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The application of a biocompatible polymer nanocarrier can provide target delivery to tumor tissues, improved pharmacokinetics, controlled drug release, etc. Therefore, the proposed strategy was to use the water-soluble star-like copolymers with a Dextran core and Poly(N-isopropylacrylamide) grafts (D-g-PNIPAM) for conjugation with the widely used chemotherapy drugs in oncology-Cisplatin (Cis-Pt) and Doxorubicin (Dox). The molecular characteristics of the copolymer were received using size-exclusion chromatography. The physicochemical characterization of the D-g-PNIPAM-Cis-Pt (or Dox) nanosystem was conducted using dynamic light scattering and FTIR spectroscopy. Using traditional biochemical methods, a comparative analysis of the enhancement of the cytotoxic effect of free Cis-Pt and Dox in combination with D-g-PNIPAM copolymers was performed in cancer cells of the Lewis lung carcinoma line, which are both sensitive and resistant to Dox; in addition, the mechanism of their action in vitro was evaluated.

Background: Cisplatin (Cis-Pt) is a widely used anticancer drug but its therapeutic efficiency is limited by hemato-, cardio-, hepato-, nephro- and neurotoxicity. Complexation of Cis-Pt with C 60 fullerene nanoparticle will allow to enhance the antitumor activity of the drug and to reduce its side toxic effects., Aim: To estimate the antitumor effects of С60-Cis-Pt nanocomplex in Lewis lung carcinoma (LLC) and analyze hematological toxicity in tumor-bearing mice., Materials and Methods: Complexation of C 60 fullerene and Cis-Pt molecule was studied by computer simulation. С60-Cis-Pt nanocomplex was i.p. injected to LLC-bearing mice in a total dose of 7.5 mg/kg (C 60 :Cis-Pt as 3.75:3.75 mg/kg). The survival of tumor-bearing mice and the relative reduction of tumor weight was recorded. Blood indices were determined using the Particle Counter PCE-210 automatic hematology analyzer., Results: Computer simulation demonstrated the formation of С60-Cis-Pt nanocomplex in physiological medium and its stability due to the hydrophobic interactions. Treatment with C 60 -Cis-Pt nanocomplex increased survival time of LLC-bearing mice by 32%, normalized hemoglobin content (up to 100 g/l), erythrocyte and platelet count as compared to the untreated LLC-bearing mice. Tumor weight decreased by 35.5%; the mitotic index of tumor cells decreased by 78%, and apoptotic index increased by 75%. The revealed effects of the C 60 -Cis-Pt nanocomplex were more pronounced than the effects of Cis-Pt or C 60 fullerene alone in equivalent dose., Conclusion: Treatment with C 60 -Cis-Pt nanocomplex prolonged the survival of LLC-bearing mice and reduced anemia in LLC-bearing mice.

Cisplatin (Cis-Pt) is the cytotoxic agent widely used against tumors of various origin, but its therapeutic efficiency is substantially limited by a non-selective effect and high toxicity. Conjugation of Cis-Pt with nanocarriers is thought to be one option to enable drug targeting. The aim of this study was to estimate toxic effects of the nanocomplex formed by noncovalent interaction of C 60 fullerene with Cis-Pt against Lewis lung carcinoma (LLC) cells in comparison with free drug. Scanning tunneling microscopy showed that the minimum size of C 60 -Cis-Pt nanoparticles in aqueous colloid solution was 1.1 nm whereas that of C 60 fullerene was 0.72 nm, thus confirming formation of the nanocomplex. The cytotoxic effect of C 60 -Cis-Pt nanocomplex against LLC cells was shown to be higher with IC 50 values 3.3 and 4.5 times lower at 48 h and 72 h, respectively, as compared to the free drug. 12.5 µM Cis-Pt had no effect on LLC cell viability and morphology while C 60 -Cis-Pt nanocomplex in Cis-Pt-equivalent concentration substantially decreased the cell viability, impaired their shape and adhesion, inhibited migration and induced accumulation in proapoptotic subG1 phase. Apoptosis induced by the C 60 -Cis-Pt nanocomplex was confirmed by caspase 3/7 activation and externalization of phosphatidylserine on the outer surface of LLC cells with the double Annexin V-FITC/PI staining. We assume that C 60 fullerene as a component of the C 60 -Cis-Pt nanocomplex promoted Cis-Pt entry and intracellular accumulation thus contributing to intensification of the drug's toxic effect against lung cancer cells.

Aim: To estimate the combined action of C60 fullerene and light irradiation on viability of L1210 leukemic cells, nitric oxide (NO) generation, p38 mitogen-activated protein kinase (MAPK) activity and cell cycle distribution., Methods: Cell viability was assessed by MTT test. Light-emitting diode lamp (λ = 410-700 nm, 2.45 J/cm(2) ) was used for C60 fullerene photoexcitation. Nitrite level and NO-synthase activity were measured by Griess reaction and by conversion of L-arginine to L-citrulline, respectively. p38 MAPK activity was assessed by Western blot analysis. Cell cycle distribution was determined by flow cytometry., Results: It was shown that light irradiation of C60 fullerene-treated L1210 cells was accompanied by 55% decrease of their viability at 48 h of culture. Nitrite level measured as an index of reactive NO generation was increased at the early period after C60 fullerene photoexcitation due to activation of both constitutive and inducible NO-synthase isoforms. The simultaneous activation of p38 MAPK was detected. Accumulation of L1210 cells in sub-G1 phase of cell cycle was observed after C60 fullerene photoexcitation., Conclusion: Photoexcited C60 fullerene exerts cytotoxic effect, at least in part, through triggering production of reactive NO species and activation of p38 kinase apoptotic pathways in L1210 leukemic cells.

The specific features of structural self-organization of C60 fullerene and antitumor drug cisplatin (Cis) in physiological solution (0.9% NaCl) have been investigated by means of small-angle neutron scattering, scanning electron and atomic force microscopies, as well as isothermal titration calorimetry, dynamic light scattering and UV-Vis spectroscopy. The formation of C60 + Cis complexes, has been reported, unveiling the mechanism of medico-biological synergy observed during administration of the mixture of these drugs.

The self-ordering of C60 fullerene, doxorubicin and their mixture precipitated from aqueous solutions was investigated using atomic-force microscopy. The results suggest the complexation between the two compounds. The genotoxicity of doxorubicin in complex with C60 fullerene (C 60+Dox) was evaluated in vitro with comet assay using human lymphocytes. The obtained results show that the C60 fullerene prevents the toxic effect of Dox in normal cells and, thus, C60+Dox complex might be proposed for biomedical application.

Background: Doxorubicin (Dox) is one of the most potent anticancer drugs, but its successful use is hampered by high toxicity caused mainly by generation of reactive oxygen species. One approach to protect against Dox-dependent chemical insult is combined use of the cytostatic drug with antioxidants. C60 fullerene has a nanostructure with both antioxidant and antitumor potential and may be useful in modulating cell responses to Dox., Objective: The aim of this study was to estimate the antitumor effect and antioxidant enzyme activity of combined C60 fullerene and Dox (C60 + Dox) in the liver and heart of mice with Lewis lung carcinoma compared with Dox treatment alone., Methods: Highly stable pristine C60 fullerene aqueous colloid solution (concentration 1.0 mg/ml, average hydrodynamic diameter of nanoparticles 50 nm) was used in the study and characterized by means of atomic force microscopy (AFM). The in vivo investigation of C60-Dox action was performed via the standard methods of histological and enzyme activity analyses., Results: Dox (total dose 2.5 mg/kg) combined with C60 fullerene (total dose 25 mg/kg) in tumor-bearing animals resulted in tumor growth inhibition, prolongation of life, metastasis inhibition, and increased number of apoptotic tumor cells and was more effective than the corresponding course of Dox treatment alone. C60 fullerene demonstrated a protective effect against superoxide dismutase and glutathione peroxidase inhibition induced by Dox-dependent oxidative insult in the liver and heart., Conclusion: Combined treatment with C60 + Dox is considered to be a promising approach for cancer chemotherapy.

The effect of the anticancer drug--doxorubicin (Dox) on hydration properties of a nanocomposite material deposited on silica and modified by small amount of DNA (0.6 wt%) was studied by means of (1)H NMR spectroscopy at low temperatures (in the range of 200-280 K). Signals of either weakly (WAW) or strongly (SAW) associated water, as well as water associated with electrondonor groups of the composite surface (ASW), were observed. The findings reveal that, depending on the temperature and the composition of the dispersion medium, fast molecular exchange takes place between different forms of interphase water. The presence of Dox (0.1-0.2 wt%) in the dispersion medium leads to change of the relative concentrations of different forms of water.

An increase of the intracellular reactive oxygen species (ROS) concentration leads to the development of oxidative stress and, thus, to the damage of cell components. The cause-and-effect relations between these processes have not been fully established yet. The ability of photo excited supramolecular composites containing fullerenes C60 immobilized at nanosilica particles to generate reactive oxygen species (ROS) in cells of two types (rat thymocytes, and transformed cells of ascite Erlich carcinoma, EAC, and leucosis L1210) is demonstrated. The damaging effect of photo excited C60-composites are shown, which appeared to be selective and manifested in transformed cells, but not in thymocytes. It has been shown that after the irradiation of aqueous solutions or cell suspensions in the presence of fullerene C60, the generation of reactive oxygen species is observed. It has been shown that the influence of photo excited fullerene C60 on metabolic processes depends on the composition of C60-containing complex and on the type of the cells. The damaging effects of photo excited fullerene C60-containing composites were demonstrated to be selective. The data presented suggest that the application of fullerene C60-containing composites for the selective activation of ROS-dependent death program in certain types of tumor cells is very promising.

Aneuploidy tests are important in evaluating genetic hazards especially when chemical exposures are suspected to affect the fidelity of chromosome segregation in oocytes and embryos. In the current study, a newly established method, mouse preantral follicle culture, was employed to grow oocytes in vitro within follicles. The sensitivity of in vitro grown follicle enclosed oocytes was compared with oocytes maturing in vivo in the ovary. In both the cases, oocytes were exposed to the cytostatic chemical, nocodazole, from the time of hormonally stimulated resumption of meiosis. The in vivo study revealed a significant decrease in the number of ovulated mouse oocytes and an increase in meiosis I-arrested and hyperploid metaphase II oocytes at a single i.p. dose of 70 mg/kg body weight of nocodazole. A significant increase was also observed in the number of meiosis I-arrested and hyperploid mouse oocytes from preantral follicle culture, when they were cultured in the presence of >or=30 nM nocodazole during the final stages of maturation. This concentration is slightly lower than that previously shown to induce nondisjunction in denuded mouse oocytes or in cultured human lymphocytes. The higher sensitivity of the in vitro matured oocytes from preantral follicle culture than that of denuded oocytes may be related to a synergistic adverse influence of nocodazole on the oocyte, on somatic cell integrity and on cell-cell communication, which possibly also affects ovulation in vivo. When expressed in molarity relative to the mouse weight, the effective dose of the acute exposure in vivo is 3-4 orders of magnitude higher than the lowest effective concentration employed continuously in vitro. Reduced bioavailability of nocodazole to the target cells due to its poor water solubility may contribute to this difference. Preantral follicle culture can be helpful in analysing mechanisms in chemically induced aneuploidy in mammalian oogenesis, and in predicting the consequences of chemical exposures in vivo.

Introduction: Landomycins are a subgroup of angucycline antibiotics that are produced by Streptomyces bacteria and possess strong antineoplastic potential. Literature data suggest that enhancement of the therapeutic activity of this drug may be achieved by means of creating specific drug delivery systems. Here we propose to adopt C60 fullerene as flexible and stable nanocarrier for landomycin delivery into tumor cells.Methods: The methods of molecular modelling, dynamic light scattering and Fourier transform infrared spectroscopy were used to study the assembly of C60 fullerene and the anticancer drug Landomycin A (LA) in aqueous solution. Cytotoxic activity of this nanocomplex was studied in vitro towards two cancer cell lines in comparison to human mesenchymal stem cells (hMSCs) using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) test and a live/dead assay. The morphology of the cells incubated with fullerene-drug nanoparticles and their uptake into target cells were studied by scanning electron microscopy and fluorescence light microscopy.Results: The viability of primary cells (hMSCs, as a model for healthy cells) and cancer cell lines (human osteosarcoma cells, MG-63, and mouse mammary cells, 4T1, as models for cancer cells) was studied after incubation with water-soluble C60 fullerenes, LA and the mixture C60 + LA. The C60 + LA nanocomplex in contrast to LA alone showed higher toxicity towards cancer cells and lower toxicity towards normal cells, whereas the water-soluble C60 fullerenes at the same concentration were not toxic for the cells.Conclusions: The obtained physico-chemical data indicate a complexation between the two compounds, leading to the formation of a C60 + LA nanocomposite. It was concluded that immobilization of LA on C60 fullerene enhances selectivity of action of this anticancer drug in vitro, indicating on possibility of further preclinical studies of novel C60 + LA nanocomposites on animal tumor models. [ABSTRACT FROM AUTHOR]

The interaction of dimethyl-N-(benzoyl)amidophosphate (HCP) and dimethyl-N-(phenylsulfonyl)amidophosphate (HSP) compounds and C60 fullerene with DNA was studied by use of molecular modeling. It was demonstrated that DNA-HCP complex is more stable as compared to the DNA-HSP one. The ability of C60 fullerene to form a stable complex with minor groove of DNA was shown. Under combined action of 10-5 M C60 fullerene and 2.5 × 10-4 M HCP the viability of leukemia L1210 cells was decreased by 37% in 24 h. The observed cytotoxic effect was intensified in 48 h. HSP compound alone as well as at combined action with C60 fullerene showed no cytotoxic effect. [ABSTRACT FROM AUTHOR]

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Copyright of Materialwissenschaft und Werkstoffechnik is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The effect of the anticancer drug-doxorubicin (Dox) on hydration properties of a nanocomposite material deposited on silica and modified by small amount of DNA (0.6 wt%) was studied by means of H NMR spectroscopy at low temperatures (in the range of 200-280 K). Signals of either weakly (WAW) or strongly (SAW) associated water, as well as water associated with electrondonor groups of the composite surface (ASW), were observed. The findings reveal that, depending on the temperature and the composition of the dispersion medium, fast molecular exchange takes place between different forms of interphase water. The presence of Dox (0.1-0.2 wt%) in the dispersion medium leads to change of the relative concentrations of different forms of water. [ABSTRACT FROM AUTHOR]