Zvonimir I. Kolar

Lanthanide(III) Complexes of Bis(phosphonate) Monoamide Analogues of DOTA : Bone-Seeking Agents for Imaging and Therapy

Lanthanide complexes of DOTA derivatives 2a (BPAMD) and 2b (BPAPD), having a monoamide pendant arm with a bis(phosphonate) moiety, were comparatively tested for application in MRI, radiotherapy, and bone pain palliation. (1)H, (31)P, and (17)O NMR spectroscopy show that they are nine-coordinated, with one water molecule in the first coordination sphere of the Ln(III) ion. The bis(phosphonate) moieties are not coordinated to the lanthanide and predominantly mono- and diprotonated at physiological pH. The parameters governing the longitudinal relaxivities of the Gd complexes are similar to those of other monoamides of DOTA reported in the literature. Upon adsorption on hydroxyapatite, the relaxivities at 20 MHz and 25 degrees C of Gd-2a and Gd-2b were 22.1 and 11 s(-1) mM(-1), respectively. An in vivo gamma-ray imaging study showed that the (177)Lu complexes of 2a and 2b have a high affinity for bones, particularly for growth plates and teeth with a prolonged retention.

Electroless Silver Deposition in 100 nm Silicon Structures

A new and simple method is described to plate silicon structures with metallic silver for ultralarge-scale integration in dimensions down to 100 nm at an aspect ratio of 4.25. The silver deposition is initiated by an exchange reaction of silicon with silver ions, and the subsequent layer growth of the activated wafers occurs by electroless plating from supersaturated aqueous silver salt solutions at pH ∼ 11. No extra reducing agents are needed since silver ions are reduced at the catalytic silver surface by hydroxyl ions. The spontaneous ion-metal transition only proceeds at pH ∼ 11 and is likely mediated by the formation of subnanometer-sized [Ag 4 (OH) 2 ] 2+ clusters. The silver plating proceeds more easily in smaller structures and yields void-free, crystallized deposits.

Complexes of DOTA−Bisphosphonate Conjugates: Probes for Determination of Adsorption Capacity and Affinity Constants of Hydroxyapatite

The adsorption on hydroxyapatite of three conjugates of a bisphosphonate and a macrocycle having C1, C2, and C3 spacers and their terbium complexes was studied by the radiotracer method using 160Tb as the label. The radiotracer-containing complex of the conjugate with the C3 spacer was used as a probe for the determination of the adsorption parameters of other bisphosphonates that lack a DOTA unit. A physicochemical model describing the competitive adsorption was successfully applied in the fitting of the obtained data. The maximum adsorption capacity of bisphosphonates containing bulky substituents is determined mainly by their size. For bisphosphonates having no DOTA moiety, the maximum adsorption capacity is determined by the electrostatic repulsion between negatively charged bisphosphonate groups. Compounds with a hydroxy or amino group attached to the alpha-carbon atom show higher affinities. Macrocyclic compounds containing a short spacer between the different bisphosphonic acid groups and the macrocyclic unit exhibit high affinities, indicating a synergic effect of the bisphosphonic and the macrocyclic groups during adsorption. The competition method described uses a well-characterized complex and allows a simple evaluation of the adsorption behavior of bisphosphonates. The application of the macrocycle-bisphosphonate conjugates allows easy radiolabeling via complexation of a suitable metal isotope.

Uptake, distribution and excretion of magnesium inOreochromis mossambicus: dependence on magnesium in diet and water

The euryhaline Mozambique tilapia (Oreochromis mossambicus) shows a more marked ability to adapt to low magnesium levels in food and water than many other fish species. Nonetheless, the internal distribution of magnesium is altered under low-magnesium conditions. The amount of magnesium in scales, and to a lesser extent the vertebral bone, is reduced and hence serve as magnesium reservoirs. The magnesium concentration of muscle is only marginally reduced by low external magnesium, suggesting that magnesium is partitioned to ensure normal muscle functioning. The water magnesium is of vital importance, as exposure to low-magnesium water markedly deminished the ability of tilapia to adapt to low-magnesium feeding. However, magnesium intake from the water, eithervia the integument or drinking, does not increase in lowmagnesium fed fish, despite an increased opercular chloride cell density. The growth related magnesium accumulation of tilapia under low-magnesium conditions approximates the total intake of the element (from the food and from the water), indicating that magnesium losses are minimized and that the magnesium absorption from the gastrointestinal tract may be highly efficient and very important.

MAGNESIUM TRANSPORT ACROSS THE BASOLATERAL PLASMA MEMBRANE OF THE FISH ENTEROCYTE

Abstract. In tilapia (Oreochromis mossambicus) intestine, Mg2+ transport across the epithelium involves a transcellular, Na+- and Na+/K+-ATPase dependent pathway. In our search for the Mg2+ extrusion mechanism of the basolateral compartment of the enterocyte, we could exclude Na+/Mg2+ antiport or ATP-driven transport. Evidence is provided, however, that Mg2+ movement across the membrane is coupled to anion transport. In basolateral plasma membrane vesicles, an inwardly directed Cl− gradient stimulated Mg2+ uptake (as followed with the radionuclide 27Mg) twofold. As Cl−-stimulated uptake was inhibited by the detergent saponin and by the ionophore A23187, Mg2+ may be accumulated intravesicularly above chemical equilibrium. Valinomycin did not affect uptake, suggesting that electroneutral symport activity occurred. The involvement of anion coupled transport was further indicated by the inhibition of Mg2+ uptake by the stilbene derivative, 4,4′-diisothiocyanato-stilbene-2,2′-disulfonic acid. Kinetic analyses of the Cl−-stimulated Mg2+ uptake yielded a Km (Mg2+) of 6.08 ± 1.29 mmol · l−1 and a Km (Cl−) of 26.5 ± 6.5 mmol · l−1, compatible with transport activity at intracellular Mg2+- and Cl−-levels. We propose that Mg2+ absorption in the tilapia intestine involves an electrically neutral anion symport mechanism.

Prolactin cell activity and sodium fluxes in tilapia (Oreochromis mossambicus) after long-term acclimation to acid water

In tilapia exposed for 3 months to water of pH 4.5, prolactin cell activity, as estimated by ultrastructural morphometry and determination of prolactin synthesis in vitro, was significantly higher than in controls from neutral water. Sodium influx from the water was 50% lower than in the controls, indicating impaired branchial sodium uptake mechanisms. In contrast to predictions based on the results of short-term exposure to acid water--which is known to induce an increase of sodium efflux--the sodium efflux rate was reduced to 70% of the control value. It is concluded that tilapia are able to acclimate to acid water by successful control--probably via prolactin--of diffusional sodium losses across the integument, in particular the gill surface. This compensates for the impaired sodium uptake, and enables the fish to reestablish a positive sodium balance in acid water.

Anodic Oxidation of Formaldehyde on Gold Studied by Electrochemical Impedance Spectroscopy: An Equivalent Circuit Approach

The anodic oxidation of formaldehyde on gold in alkaline aqueous solutions was studied by electrochemical impedance spectroscopy. One equivalent circuit was found to mimic all impedance spectra measured for normal formaldehyde and deuterated formaldehyde in various alkaline solutions at various voltages. The resistors and capacitors constituting the circuit depend logarithmically on the voltage applied, and the circuit can be explained in terms of reaction steps proposed in the literature. A negative capacitance (inductive loop) was encountered at low frequencies, which is explained by a rate‐determining C‒H bond rupture step in the overall kinetics of the reaction, as it was more apparent for solutions containing instead of . Data were Kramers‐Kronig transformable and a ‐value of or less was attained in all fits. At least four time constants were revealed by the impedance spectra as a result of positive capacitive, negative capacitive, resistive, and diffusive effects.

Targeted radiotherapy of bone malignancies.

The severe pain associated with many disorders affecting bone account for a large proportion of cases of patient morbidity, due to the encumbrance of mobility and therefore, compromised quality of life. Skeletal metastasis is one such condition, which generally complicates the treatment of the primary cancers such as that of the breast, prostate and lung - causing intense pain and eventually even mortality. This paper presents examples of various approaches explored and proposed in the ongoing search to identify better radiopharmaceuticals for the treatment of bone disorders such as metastases. The primary objective of these developments is to alleviate the debilitating pain commonly associated with bone lesions. The efficacy of a radiotherapeutic agent intended for the treatment of diseased bone is particularly dependent on the radiation dose to the tumor cells and on the extent to which suppression of bone marrow or other critical organs can be avoided. Therefore, the design rationale requires careful consideration of the choice radionuclide and especially ensuring that the drug selectively targets the lesion or tumor site. The options pursued include the use of radioisotopes with an intrinsic affinity for bone, such as (89)Sr or (223)Ra, or the design of bone-seeking ligands, such as phosphonates, to selectively deliver the radionuclide to the target, e.g. [(153)Sm]Sm-EDTMP. A combination of the above may too be possible, where the bone seeking ligand facilitates the selective accumulation of a radionuclide, which by itself is also bone homing. In terms of therapeutic application radionuclides with various decay modes are proposed, including beta (-) emitters: (153)Sm, (89)Sr, (186)Re, (188)Re, (32)P, (177)Lu and (170)Tm; alpha (α) emitters: (223)Ra and (225)Ra; and Auger or conversion electron emitter: (117)mSn. From a purely diagnostic perspective, the radioisotopes used for imaging include the well known photon emitting (99)mTc, and positron emitters (18)F and (68)Ga. The current status in the development and application of internal radiotherapy for the palliative treatment of bone pain will be discussed, summarizing the progress made and challenges encountered in the process to realizing an effective drug candidate.

Intake of magnesium from water by freshwater tilapia fed on a low-Mg diet

Abstract 1. Freshwater tilapia, weighing between 1 and 9g, can survive low-magnesium feeding for at least 3 weeks. 2. The magnesium intake from water by freshwater tilapia do not differ under control and low-magnesium dietary conditions. 3. To allow for the growth-related magnesium uptake observed, freshwater tilapia fed on a low-magnesium diet have to regulate their magnesium losses strictly.

Electrocatalytic oxidation of formaldehyde on gold studied by differential electrochemical mass spectrometry and voltammetry

The electrocatalytic oxidation of normal formaldehyde I CH 2 O) and deuterated formaldehyde (CD 2 O) has been studied on gold in aqueous, alkaline solution as a function of pH, concentration, potential, and temperature by voltammetry, chronoamperometry, and differential electrochemical mass spectrometry. The H 2 . D 2 . and CO 2 gas evolution kinetics depend to great extent on the pH, potential, and temperature but play a minor role in the overall rate of the electro-oxidation reaction. The evolution of hydrogen at the open-circuit potential and the current efficiencies larger than 100% pointed toward the occurrence of a nonelectrochemical dehydrogenation reaction parallel to the electro-oxidation reaction, The kinetic isotope effects and activation energies suggested that the overall rate of the electro-oxidation reaction is determined by the hydroxyl catalyzed, enthalpy-driven, chemisorption of the enolate anion at low potentials, by the entropy-driven desorption of the formate anion at higher potentials, and by diffusion at the highest potentials. The apparent activation energies (E a ) ranged in value between -25 and 60 kJ mol 1 confirming the highly catalytic properties of gold in the overall rate of the reaction.