Meera Venkatesh

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.

Nanoceria-PAN composite-based advanced sorbent material: a major step forward in the field of clinical-grade 68Ge/68Ga generator.

The (68)Ge/(68)Ga generator has high potential for clinical positron emission tomography (PET) imaging. However, because of the unavailability of a suitable sorbent material, the commercially available (68)Ge/(68)Ga generators are not directly adaptable for the preparation of (68)Ga-labeled radiopharmaceuticals. In view of this, a new nanoceria-polyacrylonitrile (PAN) composite sorbent has been synthesized by decomposition of a cerium oxalate precursor to cerium oxide and its subsequent incorporation in PAN matrix for the development of a clinical grade (68)Ge/(68)Ga generator. The X-ray diffraction (XRD) studies and BET nitrogen adsorption technique revealed that nanocrystalline ceria had an average particle size of approximately 10 nm, surface area of 72 +/- 3 m(2)/g and an average pore size of 3.8 +/- 0.1 A. Investigation of the distribution ratio (K(d)) values for the prepared sorbent in 0.01 N HCl medium revealed the suitability of the sorbent for the quantitative retention of (68)Ge and efficient elution of clinical grade (68)Ga. A 370 MBq (10 mCi) (68)Ge/(68)Ga chromatographic generator was developed using this sorbent. (68)Ga could be regularly eluted from this generator with >80% elution yield. The eluted (68)Ga possess high radionuclidic purity (<1 x 10(-5)% of (68)Ge impurity), chemical purity (<0.1 ppm of Ce, Fe and Mn ions) and was amenable for the preparation of (68)Ga-labeled radiopharmaceuticals. The generator gave a consistent performance with respect to the elution yield and purity of (68)Ga over an extended period of 7 months.

Development of a nano-zirconia based 68Ge/68Ga generator for biomedical applications.

INTRODUCTION Most of the commercially available (68)Ge/(68)Ga generator systems are not optimally designed for direct applications in a clinical context. We have developed a nano-zirconia based (68)Ge/(68)Ga generator system for accessing (68)Ga amenable for the preparation of radiopharmaceuticals. METHODS Nano-zirconia was synthesized by the in situ reaction of zirconyl chloride with ammonium hydroxide in alkaline medium. The physical characteristics of the material were studied by various analytical techniques. A 740 MBq (20 mCi) (68)Ge/(68)Ga generator was developed using this sorbent and its performance was evaluated for a period of 1 year. The suitability of (68)Ga for labeling biomolecules was ascertained by labeling DOTA-TATE with (68)Ga. RESULTS The material synthesized was nanocrystalline with average particle size of ~7 nm, pore-size of ~4 Å and a high surface area of 340±10 m(2) g(-1). (68)Ga could be regularly eluted from this generator in 0.01N HCl medium with an overall radiochemical yield >80% and with high radionuclidic (<10(-5)% of (68)Ge impurity) and chemical purity (<0.1 ppm of Zr, Fe and Mn ions). The compatibility of the product for preparation of (68)Ga-labeled DOTA-TATE under the optimized reaction conditions was found to be satisfactory in terms of high labeling yields (>99%). The generator gave a consistent performance with respect to the elution yield and purity of (68)Ga over a period of 1 year. CONCLUSIONS The feasibility of preparing an efficient (68)Ge/(68)Ga generator which can directly be used for biomedical applications has been demonstrated.

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.

Preparation and bioevaluation of 166Ho labelled hydroxyapatite (HA) particles for radiosynovectomy

The preparation of 166Ho labeled hydroxy apatite (HA) particles for radiosynovectomy applications is described in this paper. 166Ho was prepared by the irradiation of Ho2O3 at a flux of 1.8 x 10(13) neutrons/cm2/s for about 7 days. The irradiation resulted in the production of approximately 17 GBq of 166Ho activity at the end of six hours post end of bombardment and the corresponding specific activity was approximately 3-4 GBq/mg of Ho. The irradiated target was dissolved in 0.1 N HCl solution. Radionuclidic purity was ascertained by high resolution gamma ray spectrometry. HA particles were synthesized and characterized by X-ray diffractometry. Labeling studies were carried out with and without citric acid as a transchelating agent. Radiochemical yield and purity of the 166Ho-HA particles were ascertained by paper chromatography and by paper electrophoresis techniques. Labeling yield of >98% could be achieved at pH 7, with 40 mg of HA particles and 8.6 microg of Ho. 166Ho-HA particles prepared were stable for 72 h. Bio-evaluation of the 166Ho -HA particles were carried out by injecting approximately 74 MBq dose in 200 microL (approximately 8 mg of 166Ho-HA particles) directly into the arthritis induced knee joints as well as into the healthy knee joints of white New Zealand rabbits. Images of the injected joints of the animals recorded using a gamma camera at regular intervals showed good retention. Blood samples were collected from the animals and activity assayed in a scintillation detector. Experiments were also carried out under identical conditions in normal rabbits. In both the cases, it was observed that there was no significant extra articular leakage of the injected activity over the study period of 96 h post injection.

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.