Assessment of absorbed dose for Zr-89, Sm-153 and Lu-177 medical radioisotopes: IDAC-Dose2.1 and OLINDA experience.

OBJECTIVE: In this article, IDAC-Dose2.1 and OLINDA computer codes are compared as they are the most widely used software tools for internal dosimetry assessment at the present time. OLINDA/EXM personal computer code was created as a replacement for the widely used MIRDOSE3.1 code. IDAC-Dose2.1 was developed based on the ICRP specific absorbed fractions and computational framework of internal dose assessment given for reference adults in ICRP Publication 133. IDAC uses cumulated activities per administered activity in hours and calculates the absorbed dose and the effective dose. The program calculates the dose in the Eckerman stylized family phantoms. It is useful in standardizing and automating internal dose calculations, assessing doses in clinical trials with radiopharmaceuticals, making theoretic calculations for existing pharmaceuticals, teaching, and other purposes. METHODS: To produce such a comparison, the results of this work were compared with available published data in the literature on radiopharmaceuticals. Radiopharmaceuticals with 89Zr, 153Sm, 177Lu radionuclides are used as the basis for the comparison. 89Zr, 153Sm, 177Lu radionuclides are regarded as the future of radiopharmaceutical treatment. For 89Zr, two different labelled carriers, Zr-89_cMAb U36 and Zr-89 Panitumumab, were used on patients. RESULTS: The results show a clear difference in terms of absorbed dose of the Zr-89 radiopharmaceuticals for red bone marrow when calculated by IDAC-Dose2.1 (0.76 mGy/MBq), while the estimated absorbed dose in literature results is 0.07 mGy/MBq and 0.14 mGy/MBq when the calculation is done by OLINDA program. In the case of 177Lu-EDTMP, the absorbed dose in red bone marrow is in reasonable agreement (0.63 mGy/MBq and 0.8 mGy/MBq for IDAC-Dose2.1 and OLINDA, respectively). A significant difference was found for the absorbed dose in the bone surface, which was almost twice as high for OLINDA (2.1 mGy/MBq for IDAC-Dose2.1 and 5.4 mGy/MBq for OLINDA). In some direct cases, the calculated absorbed dose in the urinary bladder wall with OLINDA is ten times higher compared to WinAct (which was utilized to calculate the total activity in the organs and tissues) and IDAC 2.1. These results are considered key to greater accuracy in internal dose calculation.

An electrochemical approach for removal of radionuclidic contaminants of Eu from 153Sm for effective use in metastatic bone pain palliation.

INTRODUCTION: Thermal neutron activation of 152Sm [152Sm(n,γ)153Sm] using natural or isotopically enriched (by 152Sm) samarium target is the established route for production of 153Sm used for preparation of 153Sm-EDTMP for pain palliation in cancer patients with disseminated bone metastases. However, some long-lived radionuclidic contaminants of Eu, such as, 154Eu (t½=8.6y) are also produced during the target activation process. This leads to detectable amount of Eu radionuclidic contaminants in patients' skeleton even years after administration with therapeutic doses of 153Sm-EDTMP. Further, the presence of such contaminants in 153Sm raises concerns related to radioactive waste management. The aim of the present study was to develop and demonstrate a viable method for large-scale purification of 153Sm from radionuclidic contaminants of Eu. METHODS: A radiochemical separation procedure adopting electroamalgamation approach has been critically evaluated. The influence of different experimental parameters for the quantitative removal radionuclidic contaminants of Eu from 153Sm was investigated and optimized. The effectiveness of the method was demonstrated by purification of ~37 GBq of 153Sm in several batches. As a proof of concept, 153Sm-EDTMP was administered in normal Wistar rats and ex vivo γ-spectrometry of bone samples were carried out. RESULTS: After carrying out the electrolysis under the optimized conditions, the radionuclidic contaminants of Eu could not be detected in purified 153Sm solution by γ-spectrometry. The overall yield of 153Sm obtained after the purification process was >85%. The reliability of this approach was amply demonstrated in several batches, wherein the performance remained consistent. Ex vivo γ-spectrometry of bone samples of Wistar rats administered with 153Sm-EDTMP (prepared using electrochemically purified 153Sm) did not show photo peaks corresponding to radionuclidic contaminants of Eu. CONCLUSIONS: A viable electrochemical strategy for the large-scale purification of 153Sm from radionuclidic contaminants of Eu has been successfully developed and demonstrated.

Estimated human absorbed dose of a new (153)Sm bone seeking agent based on biodistribution data in mice: Comparison with (153)Sm-EDTMP.

PURPOSE: The main goal in radiotherapy is to deliver the absorbed dose within the target organs in highest possible amount, while the absorbed dose of the other organs, especially the critical organs, should be kept as low as possible. In this work, the absorbed dose to human organs for a new (153)Sm bone-seeking agent was investigated. METHODS: (153)Sm-(4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid ((153)Sm-BPAMD) complex was successfully prepared. The biodistribution of the complex was investigated in male Syrian mice up to 48 h post injection. The human absorbed dose of the complex was estimated based on the biodistribution data of the mice by radiation absorbed dose assessment resource (RADAR) method. The target to non-target absorbed dose ratios for (153)Sm-BPAMD were compared with these ratios for (153)Sm-EDTMP. RESULTS: The highest absorbed dose for (153)Sm-BPAMD was observed in bone surface with 5.828 mGy/MBq. The dose ratios of the bone surface to the red marrow and to the total body for (153)Sm-BPAMD were 5.3 and 20.0, respectively, while these ratios for (153)Sm-EDTMP were 4.4 and 18.3, respectively. This means, for a given dose to the bone surface as the target organ, the red marrow (as the main critical organ) and the total body would receive lesser absorbed dose in the case of (153)Sm-BPAMD. CONCLUSIONS: Generally, the human absorbed dose estimation of (153)Sm-BPAMD indicated that all other tissues approximately received insignificant absorbed dose in comparison with bone surface and therefore can be regarded as a new potential agent for bone pain palliation therapy.

Development of (153) Sm-folate-polyethyleneimine-conjugated chitosan nanoparticles for targeted therapy.

The aim of this study was to develop biocompatible, water-soluble (153) Sm-labeled chitosan nanoparticles (NPs) containing folate and polyethyleneimine functionalities i.e. chitosan-graft-PEI-folate (CHI-DTPA-g-PEI-FA), suitable for targeted therapy. The physicochemical properties of the obtained NPs were characterized by dynamic light-scattering analysis for their mean size, size distribution, and zeta potential; scanning electron microscopy for surface morphology; and (1) H-NMR, FT-IR analyses for molecular dispersity of folate in the NPs. NPs were spherical with mean diameter below 250 nm, polydispersity of below 0.15, and positive zeta potential values. The NP complex ((153) Sm-CHI-DTPA-g-PEI-FA) was stable at 25 °C (6-8 h, >90% radiochemical purity, instant thin layer chromatography (ITLC)). Binding studies using fluorescent NPs for internalization also demonstrated significant uptake in MCF-7 cells. MCF-7 cell internalization was significantly greater for 4T1. In blocking studies, both MCF-7 and 4T1 cell lines demonstrated specific folate receptor (FR) binding (decreasing 45%). In vivo biodistribution studies indicated major excretion of NPs metabolites and/or free (153) Sm through the kidneys. The preliminary imaging studies in 4T1 tumor-bearing mice showed minor uptake up to 96 h. The present folic acid that functionalized chitosan NP is a candidate material for folate receptor therapy.

The use of 185 MBq and 740 MBq of 153-samarium hydroxyapatite for knee synovectomy in haemophilia.

The penetration of beta energy of 153-samarium ((153) Sm) (0.8 MeV) is not only appropriate for synovectomy of median articulations but is possible to improve the radiobiological effect using increased activities. The aim of this study was to assess the effectiveness of 185 MBq and 740 MBq of 153-samarium hydroxyapatite ((153) Sm-HA) in knees of haemophilic patients. Thirty-one patients--36 knees, 30 males, were divided into two groups without coinjection of corticosteroid: A - 14 patients (17 knees) treated with intra-articular dose of 185 MBq of (153) Sm-HA, average age 23 years; B--17 patients (19 knees) with 740 MBq of (153) Sm-HA, average age 21.3 years. The evaluation before and after 1 year of synovectomy used the following criteria: reduction in the number of haemarthroses and use of the coagulation factor and improvement in articular motility. Adverse-effects occurrence was considered too. Early and late scintigraphic studies were performed after synoviorthesis and no joint immobilization was recommended. The reduction in haemarthrosis and use of coagulation factor were: group 1--31.3% and 25%; group 2--81.5% and 79% with P < 0.001 respectively; no significant improvement in knees motility was noted for both groups. Four cases of mild reactional synovitis were observed in each group. The scintigraphic control showed homogenous distribution of the radiopharmaceuticals with no articular escape; the material was considered safe by its permanence in the articulation. We have significant improvement in the synovectomy of haemophilic knees with 740 MBq of (153) Sm-HA; the less penetration of its beta radiation was compensated by the increased biological effect with the higher used activity.

Standardization of Sm-153 solution by absolute methods.

Standardization of (153)Sm by 4π(LS)-γ coincidence and anticoincidence counting and the CIEMAT/NIST method in three LS-counters is presented. This short half-life radionuclide is applied in tumor therapy and bone pain palliation. A simplified disintegration scheme of (153)Sm was applied in the calculation of the counting efficiency. Standard uncertainties of 0.4% for the (153)Sm measurements by the 4π(LS)-γ coincidence and anticoincidence techniques and 0.7% by the C/N method were evaluated, respectively. An agreement of the standardization results by both methods within the respective uncertainties was obtained. The half-life of (153)Sm of (1.92895±0.00024) days was determined during one month of measurements and correction for europium isotope impurities by the C/N method in the TriCarb 2910 LS-counter.

Biodistribution of sub-10 nm PEG-modified radioactive/upconversion nanoparticles.

The biodistribution of lanthanide-based upconversion nanophosphors (UCNPs) has attracted increasing attention, and all of the reported UCNPs display metabolism in the liver and spleen mainly. Herein, ∼8 nm poly(ethylene glycol) (PEG)-coated NaYF4 nanoparticles codoped with Yb(3+), Er(3+), and (or) radioactive (153)Sm(3+) ions were synthesized, through a hydrothermal synthetic system assisted by binary cooperative ligands with oleic acid and PEG dicarboxylic acids. The as-prepared PEG-coating NaYF4:Yb,Er and NaYF4:Yb,Er,(153)Sm are denoted as PEG-UCNPs and PEG-UCNPs((153)Sm), respectively. PEG-UCNPs were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD) analysis, and Fourier-transform infrared (FTIR) spectroscopy. The PEG-UCNPs showed excellent water solubility with a hydrodynamic diameter of ∼10 nm and displayed upconversion luminescence (UCL) under continuous-wave excitation at 980 nm. At the same time, the (153)Sm-doped nanoparticles PEG-UCNPs((153)Sm) displayed radioactivity, and time-dependent biodistribution of PEG-UCNPs((153)Sm) was investigated, through single-photon emission computed tomography (SPECT) imaging and γ-counter analysis. Interestingly, PEG-UCNPs((153)Sm) had a long blood retention time and were partly eliminated through urinary pathways in vivo. Therefore, the concept of fabricating PEG-coated, small nanosize (sub-10 nm) nanoparticles with radioactive property is a useful strategy for providing a potential method to monitor lanthanide nanoparticles renal clearable.

Hydrothermal synthesis of NaLuF4:153Sm,Yb,Tm nanoparticles and their application in dual-modality upconversion luminescence and SPECT bioimaging.

Upconversion luminescence (UCL) properties and radioactivity have been integrated into NaLuF(4):(153)Sm,Yb,Tm nanoparticles by a facile one-step hydrothermal method, making these nanoparticles potential candidates for UCL and single-photon emission computed tomography (SPECT) dual-modal bioimaging in vivo. The introduction of small amount of radioactive (153)Sm(3+) can hardly vary the upconversion luminescence properties of the nanoparticles. The as-designed nanoparticles showed very low cytotoxicity, no obvious tissue damage in 7 days, and excellent in vitro and in vivo performances in dual-modal bioimaging. By means of a combination of UCL and SPECT imaging in vivo, the distribution of the nanoparticles in living animals has been studied, and the results indicated that these particles were mainly accumulated in the liver and spleen. Therefore, the concept of (153)Sm(3+)/Yb(3+)/Tm(3+) co-doped NaLuF(4) nanoparticles for UCL and SPECT dual-modality imaging in vivo of whole-body animals may serve as a platform for next-generation probes for ultra-sensitive molecular imaging from the cellular scale to whole-body evaluation. It also introduces an easy methodology to quantify in vivo biodistribution of nanomaterials which still needs further understanding as a community.

Intracellular localization of samarium in the lactating mammary gland cells: ultrastructural and microanalytical study.

The frequent use of some rare earths in the medical and industrial domains make us worry about their intracellular behavior into the body. Reason for which we have investigated the subcellular localization of one of these elements, the samarium, in the mammary gland of lactating female wistar rats using two very sensitive methods of observation and microanalysis, the transmission electron microscopy and the secondary ion mass spectrometry. The ultrastructural study showed the presence of electron dense deposits in the lactating mammary glandular epithelial cell lysosomes of the samarium-treated rats, but no loaded lysosomes were observed in those of control rats. The microanalytical study allowed both the identification of the chemical species present in those deposits as samarium isotopes ((152) Sm(+)) and the cartography of its distribution. Our results confirm the previous ones showing that lysosomes of the glandular epithelial cells are the site of the intracellular concentration of foreign elements such as gallium. The intralysosomal deposits observed in the mammary glandular cells of the samarium-treated rats are similar in their form and density to those observed with the same element in other varieties of cells, such as liver, bone marrow, and spleen cells. Our ultrastructural and microanalytical results and those obtained in previous studies allow deducing that the intralysosomal deposits are very probably composed of an insoluble samarium phosphate salt.

A Phase II study of (153)Sm-EDTMP and high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Multiple myeloma (MM) remains an incurable illness affecting nearly 20,000 individuals in the United States per year. High-dose melphalan (HDM) with autologous hematopoietic stem cell support (ASCT) is one of the mainstays of therapy for younger patients, but little advancement has been made with regards to conditioning regimens. We opted to combine (153)Samarium ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP), a radiopharmaceutical approved for the palliation of pain caused by metastatic bone lesions, with HDM and ASCT in a Phase II study. Individualized doses of (153)Sm were based on dosimetry and were calculated to deliver 40 Gy to the bone marrow. The therapeutic dose of (153)Sm-EDTMP was followed by HDM and ASCT. Forty-six patients with newly diagnosed or relapsed disease were treated. Study patients were compared to 102 patients contemporaneously treated with HDM and ASCT. Fifty-nine percent of study patients achieved a very good partial response (VGPR) or better. With a median follow-up of 7.1 years, the median overall survival and progression free survival (PFS) from study registration was 6.2 years (95% CI 4.6-7.5 years) and 1.5 years (1.1-2.2 years), respectively, which compared favorably to contemporaneously treated non-study patients. Addition of high-dose (153)Sm-EDTMP to melphalan conditioning appears to be safe, well tolerated, and worthy of further study in the context of novel agents and in the Phase III setting.

Absorbed dose profiles for (32)P, (90)Y, (188)Re, (177)Lu, (153)Sm and (169)Er: radionuclides used in radiosynoviortheses treatment.

The main objective of this paper was to obtain the absorbed dose profiles for radionuclides of frequent or potential use in radiosynoviortheses. These profiles reveal the absorbed dose per activity of injected radionuclide (Gy/h*MBq) in the synovial membrane and the articular cartilage. The researched radionuclides were (32)P, (90)Y, (188)Re, (177)Lu, (153)Sm and (169)Er. The therapeutic range of each radionuclides in synovial tissue were also calculated. This range determines the synovial thickness that can be sufficiently irradiated and thus successfully treated. The S values for the synovial membrane and articular cartilage were calculated using as a model a cylinder with the source uniformly distributed in its volume. The synovial membrane was simulated varying the radius of the cylinder (from 0.5cm to 9cm) and its height (from 0.01cm to 0.04cm). The area in the base of the cylinder represents different sizes of the synovial surface (small, medium and large joints). The height of the cylinder represents different stages of the progression of the rheumatoid arthritis. The same model was used to simulate the articular cartilage but, the source was uniformly distributed into a cylindrical slab (0.01cm height and 1cm of radius. The results obtained allow the estimation of the dose that will be delivered to the synovial membrane and the articular cartilage for different joint sizes and different stages of progression of the rheumatoid arthritis (RA).

Clinical evaluation after 1 year of 153-samarium hydroxyapatite synovectomy in patients with haemophilic arthropathy.

The aim is to evaluate the efficiency of the treatment with 153-samarium hydroxyapatite (153-Sm-HA) in haemophilic arthropathy. Thirty-one patients (30 males) with ages ranging from 8 to 34 years (average age = 20.6 years) were treated with fixed intra-articular dose of 185 MBq (5 mCi) and divided into two groups: infantile-juvenile (13 patients with up to 18 years of age, an average age of 12.7 years and arthropathy evolution of 7.8 years), and adult (18 patients older than 18 years, an average age of 24 years and arthropathy evolution of 18.7 years). The clinical evaluation before and after 1 year of synovectomy used the following criteria: subjective (pain through visual scale, articulation inspection), objective (articular movement through flexion level, sensitivity to palpation and leakage through joint circumference), reduction on the use of the coagulation factor, number of haemarthrosis, and the occurrence of adverse effects. The results were classified as: 1, good (remission from 70% to 100% of manifestations); 2, moderate (remission from 40% to 69%); and 3, poor (remission from 0% to 39%). Seventy-eight joints were tested: 15 knees, 36 elbows, 24 ankles, 1 shoulder and 2 hips. Early scintigraphic (1-2 h) and late scintigraphic (24-72 h) studies were performed after synoviorthesis. The cost of the procedure per joint was also estimated. No significant difference in the synoviorthesis result between groups was observed. The results were good for 75% of elbows, 87.5% of ankles and 40% of knees; the reduction in haemarthrosis and use of the coagulation factor was respectively 78% and 80% for elbows, 82% and 85% for ankles and 30% and 35% for knees. Four cases of reactional synovitis were observed in the 31 patients. The scintigraphic control showed homogeneous distribution of the material with no articular escape. The use of 153 Sm-HA in the treatment of the haemophilic arthropathy is effective for intermediate-size joints (elbows and ankles), but less effective for knees. Moreover, this treatment presents an excellent safety profile and accessible cost.

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.

Effects of increasing doses of samarium-153-ethylenediaminetetramethylene phosphonate on axial and appendicular skeletal growth in juvenile rabbits.

INTRODUCTION: Targeted radiotherapy using samarium-153-ethylenediaminetetramethylene phosphonate (153 Sm-EDTMP) is currently under investigation for treatment of osteosarcoma. Osteosarcoma often occurs in children, and previous studies on a juvenile rabbit model demonstrated that clinically significant damage to developing physeal cartilage may occur as a result of systemic 153 Sm-EDTMP therapy. The aim of this study was to evaluate the late effects of 153 Sm-EDTMP on skeletal structures during growth to maturity and to determine if there is a dose response of 153 Sm-EDTMP on growth of long bones. METHODS: Female 8-week-old New Zealand white rabbits were divided into three treatment groups plus controls. Each rabbit was intravenously administered a predetermined dose of 153 Sm-EDTMP. Multiple bones of each rabbit were radiographed every 2 months until physeal closure, with subsequent measurements made to assess for abbreviated bone growth. Statistical analyses were performed to determine the differences in bone length between groups, with significance set at P<.05. RESULTS: Significant differences in lengths of multiple bones were detected between the high-dose group and other treatment groups and controls at each time interval. A significant difference in lengths of the tibias was also noted in the medium-treatment group, compared to controls. Mean reduction of bone length was first detected at 4 months and did not increase significantly over time. CONCLUSIONS: These data suggest that clinically significant bone shortening may occur as a result of high-dosage administration of 153 Sm-EDTMP. Further investigation regarding the effects of bone-seeking radiopharmaceuticals on bone growth and physeal cartilage is warranted.

Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases.

PURPOSE: (153)Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. METHODS: Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg (153)Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before (153)Sm-EDTMP treatment. Urine was collected 48 h after injection of (153)Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of (153)Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. RESULTS: The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4 +/- 11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9 +/- 10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both per-protocol (n = 13) and full-analysis sets (n = 18). Toxicity was comparable to of monotherapy with (153)Sm-EDTMP. CONCLUSION: Zoledronic acid treatment does not influence (153)Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe.

In vivo performance of an oral MR matrix tablet formulation in the beagle dog in the fed and fasted state: assessment of mechanical weakness.

PURPOSE: To evaluate the behaviour of an oral matrix modified release formulation in the canine gastrointestinal tract, and establish if a mechanical weakness previously observed in clinical studies would have been identified in the dog model. MATERIALS AND METHODS: In vitro release profiles were obtained for two modified release matrix tablets containing UK-294,315, designed to release over either 6 (formulation A) or 18 (formulation B) hours. Tablets were labelled with (153)samarium and in vivo pharmacoscintigraphy studies were performed in four beagle dogs in the fasted state for both formulations, and following ingestion of an FDA high fat meal for formulation B. RESULTS: The matrix tablet formulations displayed significantly different in vitro release profiles (F (2) < 50), with time to 80% release for formulation A and B of 406 and 987 min respectively. Complete in vivo disintegration occurred at 339 +/- 181 and 229 +/- 171 for formulation A and B respectively in the fasted state, and at 207 +/- 154 min for formulation B in the fed state, in disagreement with in vitro release. CONCLUSION: The fed/fasted dog model would have predicted a lack of physical robustness in the matrix tablet formulation B, however it would not have predicted the clear fed/fasted effects on performance observed previously in man.

Neutron activation based gamma scintigraphic evaluation of enteric-coated capsules for local treatment in colon.

The fate of two colon-specific formulations developed in our previous study was investigated using a gamma scintigraphic imaging method. The formulations contained paracetamol and samarium oxide (Sm2O3) and either microcrystalline cellulose (MCC) or hypromellose (HPMC K4M) as diluent and were coated with Eudragit S polymer. The gamma scintigraphic evaluation proved that the products remained intact in the stomach and the upper gastrointestinal tract. The gastric residence time was less that 1h. Three to four hours after administration the formulations had reached the ileo-caecal junction, i.e. the small intestine transit time was approximately 3h. The capsules disintegrated in the ileo-caecal junction or in the ascending colon. The capsules containing MCC released the marker momentarily, the capsules containing HPMC K4M gradually spreading it to the whole colon. The gamma images also verified that the HPMC gel disintegrates completely in 12-14 h. While comparing the results to those previously obtained from the bioavailability studies it could be concluded that it is possible to develop colon specific drug products that begin releasing the drug in the ileo-caecal junction or at the beginning of the ascending colon and spread the drug dose to a larger surface area by using enteric coats and hydrophilic polymers.

Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies.

The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [(153)Sm](3+) or Gd(3+) complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled [(153)Sm]-DOTAGal(2) by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50% by the presence of its high-affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmacokinetic studies on Wistar rats using the [(153)Sm](3+)-labeled glycoconjugates show a high uptake in the receptor-rich organ liver of the radiolabeled compounds containing terminal galactosyl groups, but very little uptake for those compounds with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd(3+) chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. This probably results from the quick wash-out from the liver of these highly hydrophilic complexes, before they can be sufficiently concentrated within the hepatocytes via receptor-mediated endocytosis.

Selective accumulation of light or heavy rare earth elements using gram-positive bacteria.

The accumulation of samarium from a solution only containing samarium by Arthrobacter nicotianae was examined. The amount of accumulated samarium was strongly affected by the concentration of samarium and pH of the solution. The accumulation of samarium by the strain was very rapid and reached equilibrium within 3h. The accumulation of samarium-europium or europium-gadolinium from the solution containing the two metals using various actinomycetes and gram-positive bacteria was also examined. Most of the tested strains could accumulate similar amounts of samarium and europium; however, most of the tested strains could accumulate a greater amount of europium than gadolinium. Especially, the amounts of accumulated europium using gram-positive bacteria were higher than those using actinomycetes. The selective accumulations of light or heavy rare earth elements (REEs) using A. nicotianae and Streptomyces albus were also examined. The amounts of accumulated samarium and europium were higher than those of the other light REEs using both microorganisms. S. albus can accumulate greater lutetium than other REEs from a solution containing yttrium and eight heavy REEs. On the other hand, A. nicotianae can accumulate higher amounts of terbium and ytterbium than that of the other heavy REEs from the same solution. A. nicotianae can also accumulated higher amounts of Sm than other REEs from a solution containing six light REEs.

Accumulation and distribution of samarium-153 in rat brain after intraperitoneal injection.

It is well known that rare earth elements (REEs) have come into extensive use in a number of fields. As a result, REEs are becoming closely related to human's daily life. However, until now, the distributions of REEs in the brain are not yet very clear. In this study, Sprague-Dawley male rats were intraperitoneally injected with 0.25 mL of (153)SmCl(3) solution (containing 10 microg Sm). The brains were perfused with saline to minimize the blood influence. The radioactivities of (153)Sm in the five brain regions (hypothalamus, cerebellum, hippocampus, corpus striatum, and cerebral cortex) were counted. The results suggested that Sm did enter into the brain. Although only about 0.0003% of the given dose was accumulated in the brain, Sm seemed to be remain in the brain for a long time. The highest amounts and lowest concentrations of (153)Sm were found in the cerebral cortex, and the highest concentrations of (153)Sm were found in the hypothalamus.