Hydroxyethylidene Diphosphonate Research Articles

Pearl-inspired self-extinguishing, thermal-conductive, and robust thermoplastic polyurethane composite by strengthening inter-layer packing

Fabricating thermoplastic polyurethanes (TPU) that exhibit self-extinguishing properties alongside strong mechanical characteristics and high thermal conductivity represents a challenging yet imperative endeavor within both scientific research and industrial applications. Enhancing the thermal conductivity of composites necessitates meticulous attention to surface treatment and the orientation of chemically inert hexagonal boron nitride nanosheets (BNNS). In this study, BNNS are treated by Strengthening inter-layer packing, which enriches the mechanical enhancement mechanism of the “brick-mortar” structure of natural pearl layers. The treatments use copper hydroxyethylidene diphosphonate and melamine hydroxyethylidene diphosphonate, which have a synergistic flame retardancy. Self-extinguishing TPU films with strong mechanical strength (57 MPa) and high thermal conductivity (9.12 W m−1 K−1) are produced when the functional particles are oriented to create multiple synergistic effects with the TPU simultaneously. Furthermore, when comparing CP0.02/MP@BNNS-TPU composite film to BNNS-TPU film, the limiting oxygen index of TPU composites increased to 30.2 %, and there was a significant decrease in both the peak and total heat releases (77.2 % and 80.6 %, respectively), meeting the UL-94 V-0 standard. This work offers a fresh method for creating self-extinguishing materials with high heat conductivity and robust mechanical characteristics.

Photochromism and Photomagnetism in Two Ni(II) Complexes Based on a Photoactive 2,4,6-Tris-2-Pyridyl-1,3,5-Triazine Ligand.

It is still challenging to construct novel photochromic and photomagnetic materials in the field of molecular materials. Herein, the 2,4,6-tris-2-pyridyl-1,3,5-triazine (TPTz) molecule was found to display photochromic properties under room temperature light irradiation. Two mononuclear structures, [Ni(H2O)(TPTz)(C2O4)]·2H2O (1; C2O42- = oxalate) [Ni(H2O)(TPTz)(C2O4)]·0.5H2O (2), and one chain compound [Ni(TPTz)(H2-HEDP)]·2H2O (3; HEDP = hydroxyethylidene diphosphonate) were obtained by assembling TPTz with polydentate O-ligands (oxalate and phosphonate) and the paramagnetic Ni2+ ions. The electron-transfer (ET)-dominated photochromism was observable in 1 and 2 after light irradiation with the photogeneration of relatively stable radicals, and the resultant photochromism was demonstrated via UV-vis, photoluminescence, X-ray photoelectron spectra, electron paramagnetic resonance spectra, and molecular orbital calculations. Due to the denser stacking interactions between the adjacent organic molecules, 2 exhibited a faster photochromic rate than 1. Compared with 1 and 2, compound 3 did not show photochromic behavior, which was deciphered by the theoretical calculations for all of the compounds. Importantly, the magnetic couplings appeared between photogenerated radicals and paramagnetic Ni2+ ions, resulting in a scarcely photomagnetic phenomenon of 1 and 2 in the Ni-based electron transfer photochromic materials. This work enriches the available kind of ligands for the design of ET photochromic materials, putting forward a method to tune the electron transfer photochromic efficiency in the molecular materials.

Light‐Induced Electron Transfer Toward On/Off Room Temperature Phosphorescence in Two Photochromic Coordination Polymers

AbstractPhotoswitchable room temperature phosphorescence (RTP) materials are of great interest due to their potential applications in optical devices and switches. Herein, two Zn‐based coordination polymers (CPs) (H3‐TPB)·[Zn6(H‐HEDP)(HEDP)3(H2O)2]·5H2O (complex 1; HEDP = hydroxyethylidene diphosphonate; TPB = 1,3,5‐tris(4‐pyridyl)benzene) and (H‐TPB)·[Zn3(H‐HEDP)(HEDP)(H2O)]·2H2O (complex 2) with distinguishable photochromism and tunable RTP are synthesized involving photoactive TPB molecules with different packing modes. Complex 1 exhibits bidirectionally on/off RTP regulation via on‐switch with excitation of 250−330 nm light and off‐switch with 350−380 nm, and the “turn‐on” behavior can be attributed to the advance of Förster resonance energy transfer‐assisted intersystem crossing (ISC) process while “turn‐off” process due to the transformation from H3‐TPB cations to H3‐TPB· radicals. Complex 2 exhibits photoswitchable RTP accompanied with reversible photochromism by leveraging the self‐absorption and RTP emission. Two demos based on the above compounds are further applied to demonstrate the application in information recording and encryption fields. This work supplies a strategy toward the design of switchable RTP systems using electron transfer photochromism, shedding light on broadening the frontiers of photoresponsive materials.

In situ fabrication of melamine hydroxy ethylidene diphosphonate wrapped montmorillonite for reducing the fire hazards of epoxy resin

Epoxy resin (EP) suffers from inherent flammability, many efforts had been made to address this issue. In this work, melamine hydroxy ethylidene diphosphonate wrapped montmorillonite (Mt@MHEDP) was successfully prepared through in situ fabrication to endow EP with lower fire hazards. The prepared Mt@MHEDP was well characterized by XRD, FTIR and SEM-EDS, a series of EP/Mt@MHEDP composites were prepared. The fire performance and thermal stability of EP composites were evaluated by LOI, cone calorimeter test and TGA. The flame-retardant mechanism was investigated by SEM and TG-IR. Due to the presence of MHEDP particles on Mt, the prepared Mt@MHEDP was dispersed uniformly in the EP matrix. From cone test, peak heat release rate (p-HRR) and flame growth index (FGI) of EP composites were reduced by 31.7% and 38.6%, respectively, with the addition of 8 wt% Mt@MHEDP. Moreover, the peak smoke production rate (p-SPR) and peak CO production rate were decreased by 30.9% and 40.4%, respectively. From TG-IR, the release of toxic CO and organic volatiles during the decomposition was decreased significantly, implying the lower toxicity and higher fire safety. The enhanced flame retardancy, suppressed smoke production and lower toxicity can be attributed to the synergetic effect of Mt and MHEDP.

Manipulating On/Off Single-Molecule Magnet Behavior in a Dy(III)-Based Photochromic Complex.

Exploitation of room temperature (RT) photochromism and photomagnetism to induce single-molecule magnet (SMM) behavior has potential applications toward optical switches and magnetic memories, and remains a tremendous challenge in the development of new bulk magnets. Herein, a series of chain complexes [Ln3(H-HEDP)3(H2-HEDP)3]·2H3-TPT·H4-HEDP·10H2O (QDU-1; Ln = Dy (QDU-1(Dy)), Gd (QDU-1(Gd)), and Y (QDU-1(Y)); HEDP = hydroxyethylidene diphosphonate; TPT = 2,4,6-tri(4-pyridyl)-1,3,5-triazine) were synthesized by solvothermal reactions. All the compounds exhibited reversible photochromic and photomagnetic behaviors via UV light irradiation at RT, induced by the photogenerated radicals via a photoinduced electron transfer (PET) mechanism. More importantly, the PET process induced significant variations in magnetic interactions for the Dy(III) congener. Strong ferromagnetic coupling with remarkably slow magnetic relaxation without applied dc fields was observed between DyIII ions and photogenerated O• radicals, showing SMM behavior after RT illumination. For the first time, we observed the reversible RT photochromism and photomagnetism in the lanthanide-based materials. This work realized the radicals-actuated on/off SMM behavior via RT light irradiation, providing a new strategy for constructing the light-induced SMMs.

Water-soluble double potassium and ammonium salts of iron(III) and manganese(II) with (hydroxyethylidene)diphosphonic acid

A method to multifold increase the water solubility of diiron(III) tris[(hydroxyethylidene)-diphosphonate) tetrahydrate Fe2(H2L)3·4H2O and manganese(II) (hydroxyethylidene)diphosphonate dihydrate MnH2L·2H2O, prepared by the reaction of 1-hydroxyethylidene-1,1-diphosphonic acid with iron(III)hydroxide and basic manganese carbonate. The method involves conversion of the phosphonates into their double salts Fe2K6L3·4H2O [Fe2(NH4)6L3·4H2O] and MnK1.3H0.7L·2H2O [Mn(NH4)2L·2H2O] by treatment of their aqueous suspensions with potassium or ammonium hydroxides. The solubility of the iron salt increases from 0.2 to 4.0 g per 100 mL solution (20 times) and that of the manganese salt increases from 0.1 to 4.8 g per 100 mL solution (45 times).

A phase I study of combined docetaxel and repeated high activity 186Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial)

Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and (186)Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity. A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m(2) 3-weekly). (186)Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred. Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of (186)Re-HEDP dose level 4 was not started. Combined therapy with docetaxel and (186)Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m(2) 3-weekly followed by (188)Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m(2), followed by (188)Re-HEDP 20 MBq/kg body weight.

The Tolerance and Therapeutic Efficacy of Rhenium-188 Hydroxyethylidene Diphosphonate in Advanced Cancer Patients with Painful Osseous Metastases

This study evaluated the tolerance and therapeutic efficacy of rhenium-188 hydroxyethylidene diphosphonate ((188)Re-HEDP) in patients with different types of advanced cancer suffering from bone pain caused by osseous metastases. Sixty-four patients received a single injection of escalating doses of (188)Re-HEDP with various dosages. Vital signs were observed before and after treatment for 8 weeks; adverse effects and rebound pain were recorded within 8 weeks after injection. Blood counts, biochemical parameters, and electrocardiogram were also measured over a period of 8 weeks. Clinical follow-up studies including the bone pain score and the Karnofsky performance score were performed. Pain response was scored by a four-point pain-rating scale as complete, marked, mild, and no response. No adverse effects or clinically significant changes in vital signs, electrocardiograms, and biochemical parameters in patients were observed, and there was no statistical change in alkaline phosphate levels in patients before or after treatment. The overall nadir of thrombopenia was at week 4, leucopoenia at week 3, and anemia at week 8. At week 8, the mean level of platelets and leukocytes returned to baseline levels. The pain score descended from 8.11 to 7.74 on the day of therapy, with a nadir of 4.89 at week 4, and up to 6.67 at week 8 after therapy (p < 0.05). The Karnofsky performance score continually increased from 74.81 before therapy to 82.31 at 8 weeks (p > 0.05 Pain palliation was reported by 73.33% of patients, with a mean duration of 6.85 weeks and a mean start time of 4.05 days. Of the specific tumor types, pain relief was achieved in 84.62% of patients with prostate cancer, 78.57% with breast cancer, 62.50% with lung cancer, and 55.56% with liver cancer. (188)Re-HEDP is a useful radiopharmaceutical agent for improving bone pain in patients with advanced cancer with painful bone metastases.

NUCLEAR DATA MEASUREMENT OF186RE PRODUCTION VIA VARIOUS REACTIONS

Rhenium-186, having a half-life of 90.64 h, is an important radionuclide, used in metabolic radiotherapy and radio immunotherapy. 186 Re hydroxyethylidene diphosphonate (HEDP) is a new compound used for the palliation of painful skeletal metastases. Its production is achieved via charged-particle-induced reactions; the data are available in EXFOR library. For the work discussed in this paper, production of 186 Re was done via nat W(p,n) 186 Re nuclear reaction. Pellets of nat W were used as targets and were irradiated with 15, 17.5, 20, 22.5, 25 MeV proton beams at 5 μA current. The radiochemical separation was performed by the ion exchange chromatography method. The production yield achieved at 25 MeV was 1.91 MBq·μA -1 ·h -1 . Excitation functions for the 186 Re radionuclide, via 186 W(p,n) 186 Re and 186 W(d,2n) 186 Re reactions were calculated by ALICEASH and TALYS-1.0 codes to validate and fit the experimental data and to obtain a recommended set of data for 186 W(p,n) 186 Re reaction. Required thickness of the targets was obtained by SRIM code for each reaction.

Synthesis, characterization and proton transport properties of mixed metal phosphonate-zirconium titanium hydroxy ethylidene diphosphonate

Novel hybrid material, zirconium titanium hydroxy ethylidene diphosphonate (ZTHEDP) of the class of tetravalent bimetallic acid (TBMA) salt was synthesized using sol-gel route. ZTHEDP was characterized for elemental analysis (zirconium, titanium and phosphorus by ICP-AES and carbon and hydrogen by CHN analyzer), spectral analysis (FTIR), thermal analysis (TGA), X-ray diffraction studies and SEM. Chemical resistivity of this material was assessed in various media-acids, bases and organic solvents. The protons present in the structural hydroxyl groups in ZTHEDP indicate good potential to exhibit solid state proton conduction. The proton transport property of ZTHEDP was explored by measuring specific conductance at different temperatures in the range of 303–423 K at 10 K intervals, using Solartron Impedance Analyzer (SI 1260) over a frequency range 1 Hz-32 MHz at a signal level below 1 V. Zirconium hydroxy ethylidene diphosphonate (ZrHEDP) and titanium hydroxy ethylidene diphosphonate (TiHEDP) were also synthesized under identical conditions, characterized and their proton transport properties investigated for comparative studies. It is observed that, in all cases, conductivity decreases with increasing temperature. Conductivity performance of ZTHEDP, ZrHEDP and TiHEDP is discussed based on conductivity data and activation energy. It is observed that, ZTHEDP exhibits enhanced conductance and the mechanism of transportation is proposed to be Grotthuss type.

Synthesis and Characterization of Zirconium Titanium Hydroxy Ethylidene Diphosphonate and Its Application in Separation of Metal Ions

A novel hybrid ion exchanger, zirconium titanium hydroxy ethylidene diphosphonate (ZTHEDP), of the class of tetravalent bimetallic acid (TBMA) salt has been synthesized by the sol gel route. ZTHEDP has been characterized for ICP-AES, TGA, FTIR, and XRD. Chemical resistivity of ZTHEDP in various media—acids, bases, and organic solvents have been assessed. Ion exchange capacity (IEC) and the effect of calcination (100°C to 500°C) on IEC has also been studied. The distribution behavior of metal ions Co2+, Ni2+, Cu2+, Zn2+ (d-block), Cd2+, Hg2+, Pb2+, Bi3+ (heavy) and La3+, Ce3+, Th4+, (f-block) towards ZTHEDP has been studied and the distribution coefficient (K d ) evaluated in aqueous as well as various electrolyte media/concentrations. Based on differential selectivity, the breakthrough capacity (BTC) and elution behavior of various metal ions towards ZTHEDP, a few binary and ternary metal ion separations have been carried out.

Adsorption mechanism and dispersion efficiency of three anionic additives [poly(acrylic acid), poly(styrene sulfonate) and HEDP] on zinc oxide

Adsorption on ZnO of sodium poly(acrylate) (PAA), sodium poly(styrene sulfonate) (PSS) and a monomer surfactant [hydroxyethylidene diphosphonate (HEDP)] was investigated in suspensions initially equilibrated at pH 7. Results demonstrate interplay in the adsorption mechanism between zinc complexation, salt precipitation, and ZnO dissolution. In the case of PAA, the adsorption isotherm exhibits a maximum attributed to the precipitation of zinc polyacrylate. PSS and HEDP formed high-affinity adsorption isotherms, but the plateau adsorption of HEDP was significantly lower than that of PSS. The adsorption isotherm of each additive is divided into two areas. At low additive concentration (high zinc/additive ratio), the total zinc concentration in the solution decreased and the pH increased upon addition. At a higher additive ratio, zinc concentration and pH increased with the organic concentration. The increase in pH is due to the displacement of hydroxyl ions from the surface and the increase in zinc concentration results from the dissolution of ZnO due to the complexation of zinc ions by the organics. The stability of the ZnO dispersions was investigated by measurement of the particle size distribution after addition of various amounts of polymers. The three additives stabilized the ZnO dispersions efficiently once full surface coverage was reached.

Systemic radionuclide therapy in pain palliation

Several radiopharmaceuticals were investigated to determine their efficacy and toxicity in the palliation of painful bone metastases. Data on the influence of rhenium-188 hydroxyethylidene diphosphonate (188Re-HEDP), rhenium-186 hydroxyethylidene diphosphonate (186Re-HEDP), and strontium-89 (89Sr) on pain symptoms, quality of life, and bone-marrow function were obtained in 64 patients with breast and prostate cancer. Thirty-one patients were treated with 188Re-HEDP (3194 +/- 387 MBq), 15 patients with 186Re-HEDP (1358 +/- 158 MBq), and 18 patients with 89Sr (152 +/- 19 MBq). The 188Re-HEDP group included six breast cancer patients and 25 prostate cancer patients; the 186Re-HEDP group included three breast cancer patients and 12 prostate cancer patients; and the 89Sr group included three breast cancer patients and 15 prostate cancer patients. All subjects participated in an interview using a standardized sets of questions before and after the 12-week term of therapy. Blood counts were taken weekly for six weeks and after 12 weeks. Results showed that 77 percent of patients reported pain relief after treatment with 188Re-HEDP, 67 percent after treatment with 186Re-HEDP, and 72 percent after treatment with 89Sr. Sixteen percent of patients treated with 188Re-HEDP, 13 percent treated with 186Re-HEDP, and 17 percent treated with 89Sr were able to discontinue their analgesics and were pain-free. Patients described an improvement on Karnofsky performance status (KPS) from 73 +/- 7 percent to 85 +/- 8 percent 12 weeks after 188Re-HEDP (p < 0. 05), from 72 +/- 13 percent to 79 +/- 12 percent after 186Re-HEDP (p = 0.251), and from 62 +/- 14 percent to 69 +/- 16 percent after 89Sr (p = 0.415). Only three patients undergoing 188Re-HEDP therapy, one undergoing 186Re-HEDP therapy, and three undergoing 89Sr therapy had thrombocytopenia (platelet count below 100 x 10(3)/microl) following treatment. The maximum nadir of platelet and leukocyte counts was observed between the second and fifth week after treatment for all radionuclides and was reversible within 12 weeks. The nadir was earlier for 188Re-HEDP with a shorter physical half-life compared with 89Sr. There were no significant differences in bone marrow toxicity (p = 0.123-0.421). Results of this study indicate that all evaluated radiopharmaceuticals were effective in pain palliation without induction of severe side effects. The increase in KPS after 188Re-HEDP was the only statistically significant finding (p = 0.001).

Liquid kit for preparation of 188rhenium-etidronate

The aim of this study was the preparation of a liquid kit for radiolabeling of 188Re-HEDP (hydroxyethylidene diphosphonate). 188Re was obtained from alumina based 188W/188Re generators. This paper reports the efficacy of a cold kit stored for more than two weeks, determined by the dependence of the radiolabeling yields of 188Re-HEDP on the incubation time, reducing agent concentration, the effects of concentration of ligand, the pH of the reaction and the temperature. The cold kits showed a good stability when carrie-free rhenium-188 was added in the reaction mixture.

High activity rhenium-186 hydroxyethylidene diphosphonate (HEDP) with autologous peripheral blood stem cell (PBSC) transplant: A novel treatment strategy in hormone refractory prostate cancer metastatic to bone

4562 Background: Bone marrow is the dose-limiting organ for bone seeking radionuclide therapy of bone metastases from prostate cancer. This prospective phase 2 trial investigated the potential for improvement in disease control by using autologous peripheral blood stem cell transplant to permit administration of high activities of a bone seeking radionuclide, Rhenium-186 HEDP in patients with progressive hormone refractory prostate cancer. Methods: Eligible patients had histologically confirmed prostate cancer metastatic to the skeleton, rising PSA despite castrate testosterone levels, WHO PS 0–1, and minimal soft-tissue disease. Patients received between 4500 and 5000MBq of Rhenium-186 HEDP i.v. (approximately 4 times the dose normally used for palliation), followed 14 days later by the return of pre-harvested PBSCs. Response was assessed using PSA, survival, pain scores, and quality of life measurement. Results: Thirty-eight patients with a median age of 67 years (range 50–77), and a median PSA of 57 ng/ml (range 4–3628) received a median activity of 4978 MBq Rhenium-186 HEDP (range 4400–5097). At a median follow up of 12 months (range 3–32), the most serious toxicity was short-lived (<7 days) grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 31 months with a Kaplan-Meier estimated 1 and 2-year survivals of 81% and 50% respectively. Twenty six patients (60%, 95% CI, 45–74%) had stable or reduced PSA levels 3 months post therapy, 10 of whom had PSA reductions of > 50% lasting > 4 weeks. Quality of life measures were stable or improved in 29 (76%) at 3 months. Conclusions: We believe the survival data and PSA response rates in this group of heavily pre-treated patients are encouraging and merit further investigation in a randomised trial. No significant financial relationships to disclose.

High activity rhenium-186 hydroxyethylidene diphosphonate (HEDP) with autologous peripheral blood stem cell (PBSC) transplant: A novel treatment strategy in hormone refractory prostate cancer metastatic to bone

4562 Background: Bone marrow is the dose-limiting organ for bone seeking radionuclide therapy of bone metastases from prostate cancer. This prospective phase 2 trial investigated the potential for improvement in disease control by using autologous peripheral blood stem cell transplant to permit administration of high activities of a bone seeking radionuclide, Rhenium-186 HEDP in patients with progressive hormone refractory prostate cancer. Methods: Eligible patients had histologically confirmed prostate cancer metastatic to the skeleton, rising PSA despite castrate testosterone levels, WHO PS 0–1, and minimal soft-tissue disease. Patients received between 4500 and 5000MBq of Rhenium-186 HEDP i.v. (approximately 4 times the dose normally used for palliation), followed 14 days later by the return of pre-harvested PBSCs. Response was assessed using PSA, survival, pain scores, and quality of life measurement. Results: Thirty-eight patients with a median age of 67 years (range 50–77), and a median PSA of 57 ng...

Complexation of 188Re-phosphonates: in vitro and in vivo studies

Summary MDP (methylenediphosphonate) and HEDP (hydroxyethylidene diphosphonate), both diphosphonates, and EDTMP (ethylenediamine tetramethylene phosphonic acid), a tetraphosphonate ligand, have been previously labeled with 188Re for use in metastatic bone-pain palliation. The aim of this study was a comparison between the three complexes 188Re-MDP, 188Re-HEDP and 188Re-EDTMP concerning the complexation conditions, in order to achieve maximum yield, stability and bone uptake. Methods: MDP was dissolved in water and HEDP and EDTMP were dissolved in NaOH 1N followed by reduction of pH with HCl 1N. To all mixtures stannous chloride and 188Re4 - were added in a nitrogen atmosphere. The preparations were heated in boiling water bath for 15min. Yield as well as radiochemical stability was estimated by ITLC. Different concentrations of phosphonates and stannous chloride were evaluated. Biodistribution studies in Swiss mice were done for the three 188Re-phosphonates that presented the best radiochemical yield. The optimal ligand concentration for maximum complexation was 85.2mM for MDP, 72.8mM for HEDP and 45.8mM for EDTMP. The best amount of SnCl2·2H2O} was 1.5mg/mL for 188Re-HEDP and 1mg/mL for both 188Re-MDP and 188Re-EDTMP. In these conditons the three complexes showed a complexation rate above 95. Reasonable radiochemical stability for 24 hours was achieved by 188Re-EDTMP when employing ascorbic acid. All products showed a great uptake by the kidneys. 188Re-EDTMP had the greatest uptake by femur (3.1±0.2 ID/g) followed by 188Re-MDP (1.2±0.1 ID/g) and 188Re-HEDP (1.0±0.1 ID/g), 4 hours post injection. 188Re-EDTMP displayed a femur bone/muscle ratio of 28.5, 188Re-MDP 4.9 and 188Re-HEDP 4.9. In conclusion 188Re-EDTMP demonstrated the best potential as a radiopharmaceutical for bone cancer pain relief, encouraging further dosimetric studies and clinical trials.

Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line

To test the hypothesis that radiation-induced, transient G2/M arrest could potentially sensitize tumor cells to a subsequent, well-timed radiation dose. PC-3 human prostate cancer cells were treated using either radiotherapy or (186)Re-labeled hydroxyethylidene diphosphonate ((186)Re-HEDP) treatment in different combinations. The resulting cell cycle shift and clonogenic cell death were analyzed by DNA flow cytometry and colony forming cell assay, respectively. Radiation doses of 4 Gy and 8 Gy induced a transient G2/M arrest, with a maximum after approximately 16 h. The presence of 2 mM pentoxifylline effectively abrogated this radiation-induced G2 M arrest, confirming a cell-cycle checkpoint-mediated effect. A second dose of 4 Gy, timed at the height of the G2/M arrest, significantly increased clonogenic cell-kill compared to delivery after a suboptimal interval (10 h, 20 h or 25 h after the first radiation fraction). Moreover, timed second doses of 2 Gy, 3 Gy or 4 Gy yielded improved normalized treatment effects compared to non-pretreated control. Radionuclide treatment of PC-3 cells, using (186)Re-HEDP (0.74 MBq/ml and 1.48 MBq/ml; total dose: 4.1 and 8.2 Gy, respectively) also induced a dose-dependent G2/M accumulation, which sensitized the cells to a subsequent external radiation dose of 2 Gy or 4 Gy. The observed pattern of cell-cycle shift towards a predominance of the G2/M phase is in line with the lack of functional p53 in this cell line. Radiation-induced cell-cycle shift was shown to effectively confer increased radiosensitivity to prostate tumor cells. Optimally timed combination of radiotherapy and radionuclide therapy could thus significantly increase treatment efficacy.

Preparation and biological evaluation of 188Re-ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) as a potential agent for bone pain palliation.

This study was undertaken in order to prepare 188Re labelled ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) (EDTMP), and to determine its potential as a therapeutic radiopharmaceutical for the palliation of metastatic bone pain. The effects of pH, incubation methods, and concentrations of stannous chloride, EDTMP, and ammonium perrhenate as a carrier on radiochemical yield and stability were evaluated. Biodistribution studies were performed in male Wistar rats after intravenous injection of 188Re-EDTMP and compared with those of hydroxyethylidene diphosphonate (HEDP). Greater than 95% radiochemical yield of 188Re-EDTMP was obtained under the optimal conditions (0.1 mmol x ml(-1) of EDTMP, 0.5 mg x ml(-1) of stannous chloride, and pH 1.0). Heating the reaction mixture (boiling water for 15 min, and microwave heating for 15 s) and the addition of ammonium perrhenate increased the radiochemical stability (>90% at 3 h, and >80% at 48 h). The biodistribution of 188Re-EDTMP showed high bony uptake and rapid clearance from other organs, and high bone-to-soft tissue ratios, which are similar to 188Re-HEDP. In conclusion, 188Re-EDTMP was prepared with high radiochemical yield and stability, and showed favourable biological characteristics. Microwave heating was a convenient and rapid method for the preparation of 188Re-EDTMP. It is considered that 188Re-EDTMP is a potential therapeutic agent for bone metastasis.

A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer.

A multicentre observational study was conducted by the Italian Association of Nuclear Medicine between 1996 and 1998. Twenty-nine Nuclear Medicine Departments participated. The aims of the study were to systematically evaluate the efficacy, toxicity and repeatability of radionuclide therapy of painful bone metastases (RTBM) in a large number of patients and to assess its incidence in patients with prostate cancer. Out of 818 treatments performed with a single i.v. dose of 148 MBq of strontium-89 chloride or 1,295 MBq of rhenium-186 hydroxyethylidene diphosphonate (HEDP), 610 could be evaluated (527 with 89Sr and 83 with 186Re-HEDP). Eighty-one patients received multiple (up to five) RTBM. The total number of retreatments was 100. Patients were followed up for a period of 3-24 months. Results, assessed according to pain relief and consumption of analgesic drugs, were expressed at four levels: 1, no response; 2, mild response; 3, good response; 4, excellent response. Responses were: level 1 in 19%, level 2 in 21.3%, level 3 in 33.3% and level 4 in 26.4% of cases. Retreatments showed significantly (P<0.01) worse responses (48% levels 3+4), in comparison to first RTBM. Duration of palliation was 5.0+/-3.5 months, and was longer in cases of excellent response, in first RTBM, in patients with limited metastases and when 89Sr was used. Better responses were found in cases of limited skeletal disease, under good clinical conditions, when life expectancy exceeded 3 months, and in radiologically osteoblastic or mixed bone lesions. The only statistically significant predictive factor was life expectancy (P<0.001). Flare phenomenon (14.1% of cases) did not correlate with the response. Haematological toxicity (mild to moderate in most cases) mainly affected platelets, and was observed in 25.5% of cases overall and in 38.9% of retreatments. RTBM did not seem to prolong life, though in some cases scintigraphic regression of bone metastases was observed. The two radiopharmaceuticals did not show any statistically significant differences in palliative efficacy and toxicity, either in first RTBM or in retreatments.