Adjuvant holmium-166 radioembolization after radiofrequency ablation in early-stage hepatocellular carcinoma patients: a dose-finding study (HORA EST HCC trial).

PURPOSE: The aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as adjuvant therapy after RFA of HCC 2-5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of ≥ 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume). METHODS: In this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2-5 cm, RFA was followed by (super-)selective infusion of 166Ho-MS on day 5-10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of 166Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of ≥ 120 Gy in 9/10 patients within a cohort. RESULTS: Twelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3-71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1-4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127-145]). No local recurrences were found within 1-year follow-up. CONCLUSION: Adjuvant (super-)selective infusion of 166Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of ≥ 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2-5 cm. TRIAL REGISTRATION: Clinicaltrials.gov NCT03437382 . (registered: 19-02-2018).

Intraprocedural MRI-based dosimetry during transarterial radioembolization of liver tumours with holmium-166 microspheres (EMERITUS-1): a phase I trial towards adaptive, image-controlled treatment delivery.

PURPOSE: Transarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 (166Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing 166Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry. METHODS: Six patients were treated with 166Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, 166Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for 166Ho TARE. RESULTS: Administration of 166Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3-4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend. CONCLUSION: This study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization. REGISTRATION: Clinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

To 1000 Gy and back again: a systematic review on dose-response evaluation in selective internal radiation therapy for primary and secondary liver cancer.

PURPOSE: To systematically review all current evidence into the dose-response relation of yttrium-90 and holmium-166 selective internal radiation therapy (SIRT) in primary and secondary liver cancer. METHODS: A standardized search was performed in PubMed (MEDLINE), Embase, and the Cochrane Library in order to identify all published articles on dose-response evaluation in SIRT. In order to limit the results, all articles that investigated SIRT in combination with other therapy modalities (such as chemotherapy) were excluded. RESULTS: A total of 3038 records were identified of which 487 were screened based on the full text. Ultimately, 37 studies were included for narrative analysis. Meta-analysis could not be performed due to the large heterogeneity in study and reporting designs. Out of 37 studies, 30 reported a 'mean dose threshold' that needs to be achieved in order to expect a response. This threshold appears to be higher for hepatocellular carcinoma (HCC, 100-250 Gy) than for colorectal cancer metastases (CRC, 40-60 Gy). Reported thresholds tend to be lower for resin microspheres than when glass microspheres are used. CONCLUSION: Although the existing evidence demonstrates a dose-response relationship in SIRT for both primary liver tumours and liver metastases, many pieces of the puzzle are still missing, hampering the definition of standardized dose thresholds. Nonetheless, most current evidence points towards a target mean dose of 100-250 Gy for HCC and 40-60 Gy for CRC. The field would greatly benefit from a reporting standard and prospective studies designed to elucidate the dose-response relation in different tumour types.

Characterization of holmium(iii)-acetylacetonate complexes derived from therapeutic microspheres by infrared ion spectroscopy.

Microspheres containing radioactive 166holmium-acetylacetonate are employed in emerging radionuclide therapies for the treatment of malignancies. At the molecular level, details on the coordination geometries of the Ho complexes are however elusive. Infrared ion spectroscopy (IRIS) was used to characterize several 165Ho-acetylacetonate complexes derived from non-radioactive microspheres. The coordination geometry of four distinct ionic complexes were fully assigned by comparison of their measured IR spectra with spectra calculated at the density functional theory (DFT) level. The coordination of each acetylacetonate ligand is dependent on the presence of other ligands, revealing an asymmetric chelation motif in some of the complexes. A fifth, previously unknown constituent of the microspheres was identified as a coordination complex containing an acetic acid ligand. These results pave the way for IRIS-based identification of microsphere constituents upon neutron activation of the metal center.

New insights into the HIFU-triggered release from polymeric micelles.

Continuous wave (CW), low frequency, high intensity focused ultrasound (HIFU) is a promising modality to trigger release of active compounds from polymeric micelles. The aim of the present study was to investigate whether high frequency CW as well as pulsed wave (PW) HIFU can induce the release of a hydrophobic agent from non-cross-linked (NCL) and core cross-linked (CCL) poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) micelles. It was shown that high frequency CW as well as PW HIFU was able to trigger the release (up to 85%) of a hydrophobic compound (i.e., nile red, NR) from NCL and CCL micelles. No changes in size distribution of the micelles after CW and PW HIFU exposure were observed and no degradation of polymer chain had occurred. We therefore hypothesize that the polymeric micelles are temporally destabilized upon HIFU exposure due to radiation force induced shear forces, leading to NR release on demand.

Improving MRI-based dosimetry for holmium-166 transarterial radioembolization using a nonrigid image registration for voxelwise Δ R 2 ∗ $\Delta R_2

BACKGROUND: Transarterial radioembolization (TARE) is a treatment modality for liver tumors during which radioactive microspheres are injected into the hepatic arterial system. These microspheres distribute throughout the liver as a result of the blood flow until they are trapped in the arterioles because of their size. Holmium-166 (166 Ho)-loaded microspheres used for TARE can be visualized and quantified with MRI, as holmium is a paramagnetic metal and locally increases the transverse relaxation rate R 2 ∗ $R_2^*$ . The current 166 Ho quantification method does not take regional differences in baseline R 2 ∗ $R_2^*$ values (such as between tumors and healthy tissue) into account, which intrinsically results in a systematic error in the estimated absorbed dose distribution. As this estimated absorbed dose distribution can be used to predict response to treatment of tumors and potential toxicity in healthy tissue, a high accuracy of absorbed dose estimation is required. PURPOSE: To evaluate pre-existing differences in R 2 ∗ $R_2^*$ distributions between tumor tissue and healthy tissue and assess the feasibility and accuracy of voxelwise subtraction-based Δ R 2 ∗ $\Delta R_2^*$ calculation for MRI-based dosimetry of holmium-166 transarterial radioembolization (166 Ho TARE). METHODS: MRI data obtained in six patients who underwent 166 Ho TARE of the liver as part of a clinical study was retrospectively evaluated. Pretreatment differences in R 2 ∗ $R_2^*$ distributions between tumor tissue and healthy tissue were characterized. Same-day pre- and post-treatment R 2 ∗ $R_2^*$ maps were aligned using a deformable registration algorithm and subsequently subtracted to generate voxelwise Δ R 2 ∗ $\Delta R_2^*$ maps and resultant absorbed dose maps. Image registration accuracy was quantified using the dice similarity coefficient (DSC), relative overlay (RO), and surface dice (≤4 mm; SDSC). Voxelwise subtraction-based absorbed dose maps were quantitatively (root-mean-square error, RMSE) and visually compared to the current MRI-based mean subtraction method and routinely used SPECT-based dosimetry. RESULTS: Pretreatment R 2 ∗ $R_2^*$ values were lower in tumors than in healthy liver tissue (mean 36.8 s-1 vs. 55.7 s-1 , P = 0.004). Image registration improved the mean DSC of 0.83 (range: 0.70-0.88) to 0.95 (range: 0.92-0.97), mean RO of 0.71 (range 0.53-0.78) to 0.90 (range: 0.86-0.94), and mean SDSC ≤4 mm of 0.47 (range: 0.28-0.67) to 0.97 (range: 0.96-0.98). Voxelwise subtraction-based absorbed dose maps yielded a higher tumor-absorbed dose (median increase of 9.0%) and lower healthy liver-absorbed dose (median decrease of 13.8%) compared to the mean subtraction method. Voxelwise subtraction-based absorbed dose maps corresponded better to SPECT-based absorbed dose maps, reflected by a lower RMSE in three of six patients. CONCLUSIONS: Voxelwise subtraction presents a robust alternative method for MRI-based dosimetry of 166 Ho microspheres that accounts for pre-existing R 2 ∗ $R_2^*$ differences, and appears to correspond better with SPECT-based dosimetry compared to the currently implemented mean subtraction method.

Radioactive holmium acetylacetonate microspheres for interstitial microbrachytherapy: an in vitro and in vivo stability study.

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.

Study Protocol: Adjuvant Holmium-166 Radioembolization After Radiofrequency Ablation in Early-Stage Hepatocellular Carcinoma Patients-A Dose-Finding Study (HORA EST HCC Trial).

PURPOSE: To investigate the biodistribution of holmium-166 microspheres (166Ho-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to establish a perfused liver administration dose that results in a tumoricidal dose of holmium-166 on the hyperaemic zone around the ablation necrosis (i.e. target volume). MATERIALS AND METHODS: This is a multicentre, prospective, dose-escalation study in HCC patients with a solitary lesion 2-5 cm, or a maximum of 3 lesions of ≤ 3 cm each. The day after RFA patients undergo angiography and cone-beam CT (CBCT) with (super)selective infusion of technetium-99 m labelled microalbumin aggregates (99mTc-MAA). The perfused liver volume is segmented from the CBCT and 166Ho-MS is administered to this treatment volume 5-10 days later. The dose of holmium-166 is escalated in a maximum of 3 patient cohorts (60 Gy, 90 Gy and 120 Gy) until the endpoint is reached. SPECT/CT is used to determine the biodistribution of holmium-166. The endpoint is met when a dose of ≥ 120 Gy has been reached on the target volume in 9/10 patients of a cohort. Secondary endpoints include toxicity, local recurrence, disease-free and overall survival. DISCUSSION: This study aims to find the optimal administration dose of adjuvant radioembolization with 166Ho-MS after RFA. Ultimately, the goal is to bring the efficacy of thermal ablation up to par with surgical resection for early-stage HCC patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03437382.

Development of an MRI-Guided Approach to Selective Internal Radiation Therapy Using Holmium-166 Microspheres.

Selective internal radiation therapy (SIRT) is a treatment modality for liver tumours during which radioactive microspheres are injected into the hepatic arterial tree. Holmium-166 (166Ho) microspheres used for SIRT can be visualized and quantified with MRI, potentially allowing for MRI guidance during SIRT. The purpose of this study was to investigate the MRI compatibility of two angiography catheters and a microcatheter typically used for SIRT, and to explore the detectability of 166Ho microspheres in a flow phantom using near real-time MRI. MR safety tests were performed at a 3 T MRI system according to American Society for Testing of Materials standard test methods. To assess the near real-time detectability of 166Ho microspheres, a flow phantom was placed in the MRI bore and perfused using a peristaltic pump, simulating the flow in the hepatic artery. Dynamic MR imaging was performed using a 2D FLASH sequence during injection of different concentrations of 166Ho microspheres. In the safety assessment, no significant heating (ΔTmax 0.7 °C) was found in any catheter, and no magnetic interaction was found in two out of three of the used catheters. Near real-time MRI visualization of 166Ho microsphere administration was feasible and depended on holmium concentration and vascular flow speed. Finally, we demonstrate preliminary imaging examples on the in vivo catheter visibility and near real-time imaging during 166Ho microsphere administration in an initial patient case treated with SIRT in a clinical 3 T MRI. These results support additional research to establish the feasibility and safety of this procedure in vivo and enable the further development of a personalized MRI-guided approach to SIRT.

Polymeric micelles in anticancer therapy: targeting, imaging and triggered release.

Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward.

Holmium nanoparticles: preparation and in vitro characterization of a new device for radioablation of solid malignancies.

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.

Unilateral intracarotid injection of holmium microspheres to induce bilateral MRI-validated cerebral embolization in rats.

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.

The various therapeutic applications of the medical isotope holmium-166: a narrative review.

Over the years, a broad spectrum of applications of the radionuclide holmium-166 as a medical isotope has been established. The isotope holmium-166 is attractive as it emits high-energy beta radiation which can be used for a therapeutic effect and gamma radiation which can be used for nuclear imaging purposes. Furthermore, holmium-165 can be visualized by MRI because of its paramagnetic properties and by CT because of its high density. Since holmium-165 has a natural abundance of 100%, the only by-product is metastable holmium-166 and no costly chemical purification steps are necessary for production of nuclear reactor derived holmium-166. Several compounds labelled with holmium-166 are now used in patients, such Ho166-labelled microspheres for liver malignancies, Ho166-labelled chitosan for hepatocellular carcinoma (HCC) and [166Ho]Ho DOTMP for bone metastases. The outcomes in patients are very promising, making this isotope more and more interesting for applications in interventional oncology. Both drugs as well as medical devices labelled with radioactive holmium are used for internal radiotherapy. One of the treatment possibilities is direct intratumoural treatment, in which the radioactive compound is injected with a needle directly into the tumour. Numerous other applications have been developed, like patches for treatment of skin cancer and holmium labelled antibodies and peptides. The second major application that is currently clinically applied is selective internal radiation therapy (SIRT, also called radioembolization), a novel treatment option for liver malignancies. This review discusses medical drugs and medical devices based on the therapeutic radionuclide holmium-166.

Production of novel diagnostic radionuclides in small medical cyclotrons.

The global network of cyclotrons has expanded rapidly over the last decade. The bulk of its industrial potential is composed of small medical cyclotrons with a proton energy below 20 MeV for radionuclides production. This review focuses on the recent developments of novel medical radionuclides produced by cyclotrons in the energy range of 3 MeV to 20 MeV. The production of the following medical radionuclides will be described based on available literature sources: Tc-99 m, I-123, I-124, Zr-89, Cu-64, Ga-67, Ga-68, In-111, Y-86 and Sc-44. Remarkable developments in the production process have been observed in only some cases. More research is needed to make novel radionuclide cyclotron production available for the medical industry.

Long-term toxicity of holmium-loaded poly(L-lactic acid) microspheres in rats.

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.

Intratumoral treatment with radioactive beta-emitting microparticles: a systematic review.

PURPOSE: The purpose of this study was to review the role of radioactive microparticles (1-100 µm) for the treatment of solid tumors and provide a comprehensive overview of the feasibility, safety, and efficacy. METHODS: A systematic search was performed in MEDLINE, EMBASE, and The Cochrane Library (January 2017) by combining synonyms for the determinants "tumor," "injection," and "radionuclide." Data on injection technique, toxicity, tumor response, and survival were collected. RESULTS: The search yielded 7271 studies, and 37 were included for analysis. Twelve studies were performed in human patients and 25 animal studies. The studies were heterogeneous in patient population, tumors, follow-up time, and treatment characteristics. The direct intratumoral injection of radioactive microparticles resulted in a response rate of 71% in a variety of tumors and uncomplicated procedures with high cumulative doses of >19,000 Gy were reported. CONCLUSION: The large variety of particles, techniques, and treated tumors in the studies provided an important insight into issues concerning efficacy, safety, particle and isotope choice, and other concepts for future research. Animal studies showed efficacy and a dose response. Most studies in humans concluded that intratumoral treatment with radioactive beta-emitting microparticles is relatively safe and effective. Conflicting evidence about safety and efficacy might be explained by the considerable variation in the treatment characteristics. Larger particles had a better retention which resulted in higher anti-tumor effect. Leakage seems to follow the path of least resistance depending on anatomical structures. Subsequently, a grid-like injection procedure with small volume depots is advised over a single large infusion. Controlled image-guided treatment is necessary because inadequate local delivery and inhomogeneous dose distribution result in reduced treatment efficacy and in potential complications.

Hybrid scatter correction applied to quantitative holmium-166 SPECT.

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.

Holmium-lipiodol-alginate microspheres for fluoroscopy-guided embolotherapy and multimodality imaging.

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.

Evidence for a new mechanism behind HIFU-triggered release from liposomes.

A promising approach for local drug delivery is high-intensity focused ultrasound (HIFU)-triggered release of drugs from stimuli-responsive nanoparticles such as liposomes. The aim of this study was to investigate whether another release mechanism is involved with HIFU-triggered release from liposomes beside cavitation and temperature. Furthermore, it was studied whether this new release mechanism allows the release of lipophilic compounds. Therefore, both a lipophilic (Nile red) and a hydrophilic (fluorescein) compound were loaded into thermosensitive (TSL) or non-thermosensitive liposomes (NTSL) and the liposomes were subjected both to continuous wave (CW)- and pulsed wave (PW)-HIFU. The mean liposome size varied from 97 to 139 nm with a polydispersity index (PDI)≤0.06 for the different formulations. The Tm of the phospholipid bilayer of the TSL was around 42°C. Approximately 80% of fluorescein was released within 15 min from TSL at temperatures≥42°C. In contrast, no fluorescein release from NTSL and NR release from both TSL and NTSL was observed at temperatures up to 60 °C. CW-HIFU exposure of TSL resulted in rapid temperature elevation up to 52°C and subsequently almost quantitative fluorescein release. Fluorescein release from NTSL was also substantial (~64% after 16 min at 20 W). Surprisingly, CW-HIFU exposure (20W for 16 min) resulted in the release of NR from TSL (~66% of the loaded amount), and this was even higher from NTSL (~78%). PW-HIFU exposure did not result in temperatures above the Tm of TSL. However, nearly 85% of fluorescein was released from TSL after 32 min at 20W of PW-HIFU exposure, whereas the release from NTSL was around 27%. Interestingly, NR release from NTSL was~30% after 2 min PW-HIFU exposure and increased to~70% after 32 min. Furthermore, addition of microbubbles to the liposomes prior to PW-HIFU exposure did not result in more release, which suggests that cavitation can be excluded as the main mechanism responsible for the triggered release of both a hydrophilic and a lipophilic model compound from liposomes. Dynamic light scattering analysis showed that the mean size and PDI of the liposomes did not significantly change after CW- and PW-HIFU exposure. Taken together, it is therefore concluded that neither temperature elevation nor inertial cavitation is essential for the release of both hydrophilic and lipophilic compounds from liposomes. It is assumed that the release originates from radiation force-induced acoustic streaming, causing the liposomes to collide at the walls of the exposure chamber leading to shear forces which in turn results in reversible liposome destabilization and release of both hydrophilic and lipophilic compounds.

Alginate-lanthanide microspheres for MRI-guided embolotherapy.

In cancer therapy, a promising treatment option to accomplish a high tumor-to-normal-tissue ratio is endovascular intervention with microsized particles, such as embolotherapy. In this study, alginate microspheres (ams) were prepared with the JetCutter technique, which is based on cutting a sodium alginate solution jet stream into small droplets of uniform size which are then cross-linked with different lanthanides or iron-III, resulting in microspheres of a predefined size which can be visualized by magnetic resonance imaging (MRI). The microspheres were investigated for their size and morphology (light microscopy and scanning electron microscopy analysis), cation content and MRI properties. The lanthanide-ams formulations, with a uniform size of 250 µm and a cation content between 0.72-0.94%, showed promising results for MR imaging. This was further demonstrated for Ho(3+)-cross-linked alginate microspheres (Ho(3+)-ams), the most potent microsphere formulation with respect to MR visualization, allowing single sphere detection and detailed microsphere distribution examination. Intravascular infusion of Ho(3+)-ams by catherization of ex vivo rabbit and porcine liver tissue and assessment of the procedure with MRI clearly showed accumulation and subsequently embolization of the targeted vessels, allowing accurate monitoring of the microsphere biodistribution throughout the tissue. Therefore, the different alginate-lanthanide microsphere formulations developed in this study show great potential for utilization as image-guided embolotherapy agents.