Cerium oxide nanoparticles have the unique power to act as both oxidation and reduction catalysts, thanks to the ability of cerium to rapidly switch between two oxidation states. Can Xu and Xiaogang Qu from the Chinese Academy of Sciences review how this dual catalytic activity yields enzyme-like behavior that can be harnessed for cancer-detecting assays and new biomedical applications. The nanoparticles mimic enzyme species, such as superoxide dismutases and catalases, that repair the damage caused by free radicals and reduce harmful reactive oxygen levels in the body. With tiny dimensions that allow them to enter cellular spaces inaccessible to traditional medicines - including crossing the blood-brain barrier for Alzheimer's disease treatments - these nanomaterials may offer potent remedies against degenerative diseases. Xu and Qu stress the need for systematic biological testing, however, to resolve possible toxicity concerns.

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Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications

Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.

Antitumour metal compounds: more than theme and variations

Neutral or cationic arene ruthenium complexes providing both hydrophilic as well as hydrophobic properties due to the robustness of the ruthenium–arene unit hold a high potential for the development of metal-based anticancer drugs. Mononuclear arene ruthenium complexes containing P- or N-donor ligands or N,N-, N,O- or O,O-chelating ligands, dinuclear arene ruthenium systems with adjustable organic linkers, trinuclear arene ruthenium clusters containing an oxo cap, tetranuclear arene ruthenium porphyrin derivatives that are photoactive, as well as hexanuclear ruthenium cages that are either empty or filled with other molecules have been shown to be active against a variety of cancer cells.

https://doc.rero.ch/record/29412/files/S_ss-Fink_Georg_-_Arene_ruthenium_complexes_as_anticancer_agents_20120608.pdf

Arene ruthenium complexes as anticancer agents

Challenges and Opportunities in the Development of Organometallic Anticancer Drugs

Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorganic drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clinical trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the molecular reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with molecular targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure–activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Determining and validating global mechanisms of action and molecular targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiology to increase the predictability for successful preclinical and clinical development of ruthenium and osmium metallodrugs.

Structure–activity relationships for ruthenium and osmium anticancer agents – towards clinical development

The synthesis and in vitro anticancer activity of dihalogenido(eta6-p-cymene)(3,5,6-bicyclophosphite-alpha-D-glucofuranoside)ruthenium(II) complexes are described. The compounds were characterized by NMR spectroscopy and ESI mass spectrometry, and the molecular structures of dichlorido-, dibromido- and diiodido(eta6-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-alpha-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. The complexes were shown to undergo aquation of the first halido ligand in aqueous solution, followed by hydrolysis of a P--O bond of the phosphite ligand, and finally formation of dinuclear species. The hydrolysis mechanism was confirmed by DFT calculations. The aquation of the complexes was markedly suppressed in 100 mM NaCl solution, and notably only very slow hydrolysis of the P--O bond was observed. The complexes showed affinity towards albumin and transferrin and monoadduct formation with 9-ethylguanine. In vitro studies revealed that the 3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-alpha-D-glucofuranoside complex is the most cytotoxic compound in human cancer cell lines (IC50 values from 30 to 300 microM depending on the cell line).

In vitro anticancer activity and biologically relevant metabolization of organometallic ruthenium complexes with carbohydrate-based ligands.

The lanthanide complex tris(1,10-phenanthroline)tris(thiocyanato-κN)lanthanum(III) [La(phen)3(NCS)3] (KP772) is a promising anticancer drug candidate, capable of overcoming resistance of tumors to established chemotherapeutics. The compound was characterized by elemental analysis, IR, 1H NMR spectroscopy, TG/DTA measurements, mass spectrometry and X-ray diffraction analysis. The results indicate that KP772 is a neutral, nine-coordinate complex. In addition the behavior in water, important for the application as a chemotherapeutic drug, and the binding to biomolecules was investigated by capillary electrophoresis and ICP-MS.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

New Insights into the Chemistry of the Antineoplastic Lanthanum Complex Tris(1,10-phenanthroline)tris(thiocyanato-κN)lanthanum(III) (KP772) and Its Interaction with Biomolecules

The lanthanide complex aquatrichloridobis(1,10-phenanthroline)cerium(III) [Ce(phen)(2)(H2O)Cl-3] (KP776) was fully characterized by elemental analysis, IR-, and H-1- and C-13-NMR spectroscopy, as well as TG/DTA measurements, and its behavior in H2O, important for the application as a chemotherapeutic, was studied. In addition, the binding of KP776 to nucleotides and single serum proteins was investigated by capillary electrophoresis, whereas binding to proteins in human plasma was observed by ICP-MS. The compound shows promising anticancer properties in vitro: proliferation of human cancer cell lines is strongly inhibited with IC50 values in the very low micromolar range.

A Novel Cytotoxic Cerium Complex: Aquatrichloridobis(1,10-phenanthroline)cerium(III) (KP776). Synthesis, Characterization, Behavior in H2O, Binding towards Biomolecules, and Antiproliferative Activity

Florian Biba

Papers

In vitro anticancer activity and biologically relevant metabolization of organometallic ruthenium complexes with carbohydrate-based ligands.

New Insights into the Chemistry of the Antineoplastic Lanthanum Complex Tris(1,10-phenanthroline)tris(thiocyanato-κN)lanthanum(III) (KP772) and Its Interaction with Biomolecules

A Novel Cytotoxic Cerium Complex: Aquatrichloridobis(1,10-phenanthroline)cerium(III) (KP776). Synthesis, Characterization, Behavior in H2O, Binding towards Biomolecules, and Antiproliferative Activity