulsification in an aqueous solution of a surfactant and evaporation of the solvent. The diameter, surface morphology, holmium content, and zeta potential were measured, and thermal behavior of the resulting particles was investigated. The stability of the particles was tested in HEPES buffer. The r(2)* relaxivity of protons and mass attenuation coefficient of the nanoparticles were determined. The particle diameter and surface morphology were studied after neutron activation., Results: Spherical particles with a smooth surface and diameter of 78 ± 10 nm were obtained, and the particles were stable in buffer. Neutron irradiation did not damage the particles, and adequate amounts of activity were produced for nuclear imaging and radioablation of malignancies through intratumoral injections., Conclusions: The present study demonstrates that HoAcAc nanoparticles were prepared using a solvent evaporation process. The particle diameter can easily be adapted and can be optimized for specific therapeutic applications and tumor types.

Background: Intra-arterial radioembolization with yttrium-90 microspheres ( 90Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( 166Ho-PLLA-MS) have been developed as a possible alternative to 90Y-RE. Next to high-energy beta-radiation, 166Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of 166Ho-PLLA-MS radioembolization ( 166Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of 166Ho-RE in patients with liver metastases., Methods: The HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( 99mTc-MAA) dose, a low radioactive safety dose of 60-mg 166Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of 166Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the 166Ho-PLLA-MS safety dose and the 99mTc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution., Discussion: This will be the first clinical study on 166Ho-RE. Based on preclinical studies, it is expected that 166Ho-RE has a safety and toxicity profile comparable to that of 90Y-RE. The biochemical and radionuclide characteristics of 166Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.

Objective: To assess the accuracy of a scout dose of holmium-166 poly(L-lactic acid) microspheres ((166)Ho-PLLA-MS) in predicting the distribution of a treatment dose of (166)Ho-PLLA-MS, using single photon emission tomography (SPECT)., Methods: A scout dose (60 mg) was injected into the hepatic artery of five pigs and SPECT acquired. Subsequently, a 'treatment dose' was administered (540 mg) and SPECT, computed tomography (CT) and magnetic resonance imaging (MRI) of the total dose performed. The two SPECT images of each animal were compared. To validate quantitative SPECT an ex vivo liver was instilled with (166)Ho-PLLA-MS and SPECT acquired. The liver was cut into slices and planar images were acquired, which were registered to the SPECT image., Results: Qualitatively, the scout dose and total dose images were similar, except in one animal because of catheter displacement. Quantitative analysis, feasible in two animals, tended to confirm this similarity (r(2) = 0.34); in the other animal the relation was significantly better (r(2) = 0.66). The relation between the SPECT and planar images acquired from the ex vivo liver was strong (r(2) = 0.90)., Conclusion: In the porcine model a scout dose of (166)Ho-PLLA-MS can accurately predict the biodistribution of a treatment dose. Quantitative (166)Ho SPECT was validated for clinical application.

Poly(L-lactic acid) microspheres loaded with holmium-166 acetylacetonate (166Ho-PLLA-MS) are a novel microdevice for intra-arterial radio-embolization in patients with unresectable liver malignancies. The neutron activation in a nuclear reactor, in particular the gamma heating, damages the 166Ho-PLLA-MS. The degree of damage is dependent on the irradiation characteristics and irradiation time in a particular reactor facility. The aim of this study was to standardize and objectively validate the activation procedure in a particular reactor. The methods included light- and scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry, viscometry, thermal neutron flux measurements and energy deposition calculations. Seven hours-neutron irradiation results in sufficient specific activity of the 166Ho-PLLA-MS while structural integrity is preserved. Neutron flux measurements and energy deposition calculations are required in the screening of other nuclear reactors. For the evaluation of microsphere quality, light microscopy, SEM and particle size analysis are appropriate techniques.

Purpose: The aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter., Methods: Microspheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT)., Results: Microspheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT., Conclusions: HoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration.

Background: Cerebral embolization models have been hindered by the fact that delivery is predominantly one-sided and cannot be quantified easily. We have developed a model for bilateral cerebral micro-embolization. By using holmium microspheres, it is possible to quantify intracerebral delivery using MRI., Methods: To validate the quantification of holmium microspheres a phantom study was performed in which concentration of microspheres in solution was compared with the number of holmium-induced artifacts on MRI. After that identical microspheres were administered by unilateral injection in the carotid artery, while the opposite carotid artery was clamped. On post-injection MRI scans, intracerebral delivery and right/left distribution of the microspheres was determined., Results: In the phantom study it was shown that quantification by MRI is possible and that MRI artifacts represent single microspheres. In the rat brain, about one-third of the injected dose was consistently located on the contralateral side. The administration was reproducible regarding distribution and number of microspheres., Conclusions: The use of holmium microspheres enables quantification of delivered dose as single microspheres induce artifacts on MRI. By clamping the contralateral carotid artery, one-third of the dose is diverted to the contralateral hemisphere.

This work demonstrates both theoretically and experimentally that multiple gradient-echo sampling of free induction decay (MGEFID) is superior to MGE sampling of spin echo (MGESE) for T2*-based quantification of holmium-loaded microspheres (HoMS). An interleaved sampling strategy was applied in great detail to characterize the MR signal behavior of FID and SE signals of gels and perfused rabbit livers containing HoMS in great detail. Diffusion sensitivity was demonstrated for MGESE sampling, resulting in non-exponential signal decay on both sides of the SE peak and in an underestimation of the HoMS concentration. Other than MGESE sampling, MGEFID sampling was demonstrated to be insensitive to diffusion, to exhibit exponential signal decay, and to allow accurate T2*-based quantification of HoMS. Furthermore, a fit procedure was proposed extending the upper limit of quantifiable R2* relaxation rates to at least 1500 sec(-1). With this post-processing step incorporated, MGEFID was shown to correctly estimate the integral amount of inhomogeneously distributed HoMS in liver tissue, up to a clinically relevant limit. All experimental findings could be explained with the theory of nuclear magnetic resonance (NMR) signal behavior in magnetically inhomogeneous tissues. HoMS were shown to satisfy the static dephasing regime when investigated with MGEFID and to violate the static dephasing conditions for MGESE at longer echo times typically used in SE., ((c) 2008 Wiley-Liss, Inc.)

Purpose: The aim of this study is to evaluate the toxicity of holmium-166 poly(L-lactic acid) microspheres administered into the hepatic artery in pigs., Methods: Healthy pigs (20-30 kg) were injected into the hepatic artery with holmium-165-loaded microspheres ((165)HoMS; n=5) or with holmium-166-loaded microspheres ((166)HoMS; n=13). The microspheres' biodistribution was assessed by single-photon emission computed tomography and/or MRI. The animals were monitored clinically, biochemically, and ((166)HoMS group only) hematologically over a period of 1 month ((165)HoMS group) or over 1 or 2 months ((166)HoMS group). Finally, a pathological examination was undertaken., Results: After microsphere administration, some animals exhibited a slightly diminished level of consciousness and a dip in appetite, both of which were transient. Four lethal adverse events occurred in the (166)HoMS group due either to incorrect administration or comorbidity: inadvertent delivery of microspheres into the gastric wall (n=2), preexisting gastric ulceration (n=1), and endocarditis (n=1). AST levels were transitorily elevated post-(166)HoMS administration. In the other blood parameters, no abnormalities were observed. Nuclear scans were acquired from all animals from the (166)HoMS group, and MRI scans were performed if available. In pigs from the (166)HoMS group, atrophy of one or more liver lobes was frequently observed. The actual radioactivity distribution was assessed through ex vivo (166m)Ho measurements., Conclusion: It can be concluded that the toxicity profile of HoMS is low. In pigs, hepatic arterial embolization with (166)HoMS in amounts corresponding with liver-absorbed doses of over 100 Gy, if correctly administered, is not associated with clinically relevant side effects. This result offers a good perspective for upcoming patient trials.

The aim of this study was to get insight into the toxic effects of holmium-166-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) which have very interesting features for treatment of liver malignancies. Acute, mid- and long-term effects were studied in healthy Wistar rats by evaluating clinical, biochemical and tissue response. Rats were divided into four treatment groups: sham, decayed neutron-irradiated Ho-PLLA-MS, non-irradiated Ho-PLLA-MS and PLLA-MS. After implantation of the microspheres into the liver of the rats, the animals were monitored (body weight, temperature and liver enzymes) for a period of 14-18 months. Some of the rats that received previously neutron-irradiated Ho-PLLA-MS were periodically scanned with magnetic resonance imaging (MRI) to see if holmium was released from the microspheres. After sacrifice, the liver tissue was histologically evaluated. Bone tissue was subjected to neutron-activation analysis in order to examine whether accumulation of released holmium in the bone had occurred. No measurable clinical and biochemical toxic effects were observed in any of the treatment groups. Furthermore, histological analyses of liver tissue samples only showed signs of a slight chronic inflammation and no significant differences in the tissue reaction between rats of the different treatment groups could be observed. The non-irradiated PLLA-MS and Ho-PLLA-MS stayed intact during the study. In contrast, 14 months after administration, the neutron-irradiated Ho-PLLA-MS was not completely spherical anymore, indicating that degradation had started. However, the holmium loading had not been released as was illustrated with MRI and affirmed by neutron-activation analysis of bone tissue. In conclusion, neutron-irradiated Ho-PLLA-MS does not provoke any toxic reaction and can be applied safely in vivo.

In this paper the preparation and characterization of holmium-loaded alginate microspheres is described. The rapid development of medical imaging techniques offers new opportunities for the visualisation of (drug-loaded) microparticles. Therefore, suitable imaging agents have to be incorporated into these particles. For this reason, the element holmium was used in this study in order to utilize its unique imaging characteristics. The paramagnetic behaviour of this element allows visualisation with MRI and holmium can also be neutron-activated resulting in the emission of gamma-radiation, allowing visualisation with gamma cameras, and beta-radiation, suitable for therapeutic applications. Almost monodisperse alginate microspheres were obtained by JetCutter technology where alginate droplets of a uniform size were hardened in an aqueous holmium chloride solution. Ho(3+) binds via electrostatic interactions to the carboxylate groups of the alginate polymer and as a result alginate microspheres loaded with holmium were obtained. The microspheres had a mean size of 159 microm and a holmium loading of 1.3 +/- 0.1% (w/w) (corresponding with a holmium content based on dry alginate of 18.3 +/- 0.3% (w/w)). The binding capacity of the alginate polymer for Ho(3+) (expressed in molar amounts) is equal to that for Ca(2+), which is commonly used for the hardening of alginate. This indicates that Ho(3+) has the same binding affinity as Ca(2+). In line herewith, dynamic mechanical analyses demonstrated that alginate gels hardened with Ca(2+) or Ho(3+) had similar viscoelastic properties. The MRI relaxation properties of the microspheres were determined by a MRI phantom experiment, demonstrating a strong R(2)* effect of the particles. Alginate microspheres could also be labelled with radioactive holmium by adding holmium-166 to alginate microspheres, previously hardened with calcium (labelling efficiency 96%). The labelled microspheres had a high radiochemical stability (94% after 48 h incubation in human serum), allowing therapeutic applications for treatment of cancer. The potential in vivo application of the microspheres for a MR-guided renal embolization procedure was illustrated by selective administration of microspheres to the left kidney of a pig. Anatomic MR-imaging showed the presence of holmium-loaded microspheres in the kidney. In conclusion, this study demonstrates that the incorporation of holmium into alginate microspheres allows their visualisation with a gamma camera and MRI. Holmium-loaded alginate microspheres can be used therapeutically for embolization and, when radioactive, for local radiotherapy of tumours., (Copyright 2007 Wiley Periodicals, Inc.)

Ho-166 is a combined beta-gamma emitter of which the betas can be used therapeutically. From the 81 keV gammas of Ho-166, SPECT images can be obtained, which give opportunities to guide Ho-166 therapy. Accurate reconstruction of Ho-166 images is currently hampered by photopeak-scatter in the patient, down-scatter in the detector, collimator and patient caused by the 1.4 MeV photons and by bremsstrahlung. We developed and validated a method for quantitative SPECT of Ho-166 that involves correction for both types of scatter plus non-uniform attenuation correction using attenuation maps. Photopeak-scatter (S) is compensated for by a rapid 3D Monte Carlo (MC) method that is incorporated in ordered subset (OS) reconstruction of the emission data, together with simultaneous correction for attenuation (A) and detector response (D); this method is referred to as OS-ADS. Additionally, for correction of down-scatter, we use a 14 keV wide energy window centred at 118 keV (OS-ADSS). Due to a limited number of available energy windows, the same 118 keV energy window was used for down-scatter correction of the simultaneously acquired Gd-153 transmission data. Validations were performed using physical phantom experiments carried out on a dual-head SPECT system; Gd-153 transmission line sources were used for acquiring attenuation maps. For quantitative comparison of OS-ADS and OS-ADSS, bottles filled with Ho-166 were placed in both a cylindrical phantom and an anthropomorphic thorax phantom. Both OS-ADS and OS-ADSS were compared with an ordered subset reconstruction without any scatter correction (OS-AD). Underestimations of about 20% in the attenuation map were reduced to a few per cent after down-scatter correction. The average deviation from the true activity contained in the bottles was +72% with OS-AD. Using OS-ADS, this average overestimation was reduced to +28% and with OS-ADSS the deviation was further reduced to 16%. With OS-AD and OS-ADS, these numbers were more sensitive to the choice of volumes of interest than with OS-ADSS. For the reconstructed activity distributions, erroneous background activity found with OS-AD was reduced by a factor of approximately 2 by applying OS-ADS and reduced by a factor of approximately 4 by applying OS-ADSS. The combined attenuation, photopeak-scatter and down-scatter correction framework proposed here greatly enhanced the quantitative accuracy of Ho-166 imaging, which is of the uppermost importance for image-guided therapies. It is expected that the method, with adapted window settings, also can be applied to other isotopes with high energy peaks that contaminate the photopeak data, such as I-131 or In-111.

The clinical application of holmium-loaded poly(L-lactic acid) (PLLA) microspheres for the radionuclide treatment of liver malignancies requires in depth understanding of the degradation characteristics of the microspheres. To this end, an in-vitro degradation study was conducted. PLLA-microspheres with and without HoAcAc loading, and before and after neutron or gamma irradiation, were incubated in a phosphate buffer at 37 degrees C for 12 months. In contrast with the other microsphere formulations, only the neutron-irradiated Ho-PLLA-MS disintegrated. At the end of the experiment (52 weeks) highly crystalline fragments, as evidenced from Differential Scanning Calorimetry, were present. Infrared spectroscopy showed that these fragments consisted of holmium lactate. In conclusion, this study demonstrates that the degradation of neutron-irradiated Ho-PLLA-MS was substantially accelerated by the HoAcAc incorporation and subsequent neutron irradiation. The degradation of these microspheres in aqueous solution resulted in the formation of insoluble holmium lactate microcrystals without release of Ho3+.

Radioactive holmium-166 loaded poly(L-lactic acid) microspheres are promising systems for the treatment of liver malignancies. The microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method. After preparation, the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. In this paper, the aspects of the production of a (relatively) large-scale GMP batch (4 g, suitable for treatment of 5-10 patients) of Ho-PLLA-MS are described. The critical steps of the Ho-PLLA-MS production process (sieving procedure, temperature control during evaporation and raw materials) were considered and the pharmaceutical quality of the microspheres was evaluated. The pharmaceutical characteristics (residual solvents, possible bacterial contaminations and endotoxins) of the produced Ho-PLLA-MS batches were in compliance with the requirements of the European Pharmacopoeia. Moreover, neutron irradiated Ho-PLLA-MS retained their morphological integrity and the holmium remained stably associated with the microspheres; it was observed that after 270h (10 times the half-life of Ho-166) only 0.3+/-0.1% of the loading was released from the microspheres in an aqueous solution. In conclusion, Ho-PLLA-MS which are produced as described in this paper, can be clinically applied, with respect to their pharmaceutical quality.

Radioactive holmium-166-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) are promising systems for the treatment of liver malignancies. The surface characteristics of Ho-PLLA-MS before and after both neutron and gamma irradiation were investigated in order to get insight into their suspending behaviour and to identify suitable surfactants for clinical application of these systems. X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) were used for surface characterization. The residual amounts of poly(vinyl alcohol) (PVA) of the microspheres, which was used as an emulsifier during the solvent evaporation process, were determined using a colorimetric iodine-borate method and the wettability of microspheres and PLLA films with and without holmium (Ho) loading was tested using suspending experiments and contact angle measurements. XPS showed that the surface of Ho-PLLA-MS mainly consisted of PLLA, less than 10% of the surface was covered with PVA after several washing and sieving steps. A colorimetric assay showed that the microspheres contained 0.2-0.3% (w/w) PVA. Combined with XPS data, this assay demonstrates that the PVA is likely dissolved in the core of the microspheres. XPS analysis also showed that after neutron irradiation, some holmium appeared on the surface. Moreover, Ho-loaded PLLA films had a much higher contact angle (85 degrees) than non-loaded films (70 degrees). Therefore, the Ho on the surface of neutron-irradiated Ho-PLLA-MS is probably the reason for their poor suspending behaviour in saline. No surface changes were seen with XPS after gamma irradiation. Based on their surface characteristics, a pharmaceutically acceptable solvent (1% Pluronic F68 or F127 in 10% ethanol) was formulated with which a homogeneous suspension of radioactive Ho-PLLA-MS could be easily obtained, making these systems feasible for further clinical evaluation.

In internal radiation therapy of unresectable liver tumors, microspheres containing a radionuclide are injected in the hepatic artery to achieve a preferential deposition of microspheres in the lesions. In this study, MR imaging techniques for qualitative and quantitative assessment of the biodistribution of holmium-loaded microspheres (HoMS) were investigated for their use in selective internal radiation therapy of liver tumors. To achieve this goal, the relaxivity of HoMS was first investigated in gel experiments. The resultant calibration curve was subsequently employed to quantify the biodistribution of HoMS administered to 13 excised rabbit livers and to the livers of 3 live rabbits with an implanted tumor. Finally, the feasibility of MR imaging of the biodistribution during treatment of a large animal was investigated by MR imaging of hepatic administration of HoMS to a live pig. Overall, the study showed that MRI can clearly depict the biodistribution of HoMS, but that quantification by means of the gel calibration curve yields an underestimation that increases for higher amounts of HoMS. The observed underestimation is tentatively attributed to accumulations of HoMS in larger liver vessels. The exploratory quantification experiments suggest the feasibility of MR dosimetry., (Copyright 2004 Wiley-Liss, Inc.)

Holmium-loaded microspheres are useful systems in radio-embolization therapy of liver metastases. For administration to a patient, the holmium-loaded microspheres have to be irradiated in a nuclear reactor to become radioactive. In this paper. the influence of neutron irradiation on poly(L-lactic acid) (PLLA) microspheres and films, with or without holmium acetylacetonate (HoAcAc), is investigated, in particular using differential scanning calorimetry (MDSC), scanning electron microscopy, gel permeation chromatography (GPC), infrared spectroscopy, and X-ray diffraction. After irradiation of the microspheres, only minor surface changes were seen using scanning electron microscopy, and the holmium complex remained immobilized in the polymer matrix as reflected by a relatively small release of this complex. GPC and MDSC measurements showed a decrease in molecular weight and crystallinity of the PLLA, respectively, which can be ascribed to radiation induced chain scission. Irradiation of the HoAcAc loaded PLLA matrices resulted in evaporation of the non-coordinated and one coordinated water molecule of the HoAcAc complex, as evidenced by MDSC and X-ray diffraction analysis. Infrared spectroscopy indicated that some degradation of the acetylacetonate anion occurred after irradiation. Although some radiation induced damage of both the PLLA matrix and the embedded HoAcAc-complex occurs, the microspheres retain their favourable properties (no marginal release of Ho, preservation of the microsphere size), which make these systems interesting candidates for the treatment of tumours by radio-embolization.

Holmium-loaded PLLA microspheres are useful systems in radioembolization therapy of liver metastases because of their low density, biodegradability and favourable radiation characteristics. Neutron activated Ho-loaded microspheres showed a surprisingly low release of the relatively small holmium complex. In this paper factors responsible for this behaviour are investigated, in particular by the use of differential scanning calorimetry, scanning electron microscopy, infrared spectroscopy and X-ray diffraction. The holmium complex is soluble in PLLA up to 8% in films and 17% in microspheres. Interactions between carbonyl groups of PLLA, and the Ho-ion in the HoAcAc complex, explain very satisfactorily the high stability of holmium-loaded microspheres.

A total of 22 NZW rabbits with VX2 squamous cell carcinomas transplanted into the auricles were intra-arterially (i.a.) embolized with radioactive or inactive holmium-labelled poly(L-lactic acid) (HoPLA) microspheres with a mean diameter of 38-80 microm. The effects on tumour growth, the efficiency of i.a. infusion, the efficacy of retention of microspheres in the primary tumour and the excretion of free holmium-166 were analyzed. Complete tumour remissions were obtained in 79% and 86% following embolization with radioactive and inactive microspheres, respectively. Over 95% of the microspheres were retained in the tumour and the leaching of holmium-166 in urine and faeces was less than 0.1% in 2 days. The injection efficiency was not optimal, as 40% of the microspheres were retained in the cannulation system. Arterio-arteriolar connections should be detected and closed prior to embolization to prevent stray emboli from entering the brain. It is concluded that 166HoPLA microspheres are promising candidates for further studies on radio-embolization of unresectable head-and-neck cancer.

Since one of the most frequent sites of human metastatic cancer is the liver, particularly in colon and rectum carcinoma, there is a special need for the development of an effective therapy. This study describes the parameters for reproducible production of poly lactic acid (PLA) microspheres with an average diameter of 37 microm and labelled with neutron-activated holmium-166 (Emax=1.84 MeV, t1/2=26. 8 h), suitable for use in internal radionuclide therapy of liver metastases. It is demonstrated that holmium-loaded PLA microspheres can be prepared by a relatively simple method, with incorporation of 17.0%+/-0.6% holmium (n=5), and that 20 GBq can be obtained from 400 mg neutron activatable microspheres. In order to produce this high amount of activity, the microspheres must be free of water and irradiation must be performed in a polyethylene vial, with a relatively low neutron flux (5x10(13) cm-2 s-1) within 1 h. Under these well-defined conditions minor surface changes were seen which barely affected total volume and consequently total radioactivity of the microspheres with a diameter of 20-50 microm. Overall structural integrity was maintained in terms of form and size. In vitro analyses showed that >99.3% of 166Ho activity was retained in the microspheres after 192 h incubation in PBS, plasma and leucocytes, while in liver homogenate retention was still 98.4%.