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Purpose: The purpose of this study was to evaluate the efficacy and toxicity of a novel lanthanum compound, La(XT), in an ovariectomized (OVX) rat model of osteoporosis. Methods: Twenty-four ovariectomized female Sprague Dawley rats were divided into 3 groups receiving a research diet with/without treatment compounds (alendronate: 3 mg/kg; La(XT) 100 mg/kg) for three months. At the time of sacrifice, the kidney, liver, brain, lung and spleen were collected for histological examination. The trabecular bone structure of the tibiae was evaluated using micro-CT and a three-point metaphyseal mechanical test was used to evaluate bone failure load and stiffness. Results: No significant differences were noted in plasma levels of calcium, phosphorus, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) between the La(XT) treatment compared to the non-treated OVX group. Alendronate-treated animals (positive control) showed higher BV/TV, Tb.N and lower Tb.Th and Tb.Sp when compared to the non-treated OVX group. Mechanical analysis indicated that stiffness was higher in the alendronate (32.88%, p = 0.04) when compared to the non-treated OVX group. Failure load did not differ among the groups. Conclusions: No kidney or liver toxicities of La(XT) treatments were found during the three-month study. The absence of liver and kidney toxicity with drug treatment for 3 months, as well as the increased trabecular bone stiffness are encouraging for the pursuit of further studies with La(XT) for a longer duration of time.

Abstract Background Actinium-225 (225Ac, t1/2 = 9.9 d) is a promising candidate radionuclide for use in targeted alpha therapy (TAT), though the currently limited global supply has hindered the development of a suitable Ac-chelating ligand and 225Ac-radiopharmaceuticals towards the clinic. We at TRIUMF have leveraged our Isotope Separation On-Line (ISOL) facility to produce 225Ac and use the resulting radioactivity to screen a number of potential 225Ac-radiopharmaceutical compounds. Results MBq quantities of 225Ac and parent radium-225 (225Ra, t1/2 = 14.8 d) were produced and separated using solid phase extraction DGA resin, resulting in a radiochemically pure 225Ac product in > 98% yield and in an amenable form for radiolabeling of ligands and bioconjugates. Of the many polydentate picolinic acid (“pa”) containing ligands evaluated (H4octapa [N4O4], H4 CHXoctapa [N4O4], p-NO2-Bn-H4neunpa [N5O4], and H6phospa [N4O4]), all out-performed the current gold standard, DOTA for 225Ac radiolabeling ability at ambient temperature. Moreover, a melanocortin 1 receptor-targeting peptide conjugate, DOTA-modified cyclized α-melanocyte-stimulating hormone (DOTA-CycMSH), was radiolabeled with 225Ac and proof-of-principle biodistribution studies using B16F10 tumour-bearing mice were conducted. At 2 h post-injection, tumour-to-blood ratios of 20.4 ± 3.4 and 4.8 ± 2.4 were obtained for the non-blocking (molar activity [M.A.] > 200 kBq/nmol) and blocking (M.A. = 1.6 kBq/nmol) experiment, respectively. Conclusion TRIUMF’s ISOL facility is able to provide 225Ac suitable for preclinical screening of radiopharmaceutical compounds; [225Ac(octapa)]−, [225Ac(CHXoctapa)]−, and [225Ac(DOTA-CycMSH)] may be good candidates for further targeted alpha therapy studies.

Radiopharmaceuticals are radioactive compounds which have a bound radionuclide in their structure, whose purpose is directing the radionuclide to a location to be treated or to obtain images. Nuclear medicine is the medical specialty that employs radiopharmaceuticals, which has presented itself as a tremendously useful ally for medicine assisting in various diagnoses and treatments, especially for cancer. The general objective of this work is to identify the main radionuclides and metal complexes currently used as radiopharmaceuticals. The main metal complexes used as radiopharmaceuticals are compounds of technetium (99mTc) like sodium pertechnetate and methylenediphosphonate MDP-99mTc and other compounds of indium (111In), thallium (201Tl), gallium (67Ga, 68Ga), iodine (123I and 131I), chromium (51Cr), sulphur (35S), phosphorus (32P), fluorine (as fluorodeoxyglucose, 18F-FDG and sodium fluorine, Na18F), which are widely used in the nuclear medicine for diagnosis by imaging. They have been of great importance for the early diagnosis of numerous diseases, mainly cancer.Currently, technetium compounds are the majority of radiopharmaceuticals used in all countries. In Brazil, Institute of Energy and Nuclear Research (IPEN) is one of the most important distributors of radiopharmaceuticals, producing, importing and distributing them to clinics and hospitals over the country.

The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.

Liriodenine (L), a natural alkaloid, was isolated as an active component from the anticancer traditional Chinese medicine (TCM), Zanthoxylum nitidum. It reacted with MnII, FeII, CoIIand ZnIIto afford four metal complexes: [MnCl2(L)2] (1), [FeCl2(L)2] (2), [Co(L)2(H2O)2·Co(L)2(CH3CH2OH)2](ClO4)4(3), and [Zn2(L)2(μ2-Cl)2Cl2] (4), which were characterized by elemental analysis, IR, ESI-MS. Their crystal structures were determined by the single crystal X-ray diffraction method. The in vitrocytotoxicity of Land complexes 1–4against 10 human tumour cell lines was assayed. Some of these metal-based compounds exhibited enhanced cytotoxicity vs.free Lto selected tumour cell lines. The binding properties of Land its complexes 1–4to ct-DNA were investigated by spectroscopic methods and viscosity measurements. Agarose gel electrophoresis experiments were also carried out to evaluate their unwinding ability towards plasmid DNA and their inhibition towards Topoisomerase I. All the results indicate that complexes 1–4may bind more intensively to the DNA helix than does L, and intercalative binding for complexes 1–4and electrostatic interactions for complexes 3–4to DNA should be considered. For complex 4, covalent binding to DNA may exist. Of special note, all these metal complexes effectively inhibit Topoisomerase I even at low concentration (≤10 μM). [ABSTRACT FROM AUTHOR]

The anticancer traditional Chinese medicine (TCM), plumbagin (PLN), was isolated from Plumbago Zeylanica. Reaction of plumbagin with CuIIsalt, afforded [Cu(PLN)2]·2H2O (1). With 2,2′-bipyridine (bipy) as a co-ligand, PLN reacts with CuIIto give [Cu(PLN)(bipy)(H2O)]2(NO3)2·4H2O (2). 1and 2were characterized by elemental analysis, IR, ESI-MS spectra. Their crystal structures were determined by single crystal X-ray diffraction methods. The in vitrocytotoxicity of PLN, 1and 2against seven human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs.that of free PLN, suggesting that these compounds display synergy in the combination of metal ions with PLN. The binding properties of PLN, 1and 2to DNA were investigated through UV-vis, fluorescence, CD spectra, and gel mobility shift assay, which indicated that 1and 2were non-covalent binding and mainly intercalated the neighboring base pairs of DNA. PLN, 1and 2exhibit inhibition activity to topoisomerase I (TOPO I), but 1and 2were more effective than PLN. [ABSTRACT FROM AUTHOR]

The tetrahydrosalens N,N′-bis(2-hydroxybenzyl)-ethane-1,2-diamine (H2L1), N,N′-bis(2-hydroxybenzyl)-(−)-1,2-cyclohexane-(1R,2R)-diamine (H2L2), N,N′-bis(2-hydroxybenzyl)-N,N′-dimethyl-ethane-1,2-diamine (H2L3), N,N′-bis(2-hydroxybenzyl)-N,N′-dibenzyl-ethane-1,2-diamine (H2L4), and N,N′-bis(2-(4-tert-butyl)hydroxybenzyl)-ethane-1,2-diamine (H2L5), as well as their prodrug glycosylated forms, GL1–5, have been prepared and evaluated in vitrofor their potential use as Alzheimer's disease (AD) therapeutics. Dysfunctional interactions of metal ions, especially those of Cu, Zn, and Fe, with the amyloid-β (Aβ) peptide are hypothesised to play an important role in the aetiology of AD, and disruption of these aberrant metal–peptide interactions viachelation therapy holds considerable promise as a therapeutic strategy. Tetrahydrosalens such as H2L1–5have a significant affinity for metal ions, and thus should be able to compete with the Aβ peptide for Cu, Zn, and Fe in the brain. This activity was assayed in vitroviaa turbidity assay; H2L1and H2L3were found to attenuate Aβ1–40aggregation after exposure to Cu2+and Zn2+. In addition, H2L1–5were determined to be potent antioxidants on the basis of an in vitroantioxidant assay. GL1–5were prepared as metal binding prodrugs; glycosylation is intended to prevent systemic metal binding, improve solubility, and enhance brain uptake. Enzymatic (β-glucosidase) deprotection of the carbohydrate moieties was facile, with the exception of GL4, demonstrating the general feasibility of this prodrug approach. Finally, a representative prodrug, GL3, was determined to be non-toxic over a large concentration range in a cell viability assay. [ABSTRACT FROM AUTHOR]

Liriodenine (L), an active component of the anticancer traditional Chinese medicine (TCM), was isolated from Zanthoxylum nitidum. Its reactions with Pt(ii) and Ru(ii) afforded three metal complexes: cis-[PtCl2(L)] (1), cis-[PtCl2(L)(DMSO)] (2), and cis-[RuCl2(L)(DMSO)2]·1.5H2O (3), the crystal structures of L, 2and 3were determined by single-crystal X-ray diffraction methods. These complexes were fully characterized by elemental analysis, IR spectrophotometry, 1H and 13C NMR spectroscopies, and ES mass spectrometry. The in vitrocytotoxicity of Land complexes 1–3against 11 human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs.free L, suggesting that these compounds display synergy in the combination of metal ions and liriodenine. The binding properties of Land its complexes 1–3to ct-DNA were investigated through UV-vis, fluorescence, CD spectra, viscosity and agarose gels electrophoretic measurements. [ABSTRACT FROM AUTHOR]

Selective design modifications of specifically substituted 3-hydroxy-4(1H)-pyridinones show possibly advantageous ring freedom while maintaining metal-binding ability and antioxidant capacity, moving toward an efficient potential treatment for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

This feature article covers recent reports of work towards the development of 99mTc–carbohydrate based agents for use in SPECT imaging, particularly of cancerous tissue. An outline of some of the key biological functions and coordination chemistry of carbohydrates is given, along with an introduction to bioconjugation and molecular imaging. Technetium coordination chemistry and the subset of this involving bioconjugates are discussed before moving into the focus of the article: glycoconjugates of 99mTc(v) and the more recently developed [99mTc(I)(CO)3]+. Significant work in the last decade has featured the very attractive [99mTc(CO)3]+ core, and the ligand sets designed for this core are discussed in detail. [ABSTRACT FROM AUTHOR]

Lanthanide ions, Ln(iii), are known functional mimics of Ca(ii) ions and have been shown to affect the bone remodeling cycle. Exploiting this disruption to the bone remodeling cycle has potential for the treatment of bone density disorders, such as osteoporosis. In an effort to find new orally active agents for these disorders, a series of Ln(iii) containing complexes incorporating small, non-toxic, bidentate pyrone and pyridinone ligands have been synthesized and characterized (LnL3, Ln = La, Eu, Gd, Tb, Yb, L = 3-oxy-2-methyl-4-pyrone (ma−), 3-oxy-2-ethyl-4-pyrone (ema−), 3-oxy-1,2-dimethyl-4-pyridinone (dpp−) and 3-oxy-2-methyl-4(1H)-pyridinone (mpp−)). Preliminary biological analysis included cytotoxicity, cell uptake and bidirectional transport studies in Caco-2 cells and in vitro hydroxyapatite (HA) binding studies. The proportion of intact compounds bound to HA was calculated based on determination of Ln(iii) concentration by ICP-MS and by UV-vis spectrophotometric assay of the proligand in solution. The LnL3 species were found to have IC50 values at least 6 times greater than that of cisplatin, ≥ 98% HA-binding capacity, and permeability coefficients in the moderate range. La(dpp)3 was ascertained to be the lead compound for the treatment of bone density disorders with the highest percentage cell uptake of 9.07 ± 2.33% and the highest preliminary Papp value of 3.54 ± 2.86 × 10−6 cm s−1 compared to the other LnL3 complexes tested. [ABSTRACT FROM AUTHOR]