Haladhar Dev Sarma

Tocotrienols from palm oil as effective inhibitors of protein oxidation and lipid peroxidation in rat liver microsomes

Tocotrienols from palm oil showed significant ability to inhibit oxidative damage induced by ascorbate-Fe2+ and photosensitization, involving different mechanisms, in rat liver microsomes. The tocotrienol-rich fraction from palm oil (TRF), being tried as a more economical and efficient substitute for α-tocopherol, showed time- and concentration-dependent inhibition of protein oxidation as well as lipid peroxidation. It was more effective against protein oxidation. The extent of inhibition by TRF varied with different peroxidation products such as conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS). Among the constituents of TRF, γ-tocotrienol was the most effective followed by its α- and δ-isomers. In general, at a low concentration of 5 μM, TRF was able to prevent oxidative damage to significant extent (37% inhibition of protein oxidation and 27–30% of lipid peroxidation at 1 h of incubation). The protective ability of TRF (30.1% at 5 μM with TBARS formation) was significantly higher than that of the dominant form of vitamin E, α-tocopherol (16.5% under same conditions). Hence our studies indicate that this fraction from palm oil can be considered as an effective natural antioxidant supplement capable of protecting cellular membranes against oxidative damage.

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.

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.

On the isolation and evaluation of a novel unsubstituted 5-nitroimidazole derivative as an agent to target tumor hypoxia.

The presence and extent of hypoxic regions in cancerous tissue bears a negative influence on the effectiveness of radiation therapy and chemotherapy of the cancer hence estimation of hypoxia is an important problem. Several (99m)Tc-labeled nitroimidazole-based non-invasive agents have been tried for this purpose but none had optimal characteristics and the search continues. Herein we report, for the first time to the best of our knowledge, the isolation, (99m)Tc(CO)(3) labeling and evaluation of an unsubstituted 5-nitroimidazole derivative obtained as a side product during the synthesis of 4-nitroimidazole derivative. The (99m)Tc(CO)(3)-labeled complex of 5-nitroimidazole derivative could be prepared in excellent yield under mild conditions. Its evaluation in fibrosarcoma tumor bearing Swiss mice showed uptake and slow clearance of injected activity from tumor. The tumor-to-muscle ratio was found to be very high but tumor-to-blood ratio greater than 1 could not be obtained throughout the limited time point study. The study revealed that complex under investigation has features similar to other 2-nitroimidazole complexes so far as the retention of injected activity in tumor is concerned.

Tc-99m and Re-186 complexes of tetraphosphonate ligands and their biodistribution pattern in animal models

The syntheses of four alpha-aminomethyl phosphonates and their complexation studies with (99m)Tc and (186/188)Re are reported. Complexation conditions were standardized to give maximum yields, which ranged from 90-97%. The yields of complexation were estimated by paper chromatography. The (99m)Tc complexes were stable for more than 4 h, while the (186/188)Re complexes were stable for 3-8 days when stored at 4 degrees C. Biodistribution of these complexes in Wistar rats were carried out, and the uptake in bone and other soft tissue are detailed. Bone uptake of the (99m)Tc complexes varied from 40-60% at 30 min postinjection depending on the ligands. The uptake in soft tissue was minimum with all the complexes. A comparison of the biodistribution studies of the (99m)Tc complexes with that of the well-established radiopharmaceutical (99m)Tc-MDP was carried out for the purpose of evaluating the efficacy of the radiopharmaceutical preparation with the complexes of these ligands. The bone uptake of the (186/188)Re complexes varied from 19-28% corresponding to 1.6-3% per g at 3 h postinjection. The residual activity in both (99m)Tc and (186/188)Re complexes showed renal clearance.