Feasibility of CT quantification of intratumoural 166Ho-microspheres.

BACKGROUND: Microspheres loaded with radioactive 166Ho (166Ho-MS) are novel particles for radioembolisation and intratumoural treatment. Because of the limited penetration of ß radiation, quantitative imaging of microsphere distribution is crucial for optimal intratumoural treatment. Computed tomography (CT) may provide high-resolution and fast imaging of the distribution of these microspheres, with lower costs and widespread availability in comparison with current standard single-photon emission tomography (SPECT) and magnetic resonance imaging. This phantom study investigated the feasibility of CT quantification of 166Ho-MS. METHODS: CT quantification was performed on a phantom with various concentrations of HoCl and Ho-MS to investigate the CT sensitivity and calibrate the CT recovery. 166Ho-MS were injected into ex vivo tissues, in VX-2 cancer-bearing rabbits, and in patients with head-neck cancer, to demonstrate sensitivity and clinical visibility. The amount of Ho-MS was determined by CT scanning, using a density-based threshold method and compared with a validated 166Ho SPECT quantification method. RESULTS: In the phantom, a near perfect linearity (least squares R2 > 0.99) between HU values and concentration of 166Ho was found. Ex vivo tissue experiments showed an excellent correlation (r = 0.99, p < 0.01) between the dose calibrator, SPECT, and CT imaging. CT recovery was on average 86.4% ex vivo, 76.0% in rabbits, and 99.1% in humans. CONCLUSION: This study showed that CT-based quantification of Ho microspheres is feasible and is a high-resolution alternative to SPECT-based determination of their local distribution.

Renal and Intestinal Excretion of 90Y and 166Ho After Transarterial Radioembolization of Liver Tumors.

OBJECTIVE. The aim of this study was to evaluate the amount of free radioactivity in renal and intestinal excretions during the first 48 hours after transarterial radioembolization (TARE) procedures on the liver. SUBJECTS AND METHODS. Urinary, intestinal, and biliary excretions of patients who underwent TARE with three different types of microspheres were collected during a postinterventional period of 48 hours (divided into two 24-hour intervals). Radioactivity measurements were performed. The detected amounts of activity were correlated to clinical and procedural characteristics, times of excretion, and microsphere types. RESULTS. Twenty-four patients were evaluated, 10 treated with 90Y-glass, 10 with 90Y-resin, and four with 166Ho-poly-L-lactic acid (PLLA) microspheres. Activity excretion occurred in all cases. The highest total excretion proportions of the injected activities were 0.011% for 90Y-glass, 0.119% for 90Y-resin, and 0.005% for 166Ho-PLLA microspheres. Intestinal excretion was markedly less than renal excretion (p < 0.001). Excretion after TARE with 90Y-resin was statistically significantly higher than with 90Y-glass or 166Ho-PLLA micro-spheres (p = 0.002). For each microsphere type, the excreted activity was independent of the activity of the injected microspheres. CONCLUSION. Renal and intestinal excretion of radioactivity after TARE is low but not negligible. The radiation risk for individuals interacting with patients can be minimized if contact with urine and bile is avoided, particularly during the first 24 hours after the procedure.

Glucose-holmium for radiotherapy: Characterization and in vitro assays.

BACKGROUND: The existence of saccharide-holmium complexes, containing mono or polysaccharide molecules, is an attractive hypothesis toward a radiation therapy (RT) with beta-emitters targeting high glucose metabolic human sites. To exam such hypothesis, the aim of this study was to investigate the possible chemical interactions of Ho and glucose molecules and if glucose may be a facilitator to holmium cell internalization based on in vitro uptake assays and mass spectrometry analyses. METHODS: The ionic-solution preparations were based on glucose-anhydrous and holmium-nitrate hydrated in aqueous solution, in non-radioactive condition. The uptakes in MDAMB231 cell lineage were evaluated, at 0 and 50 µg mL-1 holmium solution, in incubation times of 10, 30 and 50 min. The measurements of the holmium mass into the dried cell were evaluated by Neutron Activation Analysis - NAA method. Also, the ionic solution was tested in Electrospray Ionization Mass Spectrometry (ESI-MS) in order to identify Ho and glucose interactions. RESULTS: There were intracellular holmium-uptake in MDAMB-231 of 3.6 ±â€¯0.1, 6.8 ±â€¯0.2 and 9.7 ±â€¯0.3 µg increasing linearly with incubation time. The m/z ions at 523, 586, 649, 991 and 1054 were attributed to the positively loaded species containing Ho+3, glucose (GLU) and NO3-, making up the possible molecular compound formulae, involving Ho, GLU, and anions. CONCLUSIONS: The findings of the in vitro assay and the ESI-MS suggested a suitable holmium cell uptake, increased in function of incubation time, due to the presence of glucose and holmium chemical interactions in solution.

Biokinetics of yttrium and comparison with its geochemical twin holmium.

The transition metal yttrium (Y, atomic number 39) is chemically similar to elements in the lanthanide family (atomic numbers 57-71) and is found with the lanthanides in rare earth ores. Yttrium and the lanthanide holmium are referred to as geochemical twins because they generally show little fractionation from metamorphic or weathering processes, due to their closely similar chemical properties and nearly identical ionic radii. Extensive measurements on rocks, soils, and meteorites indicate that the Y/Ho mass concentration ratio rarely falls far from the so-called chondritic or solar system ratio of ∼26. This paper presents a new biokinetic model for yttrium in adult humans and examines whether yttrium and holmium may be biological as well as geochemical twins, considering model-based comparisons of their systemic behaviours in adult humans and model-free comparisons of their concentration ratios in human tissues and various types of vegetation. It appears that yttrium and holmium behave similarly in the human body and that their concentration ratios tend to cluster near the chondritic value in human tissues as well as plants, but the comparative information is too limited and imprecise to determine whether they are extremely close biological analogues.

Drug metabolism: Comparison of biodistribution profile of holmium in three different compositions in healthy Wistar rats.

Radioisotope holmium is a candidate to be used in cancer treatment and diagnosis. There are different holmium salts and they present distinct solubility and consequently different biodistribution profiles. In this work, we aimed to evaluate the biodistribution profiles of two holmium salts (chloride and sulfate) and holmium nanoparticles (oxide) through an in vivo biodistribution assay using animal model. Samples were labeled with technetium-99m and administered in Wistar rats by retro-orbital route. Holmium chloride is highly soluble in water and it was quickly filtered by the kidneys while holmium sulfate that presents lower solubility in water was mainly found in the liver and the spleen. However, both the salts showed a similar biodistribution profile. On the other hand, holmium oxide showed a very different biodistribution profile since it seemed to interact with all organs. Due to its particle size range (approximately 100nm) it was not intensively filtered by the kidneys being found in high quantities in many organs, for this reason its use as a nanoradiopharmaceutical could be promising in the oncology field.

Fate of Organic Functionalities Conjugated to Theranostic Nanoparticles upon Their Activation.

Neutron activation is widely applied for the preparation of radioactive isotopes to be used in imaging and/or therapy. The type of diagnostic/therapeutic agents varies from small chelates coordinating radioactive metal ions to complex nanoparticulate systems. Design of these agents often relies on conjugation of certain organic functionalities that determine their pharmacokinetics, biodistribution, targeting, and cell-penetrating abilities, or simply on tagging them with an optical label. The conjugation chemistry at the surface of nanoparticles and their final purification often require laborious procedures that become even more troublesome when radioactive materials are involved. This study represents a thorough investigation on the effects of neutron activation on the organic moieties of functionalized nanoparticles, with special focus on (166)Ho2O3 particles conjugated with PEG-fluorescein and PEG-polyarginine motives. Spectroscopic and thermogravimetric analyses demonstrate only a limited degradation of PEG-fluorescein upon irradiation of the particles up to 10 h using a thermal neutron flux of 5 × 10(16) m(-2) s(-1). Cell experiments show that the polyarginine-based mechanisms of membrane penetration remain unaltered after exposure of the functionalized particles to the mixed field of neutrons and gammas present during activation. This confirms that radiation damage on the PEG-polyarginines is minimal. Intrinsic radiations from (166)Ho do not seem to affect the integrity of conjugated organic material. These findings open up a new perspective to simplify the procedures for the preparation of functionalized metal-based nanosystems that need to be activated by neutron irradiation in order to be applied for diagnostic and/or therapeutic purposes.

Preliminary dosimetric evaluation of (166)Ho-TTHMP for human based on biodistribution data in rats.

In this work, the absorbed dose to each organ of human for (166)Ho-TTHMP was evaluated based on biodistribution studies in rats by a RADAR method and was compared with (166)Ho-DOTMP as the only clinically used Ho-166 bone marrow ablative agent. The highest absorbed dose for this complex is observed in red marrow with 0.922mGy/MBq. The results show that (166)Ho-TTHMP has considerable characteristics compared to (166)Ho-DOTMP and can be a good candidate for bone marrow ablation in patients with multiple myeloma.

(99m)Tc-MAA overestimates the absorbed dose to the lungs in radioembolization: a quantitative evaluation in patients treated with ¹66Ho-microspheres.

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.

Preclinical evaluation of holmium-166 labeled anti-VEGF-A(Bevacizumab).

Radiolabeled antiangiogenic monoclonal antibodies are potential agents for targeted therapy in specific types of malignancies. In this study, (166)Ho-DOTA-Bevacizumab was used in biodistribution studies using single-photon emission computed tomography (SPECT) to acquire dosimetric aspects of the radiolabeled antibody in mice. The liver toxicity of the radiolabeled antibody was also determined using serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase and alkaline phosphatase assay 2-7 days post-injection. The SPECT biodistribution demonstrated a similar pattern as the other radiolabeled anti-vascular endothelial growth factor A (VEGF-A) immunoconjugates. (166)Ho-DOTA-Bevacizumab was revealed as a potential compound for therapy/imaging of VEGF-A expression in oncology.

Magnetic resonance imaging-based radiation-absorbed dose estimation of 166Ho microspheres in liver radioembolization.

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.

Quantification of holmium-166 loaded microspheres: estimating high local concentrations using a conventional multiple gradient echo sequence with S0-fitting.

PURPOSE: To provide a best estimate of the R 2* value and hence of the local concentration of highly paramagnetic holmium-166 loaded microspheres (HoMS) in voxels for which R 2* cannot be characterized by conventional fitting of multigradient echo (MGE) data because of fast signal decay due to high local concentrations. MATERIALS AND METHODS: A postprocessing method, S(0)-fitting, was implemented in a conventional R 2* fitting method that is used for quantification of HoMS. S(0)-fitting incorporates the estimated initial amplitude of the free induction decay (FID) curve, S(0), of neighboring voxels into the fitting procedure for voxels for which the conventional algorithm failed. The method was applied to HoMS in vitro and ex vivo in a rabbit liver. The performance of the S(0)-fitting method was evaluated by comparing results qualitatively and quantitatively with results obtained with quantitative ultrashort TE imaging (qUTE). RESULTS: Applying S(0)-fitting provided a best estimate for R 2* up to a value of about 2300 s(-1) compared with a maximum value of about 1000 s(-1) that could be characterized using conventional fitting. A good agreement was observed both qualitatively and quantitatively for in vitro experiments as well as for ex vivo rabbit liver experiments between results obtained with S(0)-fitting and results obtained with qUTE imaging. CONCLUSION: S(0)-fitting is a postprocessing method that can provide a best estimate of high R 2* values that cannot be characterized by conventional relaxometry. The method can be applied to conventional MGE datasets and was shown to be beneficial for quantification of high local concentrations of holmium-loaded microspheres.

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.

Holmium-166 poly(L-lactic acid) microsphere radioembolisation of the liver: technical aspects studied in a large animal model.

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.

166Ho-labeled hydroxyapatite particles: a possible agent for liver cancer therapy.

PURPOSE: Intra-arterial administration of particulates labeled with -emitting radionuclides is one of the promising modalities for the treatment of liver cancer. 166Ho [T1/2=26.9 hours, E(max) = 1.85 MeV, Egamma = 81keV (6.4%)] could be envisioned as an attractive radionuclide for use in liver cancer therapy owing to its high energy emission, short half-life, and feasibility of its production with adequately high specific activity and radionuclidic purity. Hydroxyapatite (HA) particles in the size range of 20-60 micros were chosen as the particulate carrier due to their biocompatibility and ease of labeling with lanthanides. METHODS: 166Ho was produced by thermal neutron bombardment on a natural holmium target. HA particles of the desired size range were synthesized, characterized, and radiolabeled with 166Ho. The biologic behavior of166Ho-HA was tested in normal Wistar rats by carrying out biodistribution and imaging studies. RESULTS: 166Ho was produced with a specific activity of 5.55-6.48 TBq/g and radionuclidic purity of approximately 100%. HA particles were labeled with 166Ho with a high radiochemical purity of >99% and good in vitro stability up to 7 days. The biodistribution and imaging studies revealed satisfactory hepatic retention (approximately 89% of injected activity after 2 days) with insignificant uptake in any other major organ/tissue. CONCLUSIONS: 166Ho-HA exhibited promising features as an agent for liver cancer therapy in preliminary studies and warrants further investigation

Chemical and biological evaluation of 153Sm and 166Ho complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylphosphonic acid monoethylester) (H4 dotp OEt).

The novel methylphosphonic acid monoethylester (H(4)dotp(OEt)) has been synthesized and characterized and their complexes with Sm(III) and Ho(III) ions were studied. Dissociation constants of the ligand are lower than those of H(4)dota. The stability constants of the Ln(III)-H(4)dotp(OEt) complexes are surprisingly much lower that those of H(4)dota (H(4)dota=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) probably due to a lower coordination ability of the phosphonate monoester groups. Acid-assisted decomplexation studies have shown that both complexes are less kinetically inert than the H(4)dota complexes, but still much more inert than complexes of open-chain ligands. Nevertheless, the synthesis of (153)Sm and (166)Ho complexes with this ligand led to stable complexes both in vitro and in vivo. A very low binding of these complexes to hydroxyapatite (HA) and calcified tissues was observed confirming the assumption that a fully ionized phosphonate group(s) is necessary for a strong bone affinity. Both complexes show similar behaviour in vivo and, in general, follow the biodistribution trend of the H(4)dota complexes with the same metals.

Clinical effects of transcatheter hepatic arterial embolization with holmium-166 poly(L-lactic acid) microspheres in healthy pigs.

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.

166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.

UNLABELLED: 166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical. METHODS: After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. RESULTS: In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. CONCLUSION: Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.

Preparation and preliminary biological evaluation of a (166)Ho labeled polyazamacrocycle for possible use as an intravascular brachytherapy (IVBT) agent.

(166)Ho can be considered as a potential radionuclide for intravascular brachytherapy (IVBT) using liquid-filled balloons owing to its suitable nuclear decay characteristics. The possibility of producing (166)Ho with adequate specific activity using moderate flux reactors and natural holmium target makes it an attractive alternative of (188)Re for developing IVBT agents. Keeping in mind the high thermodynamic stability of lanthanide complexes with polyazamacrocycles, (166)Ho complex of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) was prepared and studied for its suitability as a possible agent for IVBT. (166)Ho was produced with adequate specific activity and high radionuclidic purity by irradiating natural Ho(2)O(3) powder. TETA was synthesized by a single step procedure using cyclam as the starting material. (166)Ho-TETA complex was prepared with excellent radiochemical purity and the complex was found to retain its stability for 7 days at room temperature. Biodistribution studies carried out in Wistar rats showed major renal clearance of the injected activity with almost no retention in any of the vital organ/tissue.

Biodistribution and excretion of radioactivity after the administration of 166Ho-chitosan complex (DW-166HC) into the prostate of rat.

PURPOSE: The objective of this study was to determine the fate of the 166Ho-chitosan complex (DW-166HC) in rats by examining its absorption, distribution and excretion after administration into the prostate. METHODS: About 100 microCi of DW-166HC [containing 0.1875 mg of Ho(NO3)3.5H2O and 0.25 mg of chitosan] was administered intraprostatically. The level of radioactivity in blood, urinary and faecal excretion, and radioactivity distribution were examined. To determine the effect of chitosan in DW-166HC, 166Ho nitrate alone [0.1875 mg of Ho(NO3)3.5H2O] was administered into the prostate of male rats, and radioactivity distribution was examined using whole-body autoradiography. RESULTS: After administration of DW-166HC into the prostate, cumulative urinary and faecal excretion over the period 0-72 h was 0.35% and 0.11%, respectively. The radioactivity at the administration site was extremely high at all time points up to 144 h (>98% of injected dose). The small amount of radioactivity which did transfer from the administration site distributed mainly to the liver, spleen, kidney cortex and bone. Compared with the DW-166HC group, the group that received 166Ho nitrate alone displayed three- to fourfold higher levels of radioactivity in the main tissues, including liver, spleen, kidney cortex and bone, at 24 h after administration (P < 0.05). CONCLUSION: The results of this study show clearly that most of the administered DW-166HC remained at the administration site. It is concluded that the chitosan complex may be used to retain 166Ho within a limited area in cancer of the prostate.

[166Dy]Dy/166Ho hydroxide macroaggregates: an in vivo generator system for radiation synovectomy.

Radiation synovectomy is an effective treatment in patients suffering from inflammatory-rheumatoid and degenerative joint diseases. The aim of this work was to examine the feasibility of preparing dysprosium-166 (166Dy)/holmium-166(166Ho) hydroxide macroaggregates ([166Dy]Dy/166Ho-HM) as an in vivo generator for radiation synovectomy evaluating whether the stability of 166Dy-HM and 166Ho-HM complexes is maintained when the daughter 166Ho is formed. The Monte Carlo (MCNP4B) theoretical depth dose profile for the in vivo [166Dy]Dy/166Ho generator system in a joint model was calculated and compared with that produced by 90Y, 153Sm and 166Ho. 166Dy was obtained by neutron irradiation of enriched 164Dy2O3 in a Triga Mark III reactor. Macroaggregates were prepared by reaction of [166Dy]DyCl3 with 0.5 M NaOH in an ultrasonic bath. [166Dy]Dy/166Ho-HM was obtained with radiochemical purity >99.5% and with the majority of particles in the 2-5 microm range. In vitro studies demonstrated that the radio-macroaggregates are stable in saline solution and human serum without a significant change in the particle size over 14 d, suggesting that no translocation of the daughter nucleus occurs subsequent to beta- decay of 166Dy. Biological studies in normal rats demonstrated high retention in the knee joint even 7 d after [166Dy]Dy/166Ho-HM administration. The Monte Carlo (MCNP4B) theoretical depth dose profiles in a joint model, showed that the in vivo [166Dy]Dy/166Ho generator system would produce 25% and 50% less radiation dose to the articular cartilage and bone surface, respectively, than that produced by 90Y or pure 166Ho in a treatment with the same therapeutic dose to the synovium surface. Despite that 153Sm showed the best depth dose profile sparing doses to healthy tissues, the use of 166Dy could provide the advantage of being applied in patients that cannot be reached within a few hours from a nuclear reactor and to produce less radiation exposure to the medical personnel during the radiopharmaceutical administration.