The aim of this study was to evaluate anti-cancer properties of hesperetin (Hsp) and hesperetin-loaded poly(lactic-co-glycolic acid) nanoparticles (HspNPs) for glioblastoma treatment. Nanoparticles prepared by single emulsion method had a size of less than 300 nm with 70.7 ± 3.9% reaction yield and 26.4 ± 1.1% Hsp loading capacity. Treatment of C6 glioma cells with HspNPs for 24 and 48 h resulted in dose-and time-dependent decrease in cell viability, with approximate IC 50 of 28 and 21 lg/mL, respectively (p ¼ .036 for 24 h, p ¼ .025 for 48 h). The percentage of PCNA positive cells decreased to 20% and 10%, respectively, for Hsp-and HspNP-treated cells at concentration of 100 mg/mL. Treatment with increasing concentrations of HspNPs (25, 50, 75 and 100 mg/mL) resulted in 9.1-, 7-, 12.5-and 12.7-fold in increase in apoptotic cell number. Optimum doses of Hsp and HspNPs were found to increase oxidative damage in C6 glioma cells. MDA levels, an indicator of lipid peroxidation, were found to be significantly elevated at 75 and 100 mg/mL exposure concentration of HspNPs with (p ¼ .002) and (p ¼ .018), respectively for 48-h treatment. The results obtained with this study showed biocompatible polymeric nanoparticle systems has great advantages to enhance anti-cancer activity and poor solubility of therapeutic agents. Overall our findings suggest that Hsp-loaded PLGA nanoparticle systems showed significant anti-cancer activity and HspNPs could be used as promising novel anti-cancer agent. ARTICLE HISTORY

The use of quercetin as a bioflavonoid is becoming increasingly common in food industries even though poor water solubility, instability, absorption, and permeability have limited its application. The oil-in-water single-emulsion solvent evaporation method to synthesize highly stable and soluble quercetin-encapsulated nanoparticles (NPs), in which the reaction yield, particle size, and polydispersity of the NPs are varied greatly within the process parameters of the synthesis method, has been optimized. NPs with different initial quercetin amounts were used to determine how the quercetin amount affected nanoparticle properties and antimicrobial efficiency. Listeria monocytogenes, Salmonella typhimurium, Escherichia coli, and Staphylococcus aureus were chosen as model bacteria due to their being foodborne pathogens. The results of antimicrobial activity evaluated by three different methods showed that the antimicrobial activity of both quercetin NPs and free quercetin was effective on gram-positive strains (L. monocytogenes and S. aureus). Additionally, it was detected that Q31 NPs have more effective antimicrobial activity than other synthesized quercetin nanoparticles depending on the amount of substance and release. Furthermore, on the basis of assessing the antibacterial effects by scanning electron microscopy, it was detected that bacteria cells lost their integrity and became pale with the release of cytoplasm and decomposed after treatment with Q31 NPs.

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Hesperetin was effectively encapsulated into poly (d,l-lactic-co-glycolic acid) nanoparticles by using experimental design methods. A seven-factor Plackett-Burman design was used in order to determine the major process parameters. A significant linear equation, which shows the effect of each process parameter on encapsulation efficiency was developed, and then the most effective factors were determined. Further investigation and optimization was carried out by applying the three-factor three-level Box-Behnken design. Significant second-order mathematical models were developed by regression analysis of the experimental data for both responses: encapsulation efficiency and nanoparticle size. The two step experimental design allowed the synthesis of the desired nanoparticle formulations with maximum encapsulation efficiency (80.5 ± 4.9%) and minimum particle size (260.2 ± 16.5 nm) at optimum process conditions: 0.5% polyvinyl alcohol (PVA) concentration, 5.13 water:organic phase ratio, and 3.59 ml min flow rate of the emulsified solution into 0.1% PVA. Furthermore, the biological activity of these optimized nanoparticles were determined with antimicrobial activity and cytotoxicity studies; results were then compared to the free hesperetin. The cytotoxicity result revealed that hesperetin and hesperetin-loaded nanoparticles were biocompatible with normal cell line L929 fibroblast cells up to 184.83 and 190.88 μg ml for 24 h, and up to 133.24 and 134.80 μg ml for 48 h, respectively. In the antimicrobial study, the optimized nanoparticle showed inhibition activity (minimal inhibitory concentration (MIC) values were 125 μg ml for Escherichia coli, and 200 μg ml for Staphylococcus aureus), while the free hesperetin did not demonstrate activity in both strains (MIC value >200 μg ml). These in vitro results may provide useful information for the investigation of hesperetin-loaded nanoparticles in diagnostic and therapeutic applications.

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