Assessment of Anti-Tumor potential and safety of application of Glutathione stabilized Gold Nanoparticles conjugated with Chemotherapeutics.

Due to the high toxicity of currently used chemotherapeutics, novel methods of cancer treatment are needed. Gold nanoparticles (AuNPs) seem to be an interesting alternative due to penetration through biological membranes and systemic barriers. AuNPs as carriers of chemotherapeutics allow for reduced concentrations whilst maintaining the expected effect, and thus reducing the costs of therapy and adverse effects. We synthesized AuNPs stabilized with reduced glutathione (GSH) and conjugated with doxorubicin (DOX), gemcitabine (GEM) or cytarabine (CTA). This is the first study in which cytarabine-AuNPs were synthesized and characterized. Transmission electron microscopy (TEM), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR) and high-performance liquid chromatography (HPLC) were used to chemically characterize obtained nanoparticles. Antitumor activity and safety of application were assessed by MTT assay in in vitro model (human osteosarcoma cells -143B, human osteoblast- hFOB1.19, breast cancer cells - MCF7, breast epithelial cells - MCF10A, pancreatic cancer cells - PANC-1, and pancreatic cells - hTERT-HPNE cells). We have shown that cellular response varies according to the type and concentration of AuNPs. At some concentrations, we were able to show selective cytotoxicity of our AuNPs conjugates only to cancer cell lines. Synthesized nanoparticles were more cytotoxic to tumor cell lines than chemotherapeutics alone.

An 1H NMR study of the cytarabine degradation in clinical conditions to avoid drug waste, decrease therapy costs and improve patient compliance in acute leukemia.

Cytarabine, the 4-amino-1-(ß-D-arabinofuranosyl)-2(1H)-pyrimidinone, (ARA-C) is an antimetabolite cytidine analogue used worldwide as key drug in the management of leukaemia. As specified in the manufacturers' instructions, once the components-sterile water and cytarabine powder-are unpackaged and mixed, the solution begins to degrade after 6 hours at room temperature and 12 hours at 4°C. To evaluate how to avoid wasting the drug in short-term, low-dose treatment regimens, the reconstituted samples, stored at 25°C and 4°C, were analyzed every day of the test week by reversed-phase HPLC and high-field NMR spectroscopy. All the samples remained unchanged for the entire week, which corresponds to the time required to administer the entire commercial drug package during low-dose therapeutic regimens. The drug solution was stored in a glass container at 4°C in an ordinary freezer and drawn with sterile plastic syringes; during this period, no bacterial or fungal contamination was observed. Our findings show that an cytarabine solution prepared and stored in the original vials retains its efficacy and safety and can, therefore, be divided into small doses to be administered over more days, thus avoiding unnecessary expensive and harmful waste of the drug preparation. Moreover, patients who require daily administration of the drug could undergo the infusion at home without need to go to hospital. The stability of the aliquots would help decrease hospitalization costs.

A comparative study on the photo-catalytic degradation of Cytarabine anticancer drug under Fe3+/H2O2, Fe3+/S2O82-, and [Fe(C2O4)3]3-/H2O2 processes. Kinetics, identification, and in silico toxicity assessment of generated transformation products.

Cytarabine (CY) is an anticancer drug which has been identified in wastewater influents, effluents, and surface waters. In the present study, the degradation of CY under simulated solar light (SSL), by photo-Fenton (Fe3+/H2O2/SSL) and photo-Fenton-like processes (Fe3+/S2O82-/SSL and [Fe(C2O4)3]3-/H2O2/SSL), was investigated. The major parameters affecting the applied treatments (e.g., concentration of CY, Fe3+, H2O2, and S2O82-) were optimized and CY's complete removal was achieved within 45 min for all techniques used. Mineralization studies indicated that [Fe(C2O4)3]3-/H2O2/SSL treatment was the most efficient procedure since faster kinetics are achieved and higher mineralization percentage is reached compared to the other techniques used. Furthermore, 12 transformation products (TPs) were identified during the applied processes, by high resolution mass spectrometry, four of which were identified for the first time, indicating that CY molecule undergoes hydroxylation and subsequent oxidation, during the applied processes. Moreover, predictions of acute and chronic ecotoxicity of CY and its TPs on fish, daphnia, and green algae were conducted, using in silico quantitative structure activity relationship (QSAR) calculations. According to these predictions, the TPs generated during the studied treatments may pose a threat to aquatic environment. Finally, the efficiency of CY degradation by photo-Fenton and photo-Fenton-like treatment in real wastewater was evaluated, under the optimized conditions, which resulted in lower degradation rate constants compared to ultrapure water.

Ecotoxicity and genotoxicity assessment of cytotoxic antineoplastic drugs and their metabolites.

In spite of growing scientific concern about pharmaceuticals in the environment, there is still a lack of information especially with regard to their metabolites. The present study investigated ecotoxicity and genotoxicity of three widely used cytostatic agents 5-fluorouracil (5-FU), cytarabine (CYT) and gemcitabine (GemC) and their major human metabolites, i.e. alpha-fluoro-beta-alanine (FBAL), uracil-1-beta-D-arabinofuranoside (AraU) and 2',2'-difluorodeoxyuridine (dFdU), respectively. Effects were studied in acute immobilization and reproduction assays with crustacean Daphnia magna and growth inhibition tests with alga Desmodesmus subspicatus and bacteria Pseudomonas putida. Genotoxicity was tested with umu-test employing Salmonella choleraesius subsp. chol. Toxicity was relatively high at parent compounds with EC(50) values ranging from 44 microg L(-1) (5-fluorouracil in the P. putida test) to 200 mg L(-1) (cytarabine in D. magna acute test). In general, the most toxic compound was 5-FU. Studied metabolites showed low or no toxicity; only FBAL (metabolite of 5-FU) showed low toxicity to D. subspicatus and P. putida with EC(50) values 80 and 140 mg L(-1), respectively. All parent cytostatics showed genotoxicity with minimum genotoxic concentrations (MGC) ranging from 40 to 330 mg L(-1). From metabolites, only FBAL was genotoxic in high concentrations. To our knowledge, the present study provides some of the first ecotoxicity data for both cytostatics and their metabolites, which might further serve for serious evaluation of ecological risks. The observed EC(50) values within the microg L(-1) range were fairly close to concentrations reported in hospital sewage water, which indicates further research needs, especially studies of chronic toxicity.