Thermal Neutron Bombardment Research Articles

Preparation and Evaluation of 177Lu-TDTMP: A Potential Theranostic Agent for Bone Metastases

177Lu was produced in high-specific activity and excellent radionuclidic purity by thermal neutron bombardment of 176Yb target.Tetramethylene diamine tetramethylenephosphonic acid (TDTMP) was radiolabeled with 177Lu and complexation parameters were studied and optimized: 8.4 µg TDTMP, ~243 Ci of 177Lu activity, pH= 8 and the reaction mixture was kept at room temperature for 30 min.The complex, formed with high yield (>99%) and retained its stability for more than 14 days. The complex structure was predicted and its binding to target enzyme was assessed in-silico..Biodistribution study carried out in normal and tumorized Wister rats showed significant skeletal uptake, the 177Lu-TDTMP, results clearly indicated that it has high affinity for bone mineral. Femur and tibia uptakes of the labelled complex were ~ 6.4 % and ~7.1 % at 3 hours post injection compared to ~ 4 % and ~ 4.3 % in case of 177LuCl3. Thereafter, the uptakes increased continuously to a maximum of ~ 7.9 % and ~ 8.3 % at 48 hours after injection were noticed.

Production, quality control, and bio-distribution studies of (159)Gd-EDTMP as a palliative agent for bone pain.

Introduction:Particle-emitting, bone-seeking radiopharmaceuticals have attracted the attention of the nuclear medicine community over the last three decades for the treatment of the pain of osteoblastic metastases. The objectives of this research were to produce quality-controlled 159Gd-EDTMP in order to provide a new therapeutic radiopharmaceutical for use in clinical applications.Methods:The investigation was an experimental study in which 159Gd (T1/2=18.479 h, Eβ (max)=970.60 keV, Eγ=363.55 (11.4%) keV] was produced by thermal neutron bombardment of natural Gd2O3 at the Tehran Research Reactor (TRR) for a period of 7 d at a flux of 3–4×1013 neutrons/cm2.s. It was then quality-controlled and used to radio-label the in-house prepared ethylene diamine tetra acetic acid (EDTM).Results:Complexation parameters were optimized to achieve maximum yields (>99%). The radiochemical purity of 159Gd-EDTMP was checked by radio thin layer chromatography RTLC. It was found to retain its stability at room temperature (>95%). Bio-distribution studies of the complexes conducted in wild rats showed significant bone uptake with rapid clearance from blood.Conclusion:The properties of the 159Gd-EDTMP that was produced suggest then use of a new, efficient, palliative therapeutic agent for metastatic bone pain instead of some other current radiopharmaceuticals.

(175)Yb-TTHMP as a good candidate for bone pain palliation and substitute of other radiopharmaceuticals.

Bone metastasis is one of the most frequent causes of pain in cancer patients. Different radioisotopes such as P-32, Sm-153, Ho-166, Lu-177, and Re-186 with several chemical ligands as ethylenediaminetetramethylene phosphonic acid (EDTMP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP), and propylenediaminetetramethylene phosphonate (PDTMP) are recommended for bone pain palliation. In this work, 175Yb-triethylenetetraminehexamethylene phosphonic acid (TTHMP) was produced as a proper alternative to other radiopharmaceuticals. Relatively long half-life (T1/2 = 4.18 days), maximum energy beta particle Eβ =470 keV (86.5%), low abundance gamma emission 396 keV (6.4%), 286 keV (3.01%), 113.8 keV (1.88%) and low cost are considered advantageous of Yb-175 are to wider usage of this isotope; in addition, TTHMP is an ideal carrier moiety for bone metastases. Production, quality control, and biodistribution studies of 175Yb-TTHMP were targeted. Yb-175 chloride was obtained by thermal neutron bombardment of a natural Yb2O3 sample at Tehran Research Reactor (TRR), radiolabeling was completed in 1 h by the addition of TTHMP at the room temperature and pH was 7.5-8, radiochemical purity was higher than 95%. Biodistribution studies in normal rats were carried out. The results showed favorable biodistribution features of 175Yb-TTHMP, indicating significant accumulation in bone tissues compared with clinically used bone-seeking radiopharmaceuticals. This research presents 175Yb-TTHMP can be a good candidate for bone pain palliation and substitute of other radiopharmaceuticals, however, further biological studies in other mammals are still needed.

Monte Carlo characterization of biocompatible beta‐emitting glass seed incorporated with the radionuclide as a SPECT marker for brachytherapy applications

A glass seed consisting of the β−‐emitting radionuclide 90Y incorporated with radionuclide 153Sm as SPECT marker is proposed for potential application in brachytherapy in order to reduce the undesirable dose to healthy adjacent organs. The aim of this work is to determine the dosimetric characteristics, as suggested in the AAPM TG‐60/TG‐149 reports, for this seed using Monte Carlo simulation. Monte Carlo codes MCNP5, EGSnrc, and FLUKA were used to calculate the absorbed dose distribution around the seed. Dosimetric parameters, such as reference absorbed dose rate, radial dose function, and one‐dimensional (1D) and two‐dimensional (2D) anisotropy functions, were obtained. The computational results from these three codes are in agreement within 5.4% difference on average. The absorbed dose rate at the reference point was estimated to be 5.01 cGy h−1 μCi−1 and self absorption of YAS glass seed amounted to 30.51%. The results showed that, with thermal neutron bombardment of 5 hours in a typical flux, sufficient activity for applications in brachytherapy may be achieved. With a 5 mCi initial activity, the total dose of a YAS glass seed was estimated to be 1.38 Gy at 1.0 cm from the seed center. Comparing with gamma emitting seeds, the 90Y seed could reduce undesirable doses to adjacent organs, because of the rapid dose falloff of beta ray. Because of the high R90 value of 5.5 mm, fewer number of 90Y seeds will be required for an interstitial brachytherapy treatment using permanent implant, in comparison with other beta‐emitting seeds. The results would be helpful in the development of the radioactive implants using 90Y glass seeds for the brachytherapy treatment.PACS numbers: 87.53.Jw, 87.56.bg

Tracer level radiochemistry to clinical dose preparation of 177Lu-labeled cyclic RGD peptide dimer

Integrin αvβ3 plays a significant role in angiogenesis during tumor growth and metastasis, and is a receptor for the extracellular matrix proteins with the exposed arginine(R)-glycine(G)-aspartic acid(D) tripeptide sequence. The over-expression of integrin αvβ3 during tumor growth and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. Considering the advantages of (177)Lu for targeted radiotherapy and enhanced tumor targeting capability of cyclic RGD peptide dimer, an attempt has been made to optimize the protocol for the preparation of clinical dose of (177)Lu labeled DOTA-E[c(RGDfK)]2 (E=Glutamic acid, f=phenyl alanine, K=lysine) as a potential agent for targeted tumor therapy. (177)Lu was produced by thermal neutron bombardment on enriched Lu2O3 (82% in (176)Lu) target at a flux of 1 × 10(14) n/cm(2).s for 21 d. Therapeutic dose of (177)Lu-DOTA-E[c(RGDfK)]2 (7.4GBq) was prepared by adding the aqueous solution of the ligand and (177)LuCl3 to 0.1M NH4OAC buffer containing gentisic acid and incubating the reaction mixture at 90°C for 30 min. The yield and radiochemical purity of the complex was determined by HPLC technique. Parameters, such as, ligand-to-metal ratio, pH of the reaction mixture, incubation time and temperature were varied using tracer quantity of (177)Lu (37 MBq) in order to arrive at the optimized protocol for the preparation of clinical dose. Biological behavior of the radiotracer prepared was studied in C57/BL6 mice bearing melanoma tumors. (177)Lu was produced with a specific activity of 950 ± 50 GBq/mg (25.7 ± 1.4 Ci/mg) and radionuclidic purity of 99.98%. A careful optimization of several parameters showed that (177)Lu-DOTA-E[c(RGDfK)]2 could be prepared with adequately high radiochemical purity using a ligand-to-metal ratio ~2. Based on these studies therapeutic dose of the agent with 7.4 GBq of (177)Lu was formulated in ~63 GBq/μM specific activity with high yield (98.2 ± 0.7%), radiochemical purity and in vitro stability. Biodistribution studies carried out in C57/BL6 mice bearing melanoma tumors revealed specific accumulation of the radiolabeled conjugate in tumor (3.80 ± 0.55% ID/g at 30 min p.i.) with high tumor to blood and tumor to muscle ratios. However, the uptake of the radiotracer in the tumor was found to be reduced to 1.51 ± 0.32 %ID/g at 72 h p.i. The present work successfully demonstrates the formulation of an optimized protocol for the preparation of (177)Lu labeled DOTA-E[c(RGDfK)]2 for PRRT applications using (177)Lu produced by direct neutron activation in a medium flux research reactor.

Preparation of radioactive praseodymium oxide as a multifunctional agent in nuclear medicine

Many studies have attempted to assess the significance of the use of the β(-)particle emitter praseodymium-142 ((142)Pr) in cancer treatment. As praseodymium oxide (Pr(2)O(3)) powder is not water soluble, it was dissolved in HCl solution and the resultant solution had to be pH adjusted to be in an injectable radiopharmaceutical form. Moreover, it was shown that the nanosized neodymium oxide (Nd(2)O(3)) induced massive vacuolization and cell death in non-small-cell lung cancer. In this work, the production of (142)Pr was studied and water-dispersible nanosized Pr(2)O(3) was proposed to improve the application of (142)Pr in nuclear medicine. Data from different databases pertaining to the production of (142)Pr were compared to evaluate the accuracy of the theoretical calculations. Water-dispersible nanosized Pr(2)O(3) was prepared using a poly(ethylene glycol) (PEG) coating or PEGylation method as a successful mode of drug delivery. Radioactive (142)Pr(2)O(3) was produced via a (142)Pr(n,γ)(142)Pr reaction by thermal neutron bombardment of the prepared sample. There was good agreement between the reported experimental data and the data based on nuclear model calculations. In addition, a small part of nano-Pr(2)O(3) particles remained in suspension and most of them settled out of the water. Interestingly, the PEGylated Pr(2)O(3) nanoparticles were water dispersible. After neutron bombardment of the sample, a stable colloidal (142)Pr(2)O(3) was formed. The radioactive (142)Pr(2)O(3) decays to the stable (142)Nd(2)O(3). The suggested colloidal (142)Pr(2)O(3) as a multifunctional therapeutic agent could have dual roles in cancer treatment as a radiotherapeutic agent using nanosized (142)Pr(2)O(3) and as an autophagy-inducing agent using nanosized (142)Nd(2)O(3).

Production, quality control and biodistribution studies of thulium-170-labeled ethylenediamine (tetramethylene phosphonic acid)

Abstract Thulium-170 (T 1/2 = 128.4 d, E β (max) = 968 keV, E γ = 84 keV (3.26%)) has radionuclidic properties suitable to be used in palliative therapy of bone metastases as an alternative to 89SrCl2. 170Tm can be produced by a relatively easy route involving thermal neutron bombardment on natural Tm2O3 (100% 169Tm) in medium flux research reactors. The requirement for an enriched target does not arise and radionuclidic impurities are not formed by radiative capture during neutron activation. In this study 170Tm was produced using Tm(NO3)3, prepared by neutron activation (3–4E13) of a natural sample. Ethylenediamine (tetramethylene phosphonic acid) (EDTMP) was synthesized and radiolabeled with 170Tm. Complexation parameters were optimized to achieve maximum yields (>99%). The radiochemical purity of 170Tm-EDTMP was checked by RTLC. It was found to retain its stability at room temperature even after 2 months of preparation (> 95%). Biodistribution studies of the complexes carried out in wild-type rats showed significant bone uptake with rapid clearance from blood. The properties of produced 170Tm-EDTMP suggest applying a new efficient bone pain palliative therapeutic agent in the country instead of some other in-use radiopharmaceuticals, such as 89SrCl2 and 32P, in order to overcome metastatic bone pains.

109Pd labeled 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin: a Potential Agent for Targeted Tumor Therapy

Radiolabeled porphyrin derivatives could be envisaged as potential agents for targeted tumor therapy owing to the inherent tumor accumulation property exhibited by porphyrins. However, to achieve adequately high tumor accumulation and retention therein along with fast clearance from all non-target organs, an optimum balance between the hydrophilicity and lipophilicity must be achieved. Based on our prior experiences of working with (109)Pd-labeled porphyrins with variable lipophilicity and hydrophilicity, we have envisioned a suitable porphyrin derivative which could be expected to have the required balance between lipophilicity and hydrophilicity when complexed with (109)Pd. Towards this, 5,10,15,20- tetrakis[4-carboxymethyleneoxyphenyl]porphyrin (PHBEPH) was synthesized, radiolabeled with (109)Pd and its biological behavior in small animal model was studied. The porphyrin derivative was synthesized and characterized following the reported procedure and radiolabeled with (109)Pd [E β(max) = 1.12 MeV, E γ = 88 keV (3.6%), T1/2 = 13.7 h], which was produced by the thermal neutron bombardment on enriched (98% in (108)Pd) metallic Pd target at a flux of 3x1013 n/cm2.s for 3 d. Biological behavior of the radiolabeled agent was studied by biodistribution studies in Swiss mice bearing fibrosarcoma tumors. (109)Pd was produced with a specific activity of ∼1.85 GBq/mg (50 mCi/mg) and radionuclidic purity of 100%. (109)Pd complex of the synthesized porphyrin derivative was prepared with excellent radiochemical purity ( > 98%) and the complex was observed to exhibit Log P value of -1.29. Biodistribution studies revealed good tumor uptake [(3.55±0.49)% injected activity (IA)/g] within 30 min post-injection (p.i.) and retention therein till 24 h [(2.56±0.25)% IA)/g], upto which the study was continued. The complex exhibited fast clearance from the non-target organs with favorable tumor/blood and tumor/muscle ratios [(5.09±0.18)% and (284.44±3.25)% at 24 h p.i.]. The complex exhibited good uptake and retention in the tumor along with encouraging target to non-target ratio. Preliminary biological studies indicated the promising attributes of the agent towards its use for targeted radiotherapy.

Development of 170Tm‐DOTA‐cetuximab for radioimmunotherapy

Thulium‐170 [T1/2 = 128.4 days, Eβ(max) = 968 keV, Eγ = 84 keV (3.26%)] has radionuclidic properties suitable for use in therapy. 170Tm can be produced by a relatively feasible route involving thermal neutron bombardment on natural Tm(NO3)3 (100% 169Tm) in medium flux research reactors. The combination of beta‐particle emission of Tm‐170 with therapeutic properties of C225 monoclonal antibody (cetuximab) as well as optimization studies for future Tm‐167 labeling was targeted in this study. Conjugated cetuximab was obtained by the addition of 0.5 ml of a cetuximab pharmaceutical solution (1 mg, in phosphate buffer, pH 7.8) to a glass tube pre‐coated with in situ prepared 1,4,7,10‐tetraazacyclododecane‐N,N,N,N‐tetraacetic acid mono‐(N‐hydroxysuccinimidyl) ester (DOTA‐NHS) (~5 mg) at 25°C. Cetuximab was labeled with 170Tm‐Thulium chloride (100 MBq) after conjugation with DOTA‐NHS in 2–3 h (radiochemical purity >99%, instant thin‐layer chromatography, specific activity = 77–385 TBq/mmol). Biodistribution studies in wild‐type rats for free Tm‐170 and the radioimmunoconjugate were performed to determine the distribution up to 72 h. A comparative time‐frame study was performed for critical organs for both radiochemical species. The major organs of accumulation were shown to be the lung, liver, and spleen, respectively. Copyright © 2012 John Wiley & Sons, Ltd.

Effect of lipophilicity on biological properties of109Pd-porphyrin complexes: a preliminary investigation

The present study is designed to investigate the effect of lipophilicity of109Pd-porphyrin complexes on their biological properties which were evaluated in tumor-bearing animal model. The insight obtained could be utilized to develop other radiometalated porphyrin complexes with optimum tumor uptake and tumor to background ratio as potential agents for targeted tumor therapy.109Pd was produced by thermal neutron bombardment on enriched (in109Pd) metallic palladium target at a flux of 3 × 1013n/cm2.s for 3 d.109Pd complexes of three different porphyrin derivatives, namely, 5,10,15,20-tetrakis[3,4- bis(carboxymethyleneoxy)phenyl]porphyrin(I), 5,10,15,20-tetrakis[3,4-bis(carboethoxymethyleneoxy)phenyl]porphyrin(II) and 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin(III), which differ in their peripheral substituents, were synthesized. The biological behavior of the complexes was studied in Swiss mice bearing fibrosarcoma tumors.109Pd was produced with a specific activity of ~1.85 GBq/mg (50 mCi/mg) and radionuclidic purity of 100%. All the109Pd complexes were obtained in high yield (>97%) and they exhibited satisfactory in vitro stability at room temperature. The lipophilicity of the complexes follows the order109Pd-II ≫109Pd-III >109Pd-I. Biodistribution studies revealed that the most lipophilic109Pd-II complex exhibited highest initial tumor uptake but poor tumor/liver ratio, while109Pd-III complex exhibited the best tumor/liver ratio with reasonably good tumor accumulation. The lipophilicity of109Pd-porphyrin complexes was found to have considerable effect on their biological characteristics and radiometal-porphyrin complexes with optimum tumor uptake and adequately high tumor to background ratio could be synthesized by optimization of the lipophilicity through proper selection of peripheral substituents.

170Tm-EDTMP: a potential cost-effective alternative to 89SrCl2 for bone pain palliation

Metastron ((89)SrCl(2)) is a radiopharmaceutical currently used for bone pain palliation in several countries since the long half-life of (89)Sr (50.5 days) favors wider distribution than other radioisotopes approved for this application, which have shorter half-lives. Strontium-89 is not ideal for bone pain palliation due to its high energy beta(-) particle emission [E(beta(max))=1.49 MeV] and is also difficult to produce in large quantities. A (170)Tm [T(1/2)=128.4 days, E(beta(max))=968 keV, E(gamma)=84 keV (3.26%)]-based radiopharmaceutical for bone pain palliation could offer significant advantages over that of (89)Sr. The present study constitutes the first report of the preparation of a (170)Tm-based agent, (170)Tm-ethylenediaminetetramethylene phosphonic acid (EDTMP), and its preliminary biological evaluation in animal models. (170)Tm was produced by thermal neutron bombardment on natural Tm(2)O(3) target for a period of 60 days at a flux of 6x10(13) neutrons/cm(2).s. (170)Tm-EDTMP complex was prepared at room temperature. Biodistribution and scintigraphic imaging studies with (170)Tm-EDTMP complex were performed in normal Wistar rats. Preliminary dosimetric estimation was made using the data to adjudge the suitability of (170)Tm-EDTMP for bone pain palliation. (170)Tm was produced with a specific activity of 6.36 GBq/mg and radionuclidic purity of 100%. The (170)Tm-EDTMP was prepared with high radiochemical purity (>99%) and the complex exhibited satisfactory in vitro stability. Biodistribution and imaging studies showed good skeletal accumulation (50-55% of the injected activity) with insignificant uptake in any other vital organ/tissue. Activity was observed to be retained in skeleton until 60 days post-injection demonstrating that (170)Tm-EDTMP exhibits good bone-seeking properties with long retention. It is predicted that a dose of approximately 0.5 microGy/MBq is accrued to red bone marrow and 4.3 Gy/MBq is delivered to the skeleton. (170)Tm-EDTMP shows promising biodistribution features, encouraging dosimetric values and warrants further investigation in order to develop it as a bone pain palliative radiopharmaceutical. Despite the relatively long half-life (128.4 days) of (170)Tm, (170)Tm-EDTMP could be explored as a cost-effective alternative to (89)SrCl(2).

Preparation of 166Ho-oxine-lipiodol and its preliminary bioevaluation for the potential application in therapy of liver cancer

Intra-arterial administration of beta-emitting radionuclides in the form of suitable radiopharmaceuticals is one of the promising modalities for the treatment of liver cancer. Ho [T1/2=26.9 h, Ebeta(max)=1.85 MeV, Egamma=81 keV (6.4%)] could be envisaged as an attractive radionuclide for the use in liver cancer therapy owing to its high-energy beta-emission, short half-life and feasibility of its production with adequately high specific activity and radionuclidic purity using moderate flux reactors. Lipiodol is chosen as the vehicle to deliver localized doses of ionizing radiation to liver cancer cells after intra-arterial hepatic infusion as it is selectively retained in the vascular periphery of the proliferating cells. Ho was produced by thermal neutron bombardment on a natural Ho2O3 target at a flux of approximately 6 x 10 n/cm.s for 7 days. Radiolabelled lipiodol was prepared by dispersing the Ho-oxine complex in lipiodol. The biological behaviour of Ho-oxine-lipiodol was studied by biodistribution and imaging studies in normal Wistar rats. Ho was produced with a specific activity of 9.25-11.10 TBq/g and radionuclidic purity of approximately 100%. The Ho-labelled oxine complex was prepared in high yield (approximately 97%). Approximately, 95% of the Ho activity was dispersed in lipiodol within 30 min. The resulting radiolabelled preparation was found to exhibit good stability in physiological saline and human serum up to 3 days. The biodistribution and imaging studies revealed satisfactory hepatic retention (88.43+/-2.85% of injected activity after 2 days) with insignificant uptake in any other major organ/tissue except skeleton (6.44+/-1.07% at 2 days postinjection). The Ho-oxine-lipiodol preparation exhibited promising features in preliminary studies and warrants further investigation.

166Ho-Labeled Hydroxyapatite Particles: A Possible Agent for Liver Cancer Therapy

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. 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. 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. 166Ho-HA exhibited promising features as an agent for liver cancer therapy in preliminary studies and warrants further investigation

A novel [109Pd] palladium labeled porphyrin for possible use in targeted radiotherapy

The preferential accumulation of porphyrins in malignant tumor cells has been adequately documented. Hence, porphyrin derivatives radiolabeled with a suitable therapeutic radionuclide could be envisaged as potential agents for targeted tumor radiotherapy. Working in this direction, we have radiolabeled a porphyrin derivative, namely, 5,10,15,20-tetrakis[3,4-bis(carboethoxymethyleneoxy)phenyl]-porphyrin, synthesized in-house, with 109Pd [E β(max)=1.12 MeV, E γ=88 keV 3.6(%), T 1/2 = 13.7 h]. The envisaged rationale towards designing of this agent is based on the assumption that 109Pd would complex with the tetrapyrrole donor array constituting the porphyrin core, thereby providing a highly stable chelated complex, and the peripheral ester groups would impart optimum lipophilicity needed for sufficiently high tumor accumulation and retention therein. 109Pd was produced with a specific activity of ∼1.85 GBq/mg and radionuclidic purity of 100% by the thermal neutron bombardment of enriched (98% in 108Pd) metallic Pd target at a flux of 3×1013 n/cm2s1 for 3 d. The porphyrin derivative was synthesized by a multi-step reaction and characterized by normal spectroscopic techniques. 109Pd complex of the synthesized porphyrin derivative was prepared with excellent radiochemical purity (>98%) and the complex was observed to be stable upto 24 h at room temperature. Biodistribution studies carried out in Swiss mice bearing fibrosarcoma tumors revealed good tumor uptake [(5.28±1.46)% injected activity (IA)/g] within 30 min post-injection (p.i.). The complex exhibited favorable tumor/blood and tumor/muscle ratios [1.69±0.23 and 5.00±1.54, respectively at 3 h p.i.], albeit with high liver uptake throughout the time of study (>20% IA).

Preparation and preliminary studies on 177Lu-labeled hydroxyapatite particles for possible use in the therapy of liver cancer

Intra-arterial administration of particulates labeled with suitable beta(-)-emitting radionuclides has emerged as one of the most successful modality for the treatment of primary and metastatic liver cancer. (177)Lu [T(1/2)=6.73 d, E(beta)(max)=0.49 MeV, E(gamma)=208 keV (11%)] could be envisaged as a viable radionuclide for use in liver cancer therapy with wider acceptability owing to its feasibility of production in large-scale and relatively longer half-life providing logistic advantages. Hydroxyapatite (HA) particles of 20-60 microm size range are chosen as the particulate carrier due to its excellent biocompatibility and ease of labeling with lanthanides. (177)Lu was produced by thermal neutron bombardment on enriched Lu target. HA particles of desired size range were synthesized and characterized. Radiolabeling of HA particles was achieved at room temperatures within 30 min. The biological behavior of (177)Lu-labeled HA particles prepared under optimized conditions was tested in Wistar rats. (177)Lu was produced with a specific activity of 444.2+/-41.8 GBq/mg and radionuclidic purity of 99.98%. (177)Lu-HA was prepared with high radiochemical purity of >99%, and the radiolabeled agent showed excellent in vitro stability. The agent exhibited approximately 73% retention of injected activity in liver after 14 days postadministration with insignificant uptake in any other major organ/tissue except skeleton in biodistribution and imaging studies. (177)Lu-HA exhibited promising features in radiochemical studies. However, preliminary biodistribution studies in normal Wistar rats exhibited suboptimum liver retention and an undesirable skeletal uptake.

175Yb labeled polyaminophosphonates as potential agents for bone pain palliation

Ytterbium-175 ( T 1/2=4.2 d, E β(max) =480 keV) has radionuclidic properties suitable to be used in palliative therapy of bone metastases. 175Yb can be produced in moderate specific activity and good radionuclidic purity by thermal neutron bombardment of natural Yb target. The analysis of the neutron irradiated sample exhibited the presence of 96.2% 175Yb along with 2.1% 169Yb and 1.7% 177Lu at 6 h post-EOB. Four polyaminomethylene phosphonic acid ligands, ethylenediamine tetramethylene phosphonic acid, propylenediamine tetramethylene phosphonic acid, triethylenetetramine hexamethylene phosphonic acid and diethylenetriamine pentamethylene phosphonic acid were synthesized and radiolabeled with 175Yb. Complexation parameters were optimized to achieve maximum yields (92–99%). All complexes were found to retain their stability at room temperature even after 10 d of preparation. Biodistribution studies of the complexes carried out in Wistar rats showed significant bone uptake (3–4.4%/g in tibia at 3 h post-injection) with rapid clearance from blood and minimum uptake in soft tissues for all the complexes (bone/blood ratio ∼40–150 and bone/muscles ratio ∼40–400 at 3 h post-injection). These studies suggest that 175Yb complexes with the phosphonate ligands have potential for use in palliative treatment of painful bone metastases.

Production logistics of 177Lu for radionuclide therapy

Owing to its favourable decay characteristics 177Lu [ T 1/2=6.71 d, E β (max)=497 keV] is an attractive radionuclide for various therapeutic applications. Production of 177Lu using [ 176Lu ( n, γ) 177Lu] reaction by thermal neutron bombardment on natural as well as enriched lutetium oxide target is described. In all, ∼4 TBq/g (108 Ci/g) of 177Lu was obtained using natural Lu target after 7 d irradiation at 3×10 13 n/cm 2/s thermal neutron flux while it was ∼110 TBq/g (3000 Ci/g) of 177Lu when 60.6% enriched 176Lu target was used. In both the cases, radionuclidic purity was ∼100%, only insignificant quantity of 177mLu [ T 1/2=160.5 d, E β (max)=200 keV] could be detected as the radionuclidic impurity. Production logistics using different routes of production is compared. Possible therapeutic applications of 177Lu are discussed and its merits highlighted by comparison with other therapeutic radionuclides.

177Lu-labeled cyclic polyaminophosphonates as potential agents for bone pain palliation

177Lu ( T 1/2=6.71 d, E β (max)=497 keV) has radionuclidic properties suitable for use in palliative therapy of bone pain due to metastasis. 177Lu was produced in high-specific activity (3–4 TBq/g) and excellent radionuclidic purity (100%) by thermal neutron bombardment of natural Lu target. Two cyclic tetraaminomethylene phosphonate ligands, namely DOTMP and CTMP were synthesized and radiolabeled with 177Lu. The 177Lu-DOTMP complex was formed with very high yield (>99%) and showed excellent stability (up to 40 d at room temperature). Biodistribution of 177Lu-DOTMP was carried out in Wistar rats and the complex showed significant bone uptake (4.23%/g in femur and 5.23% in tibia at 3 h p. i.), rapid clearance from blood (no activity at 3 h p. i.) and minimum uptake in soft tissues.

Feasibility study for production of 175Yb: a promising therapeutic radionuclide

Owing to its favourable decay characteristics 175Yb ( T 1/2=4.2 d, E β(max)=480 keV) can be regarded as a potential radionuclide for therapeutic applications. Production of 175Yb using ( 174Yb(n, γ) 175Yb) reaction by thermal neutron bombardment on natural ytterbium target is described. The activity of 175Yb produced as well as its radionuclidic purity under different irradiation conditions were determined by γ-ray spectrometry using an HPGe 4 K MCA system and compared with theoretically calculated values. The radiochemical purity after chemical processing was determined by paper chromatography as well as paper electrophoresis techniques. It is found that 31 Ci/g (1145 GBq/g) of 175Yb can be produced with >95% radionuclidic purity (with ∼3% of 169Yb and ∼2% of 177Lu) by irradiating natural Yb 2O 3 target at a thermal neutron flux of 3×10 13 n/cm 2/s for a period of 5 d.

177Lu labelled polyaminophosphonates as potential agents for bone pain palliation.

Polyphosphonate ligands labelled with radioisotopes decaying by moderate energy beta emission have shown utility as palliative agents for painful bone metastasis. 177Lu (T(1/2)=6.71 d, Ebetamax=497 keV) has radionuclidic properties suitable for use in palliative therapy of bone metastasis. 177Lu was produced at a high specific activity and excellent radionuclidic purity by thermal neutron bombardment of a target prepared from natural Lu. Three polyaminomethylene phosphonate ligands, abbreviated as EDTMP, DTPMP and TTHMP, were synthesized and radiolabelled with 177Lu. Complexation parameters were optimized to achieve maximum yields (97-99.5%). All the complexes were found to retain their stability at room temperature even 14 days after preparation. Biodistribution studies of the complexes were carried out in Wistar rats. All the complexes showed significant bone uptake (6-6.5%/g in tibia at 3 h post-injection (p.i.)) with rapid clearance from blood and minimum uptake in soft tissues. These studies reveal that 177Lu complexes with the synthesized ligands have a potential use in palliative treatment of painful bone metastasis.