A new system for delivery of anthracycline antibiotics based on chitosan-polyaminoxyls (CPA) was studied in a model of non-tumor (human embryonic mesenchymal stem cells) and tumor cells (human hepatocellular carcinoma) in vitro. The presence of CPA micelles considerably suppresses daunorubicin-induced ROS generation in normal cells without affecting this process in tumor cells. CPA micelles do not reduce the cytotoxic effect of daunorubicin and do not prevent its accumulation in cells. The use of CPA significantly increases accumulation of Nrf2 transcription factor in the nuclei of both normal and tumor cells in comparison with free daunorubicin. Increased nuclear translocation of Nrf2 leads to a significant increase in the expression of its target gene TXN1, but not the NQO1, GPX1, and HMOX1 genes, the increased expression of which can lead to the development of resistance to anthracycline antibiotics. Redox-active CPA micelles have great potential for the development of nanoparticles for the transport of anthracycline antibiotics in experimental tumor chemotherapy, and also as promising activators of Nrf2 transcription factor.

New platinum(iv)-aminoxyl complexes (PACs) 2a,b, bearing an aminoxyl radical with antioxidant properties in the equatorial position and axial dichloroacetate ligands capable of inhibiting the energy production in tumor cells through aerobic glycolysis were synthesized. Complexes 2a,b are characterized by moderate lipophilicity (log Pow ∼2) and differ in the redox properties of aminoxyls. The cytotoxicity of complexes 2a,b was studied on tumor (HeLa, HepG2, MCF-7) and non-cancer cells Vero in comparison with cisplatin (CP), satraplatin (JM216), and previously described PNCs 3a,b bearing axial acetate ligands. The cytotoxicity of 2a,b for tumor cells (IC50 19–171 µmol L−1) is 2–11 times higher than that of complexes 3a,b and comparable to IC50 values for CP and JM216 (10–187 µmol L−1). For non-cancer cells Vero, the cytotoxicity of 2a,b (62–124 µmol L−1) is significantly lower as compared to CP and JM216 (17.6–33 µmol L−1).

Nowadays, microelectronics and nanoelectronics require the search for new materials, including masks for creating structures. Today, the intermediate hard mask strategy is one of the key issues in achieving a good balance between lithography and etching at the microelectronic fabrication. One of the interesting challenges in microelectronics and photovoltaics is the creation of interspacing, vertically oriented silicon arrays on Si substrate for semiconductor devices with multi-function. The fabrication of such structures is still a serious technological problem and requires searching for new approaches and materials. In this work, we propose using scandium as a new hard mask material over silicon due to its high resistance to plasma chemical etching and low sputtering coefficient. We have shown that a wet etching of the scandium layer with a thickness of several nanometers can be used to obtain pattern structures with a resolution of up to 4 microns, which is a good result for the wet etching approach. Scandium metal was found to be an excellent resistant mask over silicon under the selected plasma etching conditions. Therefore, a scandium hard mask can open up new possibilities for the formation of different microscale topographical patterns.

Cyclic oxoammonium salts and DMSO are known as important reagents for their diverse and unique reactivity. In the present work, we have studied the reaction of six- and five-membered oxoammonium salts with DMSO. The reaction includes ∼100% selective transfer of the O atom from the >N+═O group to the S atom of DMSO and structural rearrangement of the remaining cationic framework, leading to the formation of hydrolytically unstable iminium salts. The logarithms of the bimolecular rate constants k of the reaction correlated linearly with the reduction potentials E>N+═O/>N-O•, a relationship known for other electrophile-nucleophile combinations. The kinetic data and results of the DFT calculations allow for the suggestion that the studied process proceeds via the prereactive charge-transfer complex >N+═O···S (O)Me2 and its direct concerted rearrangement to the iminium salts. An alternative mechanism that includes intermediate steps with discrete nitrenium cations can be ruled out on the basis of product analysis and DFT computations. The obtained results allow a deeper understanding of the redox chemistry of a pair of nitroxide radicals-oxoammonium cations.

Cisplatin is one of the most commonly used drugs for the treatment of various solid cancers. However, its efficacy is restricted by severe side effects, especially dose-limiting nephrotoxicity. New platinum-based compounds are designed to overcome this limitation. Previous investigations showed that the platinum(IV)–nitroxyl complex PN149 is highly cytotoxic in various tumor cell lines. In the present study, investigations with PN149 were extended to normal human kidney tubule epithelia. Coincident with higher intracellular platinum accumulation, the cytotoxicity of PN149 in the proximal tubule epithelial cell line ciPTEC was more pronounced compared to the established platinum chemotherapeutics cisplatin, carboplatin and oxaliplatin. Quantitative gene expression profiling revealed the induction of ROS-inducible and anti-oxidative genes, suggesting an oxidative stress response by PN149. However, in contrast to cisplatin, no pro-inflammatory response was observed. Genes coding for distinct DNA damage response factors and genes related to apoptosis were up-regulated, indicating the activation of the DNA damage response system and induction of the apoptotic cascade by PN149. Altogether, a comparable transcriptional response was observed for PN149 and the platinum chemotherapeutics. However, the lack of inflammatory activity, which is a possible cause contributing to toxicity in human renal proximal tubule epithelia, might indicate the reduced nephrotoxic potential of PN149.

The binding of aminoxyls to polymers extends their potential use as antioxidants and EPR-reporting groups and opens up new horizons for tailoring new smart materials. In this work, we synthesized and characterized non-sulfated and N-sulfated water-soluble amphiphilic chitosans with a critical micelle concentration of 0.02-0.05 mg/mL that contain 13-18% of aminoglycosides bound with various aminoxyls. Chitosan-polyaminoxyls (CPAs) formed micelles with hydrodynamic radii Rh of ca. 100 nm. The EPR spectra of CPAs were found to depend on the rigidity of the aminoxyl-polymer bond and structural changes caused by sulfation. CPAs demonstrated antioxidant capacity/activity in three tests against reactive oxygen species (ROS) of various nature. The charge of micelles and structure of aminoxyls significantly affected their antioxidant properties. CPAs were low toxic against tumor (HepG2, HeLa, A-172) and non-cancerous (Vero) cells (IC50 > 0.8 mM of aminoglycosides). Sulfated CPAs showed better water solubility and the ability of binding and retaining the anti-tumor antibiotic daunorubicin (DAU). DAU-loaded micelles of CPAs (CPAs-DAU) demonstrated a 1.5-4-fold potentiation of DAU cytotoxicity against several cell lines. CPAs-DAU micelles were found to affect the cell cycle in a manner markedly different from that of free DAU. Our results demonstrated the ability of CPAs to act as bioactive drug delivery vehicles.

Combined treatment of murine leukemia P388 with doxorubicin and platinum(IV)-nitroxyl complex ВС118 administered in low doses improved efficiency of treatment (cure of 83% of animals) without increasing toxicity.

We performed a comparative study of the cytotoxicity of cisplatin, JM216 complex, and aminonitroxyl platinum(IV) complexes for HeLa cells grown in monolayer and 3D culture. The growth dynamics of spheroids was studied and optimal conditions for evaluation of cytotoxicity were determined. Spheroids were less sensitive to the test compounds than cells in a monolayer. The resistance index (RI) of spheroids was determined as the ratio of IC50 for spheroids to IC50 for monolayer culture. Resistance index was 5.0±1.5 for cisplatin and ranged from 1.8 to 2.3 for platinum(IV) complexes. The observed differences are related to different physicochemical properties of the complexes and different mechanisms of their penetration into cells.

Abstract The conditions for obtaining stable aqueous solutions of prospective pharmaceutical: a lipophilic aminonitroxyl platinum complex, namely, e-amine-d-(4-amino-2, 2, 6, 6-tetramethylpiperidine 1-oxyl)-a, fbis(octanoato)-b, c-dichloroplatinum(IV) (PNC), and a dye zinc tetraphenylporphyrinate (ZnTPP) by means of their solubilization with polymer particles of N-vinylpyrrolidone with dimethacrylate. Aqueous solutions of PNC and ZnTPP encapsulated into polymer particles were investigated by dynamic light scattering, and the temperature dependence of nanostructure sizes was studied. According to transmission electron microscopy, the hybrid nanostructures are core—shell particles, in which the PtIV complex forms small clusters (∼4 nm). It was established by ESR and voltammetric measurements that the free radical fragment of the aminonitroxyl PtIV complex kept its mobility and the same ESR and redox characteristics as the 4-acetylamino-2, 2, 6, 6-tetramethylpiperidine 1-oxyl radical. The obtained results indicate that biocompatible copolymers of N-vinylpyrrolidone are of interests as carriers and delivery tools for ZnTPP and organic PtIV complexes. Hybrid structures of given dimensions and properties can be created on their basis necessary for biomedical applications.

Kinetics of the reduction of nitroxides with cysteine in the presence of a source of superoxide radicals was studied. The reactivity of nitroxides in this process is determined by the reduction potential of the N-oxoammonium cation / nitroxide pair. The rate-limiting step of the reaction is the nitroxide oxidation by the hydroperoxyl radical to the N-oxoammonium cation.

The effect of inhibition of the tumor suppressor p53 on the antioxidant system genes expression under the influence of cytotoxic compounds of the platinum group was studied. It was found that the action of platinum(II) and platinum(IV) complexes induced accumulation of p53 protein with a maximum in 12 h, which was confirmed by an increase in the expression of the P21 gene, the target gene of the p53 protein. It was shown that the action of platinum complexes activated the expression of catalase and superoxide dismutase 2 genes. Suppression of p53 protein functions with specific inhibitor α-piphitrin under the action of platinum complexes reduced the expression of catalase and superoxide dismutase 2 genes and the target gene P21, which attested to the p53-dependent regulation of these genes.

The conditions for obtaining stable aqueous solutions of a lipophilic aminonitroxyl platinum complex, namely, e -amine- d -(4-amino-2,2,6,6-tetramethylpiperidine 1-oxyl)- a, f -bis(octanoato)- b, c -dichloroplatinum( iv ), by means of its encapsulation into nanoparticles of copolymers of N -vinylpyrrolidone with triethylene glycol dimethacrylate with various monomer compositions and topologies were found. Aqueous solutions of the complex encapsulated into polymer particles were investigated by dynamic light scattering, the temperature dependence of nanostructure sizes was studied. Transmission electron microscopy established that the hybrid nanostructures are core—shell particles, in which the platinum complex forms small clusters (∼4 nm). The parameters of ESR spectra of aqueous dispersions indicate a high mobility of nitroxyl contained in hybrid nanostructures. Voltammetric measurements demonstrate a similarity of the redox reactions related to the free radical fragment of the aminonitroxyl Pt IV complex and of the 4-acetylamino-2,2,6,6-tetramethylpiperidine 1-oxyl radical. Polymer products containing the platinum complex were studied by IR spectroscopy, TGA, and DSC. The cytotoxicity index (IC 50 ) of the free and the encapsulated complex was determined for HeLa tumor cells. The cytotoxicity of the latter (IC 50 47–205 nmol L −1 ) depends on the monomeric composition of the nanoparticles and the incubation time.

Density functional theory and continuum solvent model have been used to determine standard redox potentials of oxidation of cyclic nitroxide radicals and the nitroxide derivatives of chitosan and fullerene C60 in water. Inclusion of structural relaxation of solute in water improves correlation between the measured and calculated oxidation potentials. The underlying limitations of the thermodynamic cycle model have been discussed. The computed oxidation potential of the piperidine–N–oxide derivative of chitosan is several tens mV higher than of the separate radical while the opposite trend was found for the pyrroline–N–oxide derivative of chitosan. The calculations of fullerene C60–TEMPO have shown that the 6,6–methanofullerene is more stable that the 5,6–fulleroid structure. The determined redox potential of oxidation of fullerene C60–TEMPO is significantly higher than of TEMPO in water.

The cytotoxicity and antioxidant effects of chitosan-(poly)nitoxides of different molecular weights containing a nitroxide radical of the piperidine structure were studied on tumor (HeLa, A172, and HepG2) and normal (Vero) cell lines. The chitosan-(poly)nitroxides exhibited low cytotoxicity. Under conditions of oxidative stress induced with tert -butyl hydroperoxide, the most pronounced decrease in ROS levels in the presence of chitosan-(poly)nitroxides was observed in normal cells. In cell homogenates, the decrease in malondialdehyde levels was observed only in the presence of low-molecular-weight chitosan-(poly)nitroxide irrespective of the cell line. Our data demonstrate that the cell-specific antioxidant properties of chitosan-(poly)nitroxides are related to their penetration into cells and interaction with intracellular membranes.

The efficacy of the anticancer drug cisplatin is restricted by tumor cell resistance and occurrence of severe side effects. One strategy to overcome these limitations is the development of new, improved platinum drugs. Previous investigations showed that platinum(IV)-nitroxyl complexes are able to circumvent cisplatin resistance in bladder cancer cells. In the present study the mode of action of the platinum(IV)-nitroxyl complex PN149 was investigated in the bladder cancer cell line RT112 and the renal cell carcinoma cell line A498 on the molecular and cellular level. Gene expression analysis showed that PN149 induced genes related to DNA damage response (RRM2B, GADD45A), cell cycle regulation (CDKN1A, PLK3, PPM1D) as well as those coding for the pro-apoptotic factors PUMA and Noxa. These findings on the transcriptional level were confirmed on the functional level revealing that PN149 treatment increased levels of p53 and resulted in cell cycle arrest and drug-induced cytotoxicity via induction of apoptosis. Regarding the expression of oxidative-stress sensitive genes, PN149 induced FTH1, GCLC, HMOX1 and TXNRD1 but relevant effects were restricted to RT112 cells treated with 50 µM. The pro-inflammatory IL-8 was induced by PN149 in RT112 but not A498 cells indicating a cell-type specific activation. Taken together, PN149 possessed promising activity in different tumor cell lines rendering it an interesting alternative to cisplatin in chemotherapy.

The cytotoxicity and antioxidant properties of water-soluble (at physiological pH) chitosan- (poly)nitroxides (CPNs) containing pyrroline-based nitroxide and having different molecular weights of the polysaccharide backbone were studied on normal (Vero) and tumor (HepG2) cell models. The compounds were found to exhibit low cytotoxicity and to effectively reduce the level of reactive oxygen species (ROS) generated upon the breakdown of tert-butyl hydroperoxide in normal cells. In tumor cells, the CPNs have little effect on the ROS level under the oxidative stress. The results show that CPNs also represent a promising platform for the development of cell delivery systems for biologically active compounds.

The kinetics of the oxidation of methyl linoleate in micelles inhibited by stable nitroxides under the conditions of initiation by superoxide radicals was studied. Multiple breakdown of the oxidation chains was observed in this process. The antioxidant activity of nitroxides increased when the reduction potential of the oxoammonium cation/nitroxide pair decreased and their lipophilicity increased.

The influence of solvent (DMF, MeCN, and water) and R1, R2 substituent nature on the formal oxidation potential (E°´) of 4-R1,R2-2,2,6,6-tetramethylpiperidine 1-oxyls (1a—f) on a glass carbon electrode was studied by cyclic voltammetry. It was shown that for all the solvents the observed dependence had the form E°´ = ρ″σ″ + b, where σ″ is the substituent constant. The b values decreased with an increase of the solvent solvating ability, while the values ρ″ are similar for all the solvents, surpassing the corresponding values for nitroxyls of the imidazoline series with substituents at position 3, which can be interpreted as an abnormally strong influence of the substituent remote from the reaction center in 1a—f. The experimental values E°´ were linearly correlated with the reaction free energy values (ΔG) calculated by DFT B3LYP and MP2 for the gas phase contribution and by HF/PCM for the contribution of solvation effects. When applying the B3LYP and the HF/PCM approaches in combination, the dependence of E°´ on ΔG for all the considered solvents was described by a linear correlation equation with a slope close to unity and a constant term which was close to the theoretical value of the absolute potential of the reference electrode used.

The therapeutic efficacy of the anticancer drug cisplatin is limited by the development of resistance. We therefore investigated newly synthesized platinum-nitroxyl complexes (PNCs) for their potential to circumvent cisplatin resistance. The complexes used were PNCs with bivalent cis -Pt II (R · NH 2 )(NH 3 )Cl 2 and cis -Pt II (DAPO)Ox and four-valent platinum cis , trans , cis -Pt IV (R · NH 2 )(NH 3 )(OR) 2 Cl 2 and cis , trans , cis -Pt IV (DAPO)(OR) 2 Ox, where R · are TEMPO or proxyl nitroxyl radicals, DAPO is trans -3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl, and OR and Ox are carboxylato and oxalato ligands, respectively. The complexes were characterized by spectroscopic methods, HPLC, log P ow data and elemental analysis. We studied intracellular platinum accumulation, DNA platination and cytotoxicity upon treatment with the PNCs in a model system of the bladder cancer cell line RT112 and its cisplatin-resistant subline RT112-CP. Platinum accumulation and DNA platination were similar in RT112 and RT112-CP cells for both bivalent and four-valent PNCs, in contrast to cisplatin for which a reduction in intracellular accumulation and DNA platination was observed in the resistant subline. The PNCs were found to platinate DNA in relation to the length of their axial RO-ligands. Furthermore, the PNCs were increasingly toxic in relation to the elongation of their axial RO-ligands, with similar toxicities in RT112 and its cisplatin-resistant subline. Using a cell-free assay, we observed induction of oxidative DNA damage by cisplatin but not PNCs suggesting that cisplatin exerts its toxic action by platination and oxidative DNA damage, while cells treated with PNCs are protected against oxidatively induced lesions. Altogether, our study suggests that PNCs may provide a more effective treatment for tumors which have developed resistance toward cisplatin.