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Kohay, H. ; Sarisozen, C. ; Sawant, R. ; Jhaveri, A. ; Torchilin, V. P. ; Mishael, Y. G. PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity. Acta Biomater 2017, 55, 443-454.Abstract
A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements. These measurements suggest that for the LOW composite a single layer of polymer intercalates in the clay platelets and the polymer only partially covers the external surface, while for the HIGH composite two layers of polymer intercalate and a bilayer may form on the external surface. These nanostructures have a direct effect on formulation stability and on the rate of DOX release. The release rate was reversely correlated with the degree of DOX interaction with the clay and followed the sequence: M-DOX>HIGH formulation>LOW formulation>DOX/MMT. Despite the slower release from the HIGH formulation, its cytotoxicity effect on sensitive cells was as high as the "free" DOX. Surprisingly, the LOW formulation, with the slowest release, demonstrated the highest cytotoxicity in the case of Adriamycin (ADR) resistant cells. Confocal microscopy images and association tests provided an insight into the contribution of formulation-cell interactions vs. the contribution of DOX release rate. Internalization of the formulations was suggested as a mechanism that increases DOX efficiency, particularly in the ADR resistant cell line. The employment of organic-inorganic hybrid materials as drug delivery systems, has not reached its full potential, however, its functionality as an efficient tunable release system was demonstrated. STATEMENT OF SIGNIFICANCE: DOX PEG-PE/clay formulations were design as an efficient drug delivery system. The main aim was to develop PEG-PE/clay formulations of different structures based on various PEG-PE/clay ratios in order to achieve tunable release rates, to control the external surface characteristics and formulation stability. The formulations showed significantly higher toxicity in comparison to "free" DOX, explained by formulation internalization. For each cell line tested, sensitive and ADR resistant, a different formulation structure was found most efficient. The potential of PEG-PE/clay-DOX formulations to improve DOX administration efficacy was demonstrated and should be further explored and implemented for other cancer drugs and cells.
Avneri-Katz, S. ; Young, R. B. ; McKenna, A. M. ; Chen, H. ; Corilo, Y. E. ; Polubesova, T. ; Borch, T. ; Chefetz, B. Adsorptive fractionation of dissolved organic matter (DOM) by mineral soil: Macroscale approach and molecular insight. Organic Geochemistry 2017, 103, 113 - 124. Publisher's VersionAbstract
Adsorption of dissolved organic matter (DOM) to mineral surfaces is an important process determining DOM bioavailability and carbon sequestration in soils. However, little is known about preferential adsorption of DOM at the molecular level. In this study, DOM originating from composted biosolids was analyzed in order to elucidate DOM adsorptive fractionation by clay soil. Structural changes in DOM due to adsorption to soil were studied using two complementary approaches: (i) macroscale analysis including resin separation and (ii) molecular characterization using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Both approaches demonstrated consistency regarding the DOM adsorptive fractionation. Resin separation showed preferential adsorption of the hydrophobic acid (HoA) fraction by soil surfaces, with up to 70% of total adsorbed carbon; this fraction was apparently responsible for low DOM desorption. FT-ICR MS data demonstrated preferential adsorption of polyphenols, which are components of the HoA fraction. Adsorption of highly oxidized, saturated “carbohydrate-like” molecules was also observed, which might be a result of adsorption of the hydrophilic neutral (HiN) fraction. DOM exhibited concentration-dependent fractionation: enhanced adsorption of highly oxidized compounds at low DOM concentrations, and selective adsorption of less oxidized components at higher DOM concentrations, suggesting that adsorptive fractionation of DOM depended on the extent of its loading. Our findings suggest that a significant amount of carbon originating from the applied DOM was irreversibly stabilized by mineral surfaces. The study demonstrates that both DOM chemical heterogeneity and DOM concentration need to be considered in order to predict DOM reactivity and carbon stabilization in soils.
Riemenschneider, C. ; Seiwert, B. ; Goldstein, M. ; Al-Raggad, M. ; Salameh, E. ; Chefetz, B. ; Reemtsma, T. An LC-MS/MS method for the determination of 28 polar environmental contaminants and metabolites in vegetables irrigated with treated municipal wastewater. Anal. Methods 2017, 9 1273-1281. Publisher's VersionAbstract
An analytical method for the simultaneous determination of 28 wastewater-derived contaminants and possible metabolites (e.g. carbamazepine, 10,11-epoxy-carbamazepine, benzotriazole, lamotrigine, and diclofenac) in common plant tissues with high water content (lettuce, cabbage, and tomato) was developed and validated. The developed method combines solid–liquid extraction, without the need for a clean-up step, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) with electrospray ionization in positive and negative modes. This method was compared with the known QuEChERS method and exhibited better analytical performance. Method detection limits of ≤2.0 ng g−1 dry weight and absolute recoveries of >60% with high intra- and inter-day precision (RSD < 10%) could be achieved for 71% of the target analytes in four different matrices (cabbage, lettuce and tomato leaves, and tomato fruits). Compared to the QuEChERS method, the developed method allows the determination of a wide range of compounds with different physical–chemical properties (neutral, acidic, and basic) and considers even possible metabolites of pharmaceuticals in plant materials. The developed method was successfully applied to analyse wastewater-derived contaminants and their metabolites in plants which were grown under greenhouse and real field conditions. It could be shown that this method is suitable for the sensitive determination of environmental contaminants originating from treated wastewater and a range of their metabolites in irrigated plants and their edible parts. Due to its broadness the extraction method should also be suitable for screening of unknown contaminants and metabolites by LC high-resolution mass spectrometry.
Levy, Y. ; Shapira, R. H. ; Chefetz, B. ; Kurtzman, D. Modeling nitrate from land surface to wells' perforations under agricultural land: success, failure, and future scenarios in a Mediterranean case study. Hydrology and Earth System Sciences 2017, 21, 3811–3825. Publisher's Version