Optimal antibody-radionuclide combinations for clinical radioimmunotherapy: a predictive model based on mouse pharmacokinetics

A theoretical comparison was made of radioimmunotherapy (RIT) dosimetry estimates for eight radionuclides (⁹⁰Y,¹⁰⁵Rh, ¹³¹I, ¹⁵³Sm, ¹⁸⁶Re, ¹⁸⁸Re,¹⁹⁸Au, ²¹¹At) conjugated to IgG, F(ab′)₂, and Fab antibody forms. Antibody pharmacokinetics, derived from a nude mouse animal model were combined with appropriate physical data and S values to evaluate absorbed dose to a 0.5 kg centrally located tumor, total body and kidney. Radioimmunoconjugates of F(ab′)₂ with ⁹⁰Y, ¹⁵³Sm and ¹⁸⁶Re were predicted to be the most promising for RIT.     

The chemistry of rhenium and technetium as related to the use of isotopes of these elements in therapeutic and diagnostic nuclear medicine

The β emitting isotopes ¹⁸⁶Re and ¹⁸⁸Re are logical choices on which to base therapeutic radiopharmaceuticals that might be expected to be analogous to diagnostic radiopharmaceuticals based on ^99mTc. However, the chemistry of rhenium is sufficiently different from that of technetium so that the development of Re radiopharmaceuticals often cannot be predicated on the known chemistry and biological behavior of ^99mTc radiopharmaceuticals. The relevant chemical differences involve the greater stability of the higher oxidation states of Re (and thus the greater tendency of reduced Re radiopharmaceuticals to undergo re-oxidation to perrhenate), and the greater substitution inertness of reduced Re complexes. These differences are illustrated (1) in the preparation and use of ¹⁸⁶Re (Sn)-HEDP and ^99mTc(Sn)-HEDP diphosphonate radiopharmaceuticals designed, respectively, for palliative therapy and diagnosis of metastatic cancer to bone, and (2) in the preparation and biodistribution of tr-[¹⁸⁶Re(DMPE)₂Cl₂]⁺ and [¹⁸⁶Re(DMPE)₃]⁺, analogs to the potential myocardial perfusion imaging agents tr-[^99mTc(DMPE)₂Cl₂]⁺ and [^99mTc(DMPE)₃]⁺. [HEDP = (1-hydroxyethylidene)diphosphonate; DMPE = 1,2-bis(dimethylphosphino)ethane].     

Metal-ion speciation in blood plasma incorporating the tetraphosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropilydenediphosphonate (APDDMP), in therapeutic radiopharmaceuticals

In a quest for more effective radiopharmaceuticals for pain palliation of metastatic bone cancer, this paper relates results obtained with 166Ho and 153Sm complexed to the bone seeking phosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropylidenediphosphonate (APDDMP). APDDMP is synthesised from the known bone cancer pain palliation agent 1-hydroxy-3-aminopropylidenediphosphonate (APD) and was complexed to lanthanide trivalent metal ions. This work is performed to utilise the idea that the energetic beta-particle emitter, 166 Ho, coupled with phosphonate ligands such as APD and APDDMP could afford a highly effective radiopharmaceutical in the treatment of bone cancer. Complex-formation constants of APDDMP with the important blood plasma metal-ions, Ca2+, Mg2+, and Zn2+ and the trivalent lanthanides Ho3+ and Sm3+ were measured by glass electrode potentiometry at 37 degrees C and I = 150 mM. Blood plasma models were constructed using the computer code ECCLES and the results compared with those gathered from animal tests. The 166Ho-APDDMP complex was found to have little liver or bone uptake while 153Sm-APDDMP had a moderate bone uptake. This was primarily due to the high affinity of APDDMP for Ca(II). Clinical observations could be explained by the blood plasma modelling.     

<Superscript>153</Superscript>Sm and <Superscript>166</Superscript>Ho complexes with tetraaza macrocycles containing pyridine and methylcarboxylate or methylphosphonate pendant arms

A set of tetraaza macrocycles containing pyridine and methylcarboxylate (ac₃py14) or methylphosphonate (MeP₂py14 and P₃py14) pendant arms were prepared and their stability constants with La³⁺, Sm³⁺, Gd³⁺ and Ho³⁺ determined by potentiometry at 25 °C and 0.10 M ionic strength in NMe₄NO₃. The metal:ligand ratio for ¹⁵³Sm and ¹⁶⁶Ho and for ac₃py14, MeP₂py14 and P₃py14, as well as the pH of the reaction mixtures, were optimized to achieve a chelation efficiency higher than 98%. These radiocomplexes are hydrophilic and have a significant plasmatic protein binding. In vitro stability was studied in physiological solutions and in human serum. All complexes are stable in saline and PBS, but 20% of radiochemical impurities were detected after 24 h of incubation in serum. Biodistribution studies in mice indicated a slow rate of clearance from blood and muscle, a high and rapid liver uptake and a very slow rate of total radioactivity excretion. Some bone uptake was observed for complexes with MeP₂py14 and P₃py14, which was enhanced with time and the number of methylphosphonate groups. This biological profile supports the in vitro instability found in serum and is consistent with the thermodynamic stability constants found for these complexes.     

Complexes with the fac-{M(CO)3} (M = Tc, Re) moiety and long alkyl chain ligands as Lipiodol surrogates

Accumulation of radiopharmaceuticals in the liver is frequently observed and represents in general a limiting factor when developing novel labeled compounds for any purpose in nuclear medicine. Aiming at the treatment of liver cancer with radiopharmaceuticals, such accumulation is desired but the compounds have to remain in the liver over an extended time period rather than being washed out or redistributed over time in the whole body. Lipiodol is known to remain in the liver and we present here a study for the preparation of ¹⁸⁶Re and ^99mTc labeled Lipiodol surrogates expected to behave similarly. We have synthesized two bidentate and two tridentate ligands conjugated to a pendant C18 chain as well as their corresponding fac-[Re(CO)₃]⁺ and fac-[Tc(CO)₃]⁺ complexes. Three of the rhenium complexes have been structurally characterized. Labelling with [¹⁸⁶Re(OH₂)₃(CO)₃]⁺ and [^99mTc(OH₂)₃(CO)₃]⁺, respectively, gave yields in the range of 90%. The complexes could be extracted into Lipiodol due to their high lipophilicity and close structural relationship with the major components of Lipiodol. The complexes are stable in water and in Lipiodol for more than 24 h. These Lipiodol surrogates present new low-valent technetium and rhenium complexes for applications in liver cancer imaging and therapy.     

13- and 14-membered macrocyclic ligands containing methylcarboxylate or methylphosphonate pendant arms: chemical and biological evaluation of their (153)Sm and (166)Ho complexes as potential agents for therapy or bone pain palliation

The stability constants of La(3+), Sm(3+) and Ho(3+) complexes with 13- and 14-membered macrocycles having methylcarboxylate (trita and teta) or methylphosphonate (tritp and tetp) arms were determined. All the ligands were labelled with (153)Sm and (166)Ho in order to evaluate the effect of the macrocyclic cavity size and type of appended arms on their in vitro and in vivo behaviour. The radiolabelling efficiency was found to be higher than 98% for all the complexes, except for those of tetp. All radiocomplexes studied are hydrophilic with an overall negative charge and low plasmatic protein binding. Good in vitro stability in physiological media and human serum was found for all complexes, except the (153)Sm/(166)Ho-teta, which are unstable in phosphate buffer (pH 7.4). In vitro hydroxyapatite (HA) adsorption studies indicated that (153)Sm/(166)Ho-tritp complexes bind to HA having the (166)Ho complex the highest degree of adsorption (>80%, 10 mg). Biodistribution studies in mice demonstrated that (153)Sm/(166)Ho-trita complexes have a fast tissue clearance with more than 95% of the injected activity excreted after 2 h, value that is comparable to the corresponding dota complexes. In contrast, the (153)Sm-teta complex has a significantly lower total excretion. (153)Sm/(166)Ho-tritp complexes are retained by the bone, particularly (166)Ho-tritp that has 5-6% (% I.D./g) bone uptake and also a high rate of total excretion. Thus, these studies support the potential interest of (153)Sm/(166)Ho-trita complexes for therapy when conjugated to a biomolecule and the potential usefulness of the (166)Ho-tritp complex in bone pain palliation.     

153Sm radiotherapeutic bone agents

Samarium-153 is a radionuclide which can be produced in high yield by neutron irradiation and which has nuclear properties that make it attractive for use as a radiotherapeutic agent. Several phosphonate complexes of ¹⁵³Sm were synthesized and characterized by electrophoresis and HPLC. A procedure based on cation exchange chromatography was developed for measuring complex yields. The complexes could be produced in yields greater than 99%, were anionic, and most exhibited a single HPLC peak.     

An efficient orange–red‐emitting LiNa3P2O7:Sm3+ pyrophosphate: Structural and optical analysis for solid‐state lighting

A trivalent rare‐earth ion (Sm³⁺)‐doped LiNa₃P₂O₇ (LNPO) phosphor was synthesized using a conventional high‐temperature solid‐state reaction route. A predominant orthorhombic phase of LNPO was observed in all X‐ray diffraction patterns. The surface states of the LNPO:Sm phosphor were confirmed by X‐ray photoelectron spectroscopy. Under 401 nm excitation, the Sm‐doped LNPO phosphors showed sharp emission peaks at 563, 600 and 647 nm that are related to the f–f transition of Sm³⁺ ions. The optimum concentration of Sm³⁺ (9 mol%) produced Commission Internationale de l'Eclairage chromaticity coordinates, color rendering index and correlated color temperature of (0.564, 0.434), 42 and 1843 K, respectively.     

Chemical and biological evaluation of 153Sm and 166Ho complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylphosphonic acid monoethylester) (H4 dotp OEt)

The novel methylphosphonic acid monoethylester (H₄dotp^OEt) has been synthesized and characterized and their complexes with Sm(III) and Ho(III) ions were studied. Dissociation constants of the ligand are lower than those of H₄dota. The stability constants of the Ln(III)-H₄dotp^OEt complexes are surprisingly much lower that those of H₄dota (H₄dota = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) probably due to a lower coordination ability of the phosphonate monoester groups. Acid-assisted decomplexation studies have shown that both complexes are less kinetically inert than the H₄dota complexes, but still much more inert than complexes of open-chain ligands. Nevertheless, the synthesis of ¹⁵³Sm and ¹⁶⁶Ho complexes with this ligand led to stable complexes both in vitro and in vivo. A very low binding of these complexes to hydroxyapatite (HA) and calcified tissues was observed confirming the assumption that a fully ionized phosphonate group(s) is necessary for a strong bone affinity. Both complexes show similar behaviour in vivo and, in general, follow the biodistribution trend of the H₄dota complexes with the same metals.     

The evaluation of 186Re-labeled antibodies using N2S4 chelate in vitro and in vivo using tumor-bearing nude mice

We have recently described a method for radiolabeling monoclonal antibodies, with metallic radionuclides using a new chelating agent N₂S₃. Using this chelate the monoclonal antibodies Lym-1 and B72.3 were labeled with ¹⁸⁶Re and their biological integrity was evaluated in vitro and in vivo. ¹⁸⁶Re-labeled antibodies using N₂S₄ methodology were found to be stable in human serum and retained their immunoreactivity. Intravenous administration of 0.5 mCi ¹⁸⁶Re-labeled antibodies resulted in partial or complete regression of tumor tissue in mice.     

Study of trivalent samarium ion embedded lithium‐based borate glass for high‐density optical memory devices

Sm³⁺ ions doped strontium lithium lead borate glasses (SLLB:Sm) were prepared using a conventional melt‐quenching technique. The glasses were analyzed using X‐ray diffractometry and Fourier transform infrared spectroscopy, optical absorption, fluorescence spectral analysis, and fluorescence lifetime decay. The Judd–Ofelt (J–O) parameters and radiative parameters of the SLLB:Sm10 glass (1.0 mol% Sm³⁺ ion‐doped glass) were calculated using J–O theory. From the emission spectra, among all the synthesized glass, SLLB:Sm10 glass had the highest emission intensity for ⁴G_5/2→⁶H_11/2 transition (610 nm). Emission parameters, such as stimulated emission cross‐section and optical gain bandwidth, were calculated. For all concentrations of Sm³⁺ ions, the decay profile showed an exponential nature and decreased when the Sm³⁺ ion concentration was increased due to a concentration quenching effect. This result suggests that the synthesized SLLB:Sm10 glass could be used for application in high‐density optical memory devices.     

A novel red emitting phosphor LiBaB9O15:Sm2+/Sm3+, li+ with broad excitation band for white LEDs

A novel tunable red emitting phosphor LiBaB₉O₁₅:Sm²⁺/Sm³⁺, Li⁺ with broad excitation band was synthesized by a high temperature solid‐state method. Luminescence properties were investigated in detail by luminescence, X‐ray photoelectron spectroscopy (XPS) spectra and CIE chromaticity coordinates. XPS data confirmed that there were Sm³⁺ in LiBaB₉O₁₅:Sm³⁺ and Sm²⁺/Sm³⁺ in LiBaB₉O₁₅:Sm²⁺/Sm³⁺, respectively. Spectral property of LiBaB₉O₁₅:Sm³⁺, LiBaB₉O₁₅:Sm³⁺/Sm²⁺ and LiBaB₉O₁₅:Sm²⁺, Li⁺ presented that the excitation band of Sm³⁺ widened and the excitation band of Sm²⁺ ranged from 350 to 450 nm. And the red light color is tunable with changing Li⁺ concentration. The results indicated that LiBaB₉O₁₅:Sm²⁺/Sm³⁺, Li⁺ may be promising red phosphor for white light emitting diodes.     

Isolation,structural and toxicological characterization of three new mycotoxins produced by the fungusAureobasidium pullulans

3 substances, B₁, B₂, and E₁ were isolated from culture medium extracts ofAureobasidium pullulans by reversed phase liquid chromatography and subsequent liquid chromatographic purification steps on silica gel. The 3 compounds inhibited the metabolism ofSaccharomyces cerevisiae and showed toxic effects in the growth inhibition test toEscherichia coli andBacillus subtilis. Elementary analysis and mass spectroscopical methods revealed sum formulas of C₂₃H₂₂O₆, C₂₂H₂₀O₆ and C₂₄H₂₈O₃ for B₁ B₂, and E₁ and molecular weights of 394, 380, and 364, respectively. Mass spectroscopical, UV-, IR-,¹³C-NMR, and¹H-NMR-spectroscopical investigations revealed polycyclic, non-aromatic compounds containing several carbonyl functions and double bonds and, most notably, spiroepoxy-functions, in the case of B₁ and B₂.     

Luminescence properties of neodymium,samarium, and europium niobate and tantalate thin films

Thin films of lanthanide orthoniobate LnNbO₄ (LnNO) and orthotantalate LnTaO₄ (LnTO), (Ln = Nd, Sm, Eu) were fabricated using the sol–gel method with subsequent spin-coating on the PbZrO₃/Al₂O₃ substrate and annealing at 1000°C. X-ray diffraction patterns showed monoclinic M-LnNbO₄ or M´-LnTaO₄, which coexists with the orthorhombic or tetragonal phase. X-ray photoelectron spectroscopy demonstrated the presence of Nd³⁺, Sm³⁺/Sm²⁺ and Eu³⁺/Eu²⁺ ions. The luminescence properties of polymorphic films were investigated. Excitation spectra of PbZrO₃ interlayer represented broad bands at 410 and 550 nm that were assigned to charge transfer bands (CTB). In all films, the CTB broad band at ~275 nm related to charge transfer transition of Ln³⁺→O²⁻ and NbO₄³⁻ or TaO₄³⁻ groups. In excitation spectra, ⁴I_9/2→⁴G_5/2 (Nd³⁺), ⁶H_5/2→⁶P_3/2 (Sm³⁺) and ⁷F₀→⁵L₆ (Eu³⁺) transitions (at 585, 402 and 395 nm), respectively were found to be more intense than any other Ln³⁺ transition. The emission spectra showed narrow and intense bands at 1065, 600, and 614 nm that were ascribed to Nd³⁺, Sm³⁺, and Eu³⁺ 4f–f intraconfigurational transitions ⁴F_3/2→⁴I_11/2, ⁴G_5/2→⁶H_7/2, and ⁵D₀→⁷F₂, respectively. The excellent luminescence properties of films make them new potential groups for visible and/or near-infrared applications such as sensors and imaging equipment.     

Joint meeting of the Belgische Vereniging voor Biofysica Société Belge de Biophysique

Summary The rare earth radionuclides¹⁷⁷Lu and¹⁵³Sm were administered as single i.p. injections in NMRI mice. Lu was deposited principally (up to 60%) in the skeleton if the quantity of stable carrier was low. Increase of stable carrier enhanced deposition in the reticulo-endothelial system. Sm was preferentially deposited in the liver; the liver deposits were further increased by the addition of stable Sm. Liver doses of between 75 and 150 Gy, resulting from a single injection of¹⁵³Sm together with 2 mg/kg stable carrier, led to severe lesions in the liver five months after treatment.Administration of¹⁷⁷Lu resulting in skeletal doses of between 28 and 224 Gy was found to be osteosarcomogenic. Up to 40% osteosarcoma incidence was obtained in animals with 56 and 112 Gy doses in the skeleton. Skeletal doses of this order of magnitude are also known to be osteosarcomogenic when given as⁹⁰Sr injections. The analogous situation with-emitters is discussed.Dedicated to Prof. Dr. Wolfgang Gössner on the occasion of his 60th birthdayIn Association with EURATOM (Contr. Nr. 218-76-1)     

Photoluminescence and piezoelectric behaviour of Y2Zr2O7 pyrochlore‐based multifunctional materials and the influence of Eu3+ and Sm3+

Y₂Zr₂O₇‐doped with Eu³⁺ and Sm³⁺ phosphors were prepared for the first time as multifunctional smart materials using a solid‐state reaction method at 1400^oC. Thermal behaviour, crystal structure, surface morphology, and elemental analysis were characterized using thermogravimetric (TG) and differential thermal (DTA) analyses, X‐ray diffraction (XRD) and scanning electron microscope equipped with energy‐dispersive X‐ray spectroscopy (SEM‐EDX). Experimental results revealed that both phosphors have a pyrochlore structure with a cubic crystal system. Photoluminescence properties were also measured and red emission was observed from Y_1.90Eu_0.10Zr₂O₇ and Y_1.90Sm_0.10Zr₂O₇ phosphors. Dielectric constant, loss tangent, piezoelectric charge constant, and Curie temperature of all the samples were determined using an LCR‐meter, d₃₃‐meter, and TG/DTA. Eu doping in Y₂Zr₂O₇ resulted in a high dielectric constant (9.61) and low loss tangent (1.67%) values, whereas high piezoelectric charge constant (0.68 pC/N) and high Curie temperature (820°C) could be obtained using Sm‐doped Y₂Zr₂O₇.     

Sol–gel preparation and luminescent properties of red‐emitting phosphor Sr‐Ba‐Mo‐W‐O‐(Eu3+,Sm3+)

Two series of red‐emitting phosphors Sr‐Ba‐Mo‐W‐O:Eu,Sm and Sr‐Ba‐Mo‐W‐O:Eu have been synthesized by a sol–gel method. The effects of the chemical composition, concentrations of Sm³⁺ and Eu³⁺, the Sr²⁺/Ba²⁺ ratio, and the W⁶⁺/Mo⁶⁺ ratio on the luminescent properties were investigated. The as‐prepared phosphors were characterized by X‐ray diffraction and Raman spectra. Results showed that single phases of the two series were prepared. The compositions of Sr_0.6Ba_0.13Mo_0.8 W_0.2O₄:Eu_0.10Sm_0.08 and Sr_0.75Ba_0.1Mo_0.8 W_0.2O₄:Eu_0.10 had the strongest luminescent intensity. The excitation spectra of Sm³⁺, Eu³⁺ co‐doped phosphors were broader and the strongest peak moved to 404 nm when compared with that of Eu³⁺ single‐doped phosphors. The luminescent intensity of the Sr_0.6Ba_0.13Mo_0.8 W_0.2O₄:Eu_0.10Sm_0.08 at 618 nm were 2.8 times greater than that of Sr_0.75Ba_0.1Mo_0.8 W_0.2O₄:Eu_0.10. The luminescent intensity of Sr_0.6Ba_0.13Mo_0.8 W_0.2O₄:Eu_0.10Sm_0.08 and Sr_0.75Ba_0.1Mo_0.8 W_0.2O₄:Eu_0.10 at 150 °C decreased to 56.8% and 50.3% of the initial value at room temperature, respectively. Copyright © 2015 John Wiley & Sons, Ltd.     

Synthesis and luminescence characterization of a new yellowish‐orange phosphor: Ba2B10O17:Sm3+

A new yellowish‐orange emitting phosphor, Ba₂B₁₀O₁₇:Sm³⁺ for use as a white light‐emitting diode (W‐LED) was synthesized by a solid‐state reaction method. The X‐ray diffraction results indicated that a pure Ba₂B₁₀O₁₇ material was obtained. As a potential yellowish‐orange luminescent material for W‐LEDs, the Ba₂B₁₀O₁₇:Sm³⁺ phosphor could be excited effectively by near‐ultraviolet (n‐UV) light and exhibited yellowish‐orange emission centered at 560 nm corresponding to the ⁴G_5/2 → ⁶H_5/2 transition of Sm³⁺ ions. The optimum concentration of Sm³⁺ ions in Ba₂B₁₀O₁₇, critical transfer distance (Ra) and concentration quenching mechanism of the presented phosphor were investigated. Moreover, CIE chromaticity coordinates and color purity performance of the Ba₂B₁₀O₁₇:Sm³⁺ phosphor were also discussed. The present work suggests that the Ba₂B₁₀O₁₇:Sm³⁺ phosphor has potential as a type of yellowish‐orange emitting phosphor. Copyright © 2016 John Wiley & Sons, Ltd.     

Accumulation and distribution of samarium-153 in rat brain after intraperitoneal injection

It is well known that rare earth elements (REEs) have come into extensive use in a number of fields. As a result, REEs are becoming closely related to human's daily life. However, until now, the distributions of REEs in the brain are not yet very clear. In this study, Sprague-Dawley male rats were intraperitoneally injected with 0.25 mL of ¹⁵³SmCl₃ solution (containing 10 μg Sm). The brain were perfused with saline to minimize the blood influence. The radioactivities of ¹⁵³Sm in the five brain regions (hypothalamus, cerebellum, hippocampus, corpus striatum, and cerebral cortex) were counted. The results suggested that Sm did enter into the brain. Although only about 0.0003% of the given dose was accumulated in the brain, Sm seemed to be remain in the brain for a long time. The highest amounts and lowest concentrations of ¹⁵³Sm were found in the cerebral cortex, and the highest concentrations of ¹⁵³Sm were found in the hypothalamus.     

Multi-color luminescence of Sm3+-doped Na2YMg2V3O12 phosphor potentially applicable in white-LEDs

A novel multi-color emitting Na₂YMg₂V₃O₁₂:Sm³⁺ phosphor was synthesized using a solid-state reaction, and its crystal structure, luminescence properties, and thermal stability were studied. Charge transfer within the (VO₄)³⁻ groups in the Na₂YMg₂V₃O₁₂ host led to a broad emission band between 400 and 700 nm, with a maximum at 530 nm. The Na₂Y_1−xMg₂V₃O₁₂:xSm³⁺ phosphors exhibited a multi-color emission band under 365 nm near-ultraviolet (near-UV) light, consisting of the green emission of the (VO₄)³⁻ groups and sharp emission peaks at 570 nm (yellow), 618 nm (orange), 657 nm (red), and 714 nm (deep red) of Sm³⁺ ions. The optimal doping concentration of Sm³⁺ ions was found to be 0.05 mol%, and the dipole–dipole (d–d) interaction was primarily responsible for the concentration quenching phenomenon. Using the acquired Na₂YMg₂V₃O₁₂:Sm³⁺ phosphors, commercial BaMgAl₁₀O₁₇:Eu²⁺ blue phosphor, and a near-UV light-emitting diode (LED) chip, a white-LED lamp was designed and packaged. It produced bright neutral white light, manifesting a CIE coordinate of (0.314, 0.373), a color rendering index (CRI) of 84.9, and a correlated color temperature (CCT) of 6377 K. These findings indicate the potential of Na₂YMg₂V₃O₁₂:Sm³⁺ phosphor to be used as a multi-color component for solid-state illumination.