Lipophilic phosphonium-lanthanide compounds with magnetic, luminescent, and tumor targeting properties.

Multifunctional phosphonium-lanthanide compounds that simultaneously possess paramagnetism, luminescence, and tumor mitochondrial targeting properties were prepared by use of a facile method. These compounds were fully characterized by use of (1)H, (13)C, (31)P NMR, FT-IR, and elemental analyses. The thermal properties of these compounds including melting points and decomposition temperatures were investigated using DSC and TGA analyses. In addition, the paramagnetism, luminescence, and tumor targeting properties of these multifunctional compounds were confirmed by respective use of SQUID, fluorescence, and cell cytotoxicity studies. All compounds exhibited paramagnetism at room temperature, which could provide target delivery of these compounds to parts of the body containing tumor cells using a strong external magnetic field. In addition, these compounds display two major characteristic emissions originating from Dy(3+), which can be utilized for imaging tumor cells. The IC(50) values of these compounds measured against normal breast cell line (Hs578Bst) are significantly greater than those measured against the corresponding carcinoma breast cell line (Hs578T), clearly indicating the selective tumor targeting properties of these compounds. Confocal fluorescence microscopy studies were used to confirm the yellowish-green fluorescence corresponding to the emission of dysprosium thiocyanate anion within cancer cells upon exposure of cancer cell lines such as human pancreatic carcinoma cell line (MIAPaCa-2) and human breast carcinoma (MDA-MB-231) to a solution of these phosphonium-dysprosium compounds.

Ratiometric coumarin-neutral red (CONER) nanoprobe for detection of hydroxyl radicals.

Excessive production of reactive oxygen species can lead to alteration of cellular functions responsible for many diseases including cardiovascular diseases, neurodegenerative diseases, cancer, and aging. Hydroxyl radical is a short-lived radical which is considered very aggressive due to its high reactivity toward biological molecules. In this study, a COumarin-NEutral Red (CONER) nanoprobe was developed for detection of hydroxyl radical based on the ratiometric fluorescence signal between 7-hydroxy coumarin 3-carboxylic acid and neutral red dyes. Biocompatible poly lactide-co-glycolide (PLGA) nanoparticles containing encapsulated neutral red were produced using a coumarin 3-carboxylic acid conjugated poly(sodium N-undecylenyl-Nε-lysinate) (C3C-poly-Nε-SUK) as moiety reactive to hydroxyl radicals. The response of the CONER nanoprobe was dependent on various parameters such as reaction time and nanoparticle concentration. The probe was selective for hydroxyl radicals as compared with other reactive oxygen species including O(2)(•-), H(2)O(2), (1)O(2), and OCl(-). Furthermore, the CONER nanoprobe was used to detect hydroxyl radicals in vitro using viable breast cancer cells exposed to oxidative stress. The results suggest that this nanoprobe represents a promising approach for detection of hydroxyl radicals in biological systems.

Delivery of phytochemical thymoquinone using molecular micelle modified poly(D, L lactide-co-glycolide) (PLGA) nanoparticles.

Continuous efforts have been made in the development of potent benzoquinone-based anticancer drugs aiming for improved water solubility and reduced adverse reactions. Thymoquinone is a liposoluble benzoquinone-based phytochemical that has been shown to have remarkable antioxidant and anticancer activities. In the study reported here, thymoquinone-loaded PLGA nanoparticles were synthesized and evaluated for physico-chemical, antioxidant and anticancer properties. The nanoparticles were synthesized by an emulsion solvent evaporation method using anionic molecular micelles as emulsifiers. The system was optimized for maximum entrapment efficiency using a Box-Behnken experimental design. Optimum conditions were found for 100 mg PLGA, 15 mg TQ and 0.5% w/v poly(sodium N-undecylenyl-glycinate) (poly-SUG). In addition, other structurally related molecular micelles such as poly(sodium N-heptenyl-glycinate) (poly-SHG), poly(sodium N-undecylenyl-leucinate) (poly-SUL), and poly(sodium N-undecylenyl-valinate) (poly-SUV) were also examined as emulsifiers. All investigated molecular micelles provided excellent emulsifier properties, leading to maximum optimized TQ entrapment efficiency, and monodispersed particle sizes below 200 nm. The release of TQ from molecular micelle modified nanoparticles was investigated by dialysis and reached lower levels than the free drug. The antioxidant activity of TQ-loaded nanoparticles, indicated by IC50 (mg ml( - 1) TQ for 50% 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity), was highest for poly-SUV emulsified nanoparticles (0.030 +/- 0.002 mg ml( - 1)) as compared to free TQ. In addition, it was observed that TQ-loaded nanoparticles emulsified with poly-SUV were more effective than free TQ against MDA-MB-231 cancer cell growth inhibition, presenting a cell viability of 16.0 +/- 5.6% after 96 h.

Experimental design and multivariate analysis for optimizing poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle synthesis using molecular micelles.

The utility of polymeric nanoparticles as drug delivery systems depends on effective control of synthetic parameters with a significant impact on their physico-chemical characteristics. In this study, a chemometric central composite experimental design (CCD) was used to optimize the synthesis of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles by emulsification solvent evaporation using anionic molecular micelles, such as poly(sodium N-undecylenic sulfate) (poly-SUS), poly(sodium N-undecanoyl-glycinate) (poly-SUG) and poly(sodium N-undecanoyl-L-leucyl-valinate) (poly-L-SULV) as well as conventional emulsifiers, such as anionic sodium dodecyl sulfate (SDS) and non-ionic poly(vinyl alcohol) (PVA). The individual and combined effects of PLGA concentration, emulsifier concentration, homogenization speed, and sonication time (design variables) on particle size and polydispersity index (responses) were investigated using multivariate analysis. The most significant design variables influencing the nanoparticle size and size distribution were PLGA concentration and emulsifier concentration (p < 0.05) in comparison to the other design variables. The quadratic model demonstrated the highest predictive ability when the molecular micelles were used as emulsifiers. The PLGA nanoparticles optimally synthesized according to the CCD were further purified by dialysis and then freeze-dried. Dried nanoparticles synthesized with molecular micelles and PVA were readily re-suspended in water, as compared with SDS for which nanoparticle aggregation occurred. The size of PLGA nanoparticles synthesized using molecular micelles increased after freeze-drying, but remained smaller than 100 nm when poly-L-SULV was used as emulsifier. The PDI values indicated monodisperse nanoparticle suspensions after purification and freeze-drying for all investigated molecular micelles (PDI < 0.100). The nanoparticle suspensions synthesized using molecular micelles were the most stable after dialysis and freeze-drying, having low negative zeta potential values ranging from -54 +/- 1.6 mV for poly-L-SULV to -63.2 +/- 0.4 mV for poly-SUS. Transmission electron microscopy (TEM) micrographs showed spherical shape and smooth surface for the PLGA nanoparticles synthesized using molecular micelles.

Gold nanoparticle sensor for homocysteine thiolactone-induced protein modification.

Homocysteine thiolactone-induced protein modification (HTPM) is a unique post-translational protein modification that is recognized as an emergent biomarker for cardiovascular disease. HTPM involves the site-specific acylation of proteins at lysine residues by homocysteine thiolactone (HTL) to produce protein homocystamide, which has been found at elevated levels in patients with coronary heart disease. Herein, we report the development of a novel gold nanoparticle (GNP) biochemical sensor for detection of protein homocystamide in an in vitro serum protein-based model system. Human serum albumin (HSA) and human sera were subjected to HTPM in vitro to produce HSA-homocystamide or serum protein homocystamide, respectively, which was subsequently treated with citrate-capped GNPs. This GNP sensor typically provided instantaneous visual confirmation of HTPM in the protein model systems. Transmission electron microscopy images of the GNPs in the presence of HSA-homocystamide suggest that modification-directed nanoparticle assembly is the mechanism by which the biochemical sensor produces a colorimetric signal. The resultant nanoparticle-protein assembly exhibited excellent thermal and dilutional stability, which is expected for a system stabilized by chemisorption and intermolecular disulfide bonding. The sensor typically provided a linear response for modified human sera concentrations greater than approximately 5 mg/mL. The calculated limit of detection and calibration sensitivity for the method in human sera were 5.2 mg/mL and 13.6 AU . (microg/mL)-1, respectively.