Tapas Das

Production logistics of 177Lu for radionuclide therapy.

Owing to its favourable decay characteristics 177Lu [T(1/2)=6.71 d, Ebeta(max)=497 keV] is an attractive radionuclide for various therapeutic applications. Production of 177Lu using [176Lu (n,gamma)177Lu] reaction by thermal neutron bombardment on natural as well as enriched lutetium oxide target is described. In all, approximately 4 TBq/g (108 Ci/g) of 177Lu was obtained using natural Lu target after 7 d irradiation at 3 x 10(13) n/cm2/s thermal neutron flux while it was approximately 110 TBq/g (3000 Ci/g) of 177Lu when 60.6% enriched 176Lu target was used. In both the cases, radionuclidic purity was approximately 100%, only insignificant quantity of 177mLu [T(1/2)=160.5 d, Ebeta(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, Ebeta(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 (3-4TBq/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.

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 (T½ = 6.71 d, Eβmax = 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.

177Lu-EDTMP: A Viable Bone Pain Palliative in Skeletal Metastasis

Designing ideal radiopharmaceuticals for use as bone pain palliatives require the use of a moderate energy beta() emitter as a radionuclide and a suitable polyaminophosphonic acid as a carrier molecule. Owing to its suitable decay characteristics [T(1/2) = 6.73 d, E((max)) = 497 keV, E() = 113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production in adequate specific activity and radionuclidic purity using a moderate flux reactor, 177Lu could be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study was therefore, oriented toward the preparation and biologic evaluation of 177Lu complex of ethylenediaminetetramethylene phosphonic acid (EDTMP) in various animal models, with an aim to prepare a viable radiopharmaceutical for bone pain palliation. 177Lu was produced with a specific activity of approximately 12 GBq/mg (approximately 324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural Lu2O3 targeted at a thermal neutron flux of approximately 6 x 10(13) n/cm(2).s for 21 days. 177Lu-EDTMP complex was prepared in high-yield and excellent radiochemical purity (>99%), using EDTMP synthesized and characterized in-house. The complex exhibited excellent in vitro stability at room temperature. Biodistribution studies in Wistar rats showed a rapid skeletal accumulation of injected activity [(1.74 +/- 0.30)% per gram in femur at 3 hours postinjection] with a fast clearance from blood and minimal uptake in any of the major organs. Scintigraphic imaging studies carried out in normal Wistar rats, New Zealand white rabbits, as well as in Beagle dogs also demonstrated significant accumulation of the agent in the skeleton and almost no retention of activity in any other vital organs.

Comparative studies of 177Lu-EDTMP and 177Lu-DOTMP as potential agents for palliative radiotherapy of bone metastasis

(177)Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents owing to its suitable nuclear decay characteristics [T(1/2)=6.73d, E(beta)((max))=497keV, E(gamma)=113keV (6.4%) and 208keV (11%)] and large-scale production feasibility with adequate specific activity using moderate flux research reactors. Multidentate polyaminophosphonic acids have already been proven as the carrier molecule of choice for radiolanthanides and similar +3 metal ions in designing agents for palliative radiotherapy of bone pain due to skeletal metastases. The present paper describes a comparison between (177)Lu complexes of two potential polyaminophosphonic acid ligands, namely Ethylenediaminetetramethylene phosphonic acid (EDTMP) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) with respect to their radiochemical and in-vivo biological characteristics. Although both the agents have exhibited promising features, the study reveals that (177)Lu-EDTMP has marginally higher skeletal accumulation in comparison to that of (177)Lu-DOTMP, while the latter has slightly faster blood clearance along with lower retention in liver and kidneys in animal models.

Options to meet the future global demand of radionuclides for radionuclide therapy

Nuclear medicine continues to represent one of the important modalities for cancer management. While diagnostic nuclear medicine for cancer management is fairly well established, therapeutic strategies using radionuclides are yet to be utilized to their full potential. Even if 1% of the patients undergoing diagnostic nuclear medicine procedures can benefit from subsequent nuclear therapeutic intervention, the radionuclide requirement for nuclear therapeutics would be expected to be in the multi-million Curie levels. Meeting the demand for such high levels of therapeutic radionuclides at an affordable price is an important task for the success of radionuclide therapy. Although different types of particle emitters (beta, alpha, Auger electron etc.) have been evaluated for treating a wide variety of diseases, the use of β⁻ emitting radionuclides is most feasible owing to their ease of production and availability. Several β⁻ emitting radionuclides have been successfully used to treat different kind of diseases. However, many of these radionuclides are not suitable to meet the projected demand owing to the non-availability with sufficiently high specific activity and adequate quantity because of high production costs, relatively short half-lives etc. This article describes the advantages and disadvantages for broader uses of some of the well known therapeutic radionuclides. In addition, radioisotopes which are expected to have the potential to meet the growing demand of therapeutic radionuclides are also discussed.

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

INTRODUCTION 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. METHODS (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. RESULTS (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. CONCLUSION (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 and preliminary biological evaluation of 177Lu-labelled hydroxyapatite as a promising agent for radiation synovectomy of small joints

AimLutetium-177 (177Lu) is considered to be a promising radionuclide for use in radiation synovectomy of small-sized joints owing to its favourable decay characteristics [t1/2=6.73 days, E&bgr;(max)=0.49 MeV, E&ggr;=113 keV (6.4%), 208 keV (11%)] and feasible and cost-effective production route. Hydroxyapatite particles are regarded as one of the most suitable carriers for applications in radiation synovectomy, and labelling with 177Lu has been envisaged. The present work describes the preparation and preliminary biological evaluation of 177Lu-labelled hydroxyapatite particles. Methods177Lu-labelled hydroxyapatite particles were prepared using 177Lu produced by thermal neutron irradiation of a natural (2.6% 176Lu) Lu2O3 target and hydroxyapatite particles (particle size, 2–10 μm) prepared in-house. The biological efficacy of the radiolabelled preparation was tested by recording serial gamma scintigraphic images after injecting the agent in both normal and arthritic knee joints of Wistar rats. Results177Lu-hydroxyapatite was prepared with high yield and high radiochemical purity (∼99%) and the radiolabelled particles showed excellent in-vitro stability at room temperature. Serial scintigraphic images of normal and arthritic Wistar rats showed complete retention of activity within the synovial cavity, with no measurable activity leaching out from the joint until 168 h post-injection. ConclusionStudies with 177Lu-hydroxyapatite indicate its potential for use as an agent for radiation synovectomy of digital joints, as a viable alternative to 169Er-based agents. The results also demonstrate the possibility of preparing a large number of patient doses of 177Lu-hydroxyapatite from indigenously produced 177Lu using a natural target.

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

INTRODUCTION 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. METHODS (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. RESULTS (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. CONCLUSION (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.

An electro-amalgamation approach to isolate no-carrier-added 177Lu from neutron irradiated Yb for biomedical applications

INTRODUCTION A novel two-step separation process for the production of no-carrier-added (NCA) (177)Lu from neutron irradiated Yb target through an electrochemical pathway employing mercury-pool cathode has been developed. METHODS A two-cycle electrolysis procedure was adopted for separation of (177)Lu from (177)Lu/Yb mixture in lithium citrate medium. The influence of different experimental parameters on the separation process was investigated and optimized for the quantitative deposition of Yb in presence of (177)Lu. The first electrolysis was performed for 50 min in the (177)Lu/Yb feed solution at pH 6 applying a potential of 8 V using platinum electrode as anode and mercury as the cathode. The second electrolysis was performed under the same conditions using fresh electrodes. The radionuclidic and chemical purity of (177)Lu was determined by using gamma ray spectrometry and atomic absorption spectrometry. The suitability of (177)Lu for biomedical applications was ascertained by labeling 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid D-Phe(1)-Tyr(3)-octreotate(DOTA-TATE) with (177)Lu. RESULTS This process could provide NCA (177)Lu with >99.99% radionuclidic purity and an overall separation yield of ∼99% was achieved within 3-4 h. The Hg content in the product was determined to be <1 ppm. Radiolabeling yield of >98% was obtained with DOTA-TATE under the optimized reaction conditions. CONCLUSIONS An efficient strategy for the separation of NCA (177)Lu, suitable for biomedical applications, has been developed.