The antimicrobial activity of zinc against group B Streptococcus is strain-dependent across diverse sequence types, capsular serotypes, and invasive versus colonizing isolates.

BACKGROUND: Streptococcus agalactiae or Group B Streptococcus (GBS) is an encapsulated gram-positive bacterial pathobiont that commonly colonizes the lower gastrointestinal tract and reproductive tract of human hosts. This bacterium can infect the gravid reproductive tract and cause invasive infections of pregnant patients and neonates. Upon colonizing the reproductive tract, the bacterial cell is presented with numerous nutritional challenges imposed by the host. One strategy employed by the host innate immune system is intoxication of bacterial invaders with certain transition metals such as zinc. METHODOLOGY: Previous work has demonstrated that GBS must employ elegant strategies to circumnavigate zinc stress in order to survive in the vertebrate host. We assessed 30 strains of GBS from diverse isolation sources, capsular serotypes, and sequence types for susceptibility or resistance to zinc intoxication. RESULTS: Invasive strains, such as those isolated from early onset disease manifestations of GBS infection were significantly less susceptible to zinc toxicity than colonizing strains isolated from rectovaginal swabs of pregnant patients. Additionally, capsular type III (cpsIII) strains and the ST-17 and ST-19 strains exhibited the greatest resilience to zinc stress, whereas ST-1 and ST-12 strains as well as those possessing capsular type Ib (cpsIb) were more sensitive to zinc intoxication. Thus, this study demonstrates that the transition metal zinc possesses antimicrobial properties against a wide range of GBS strains, with isolation source, capsular serotype, and sequence type contributing to susceptibility or resistance to zinc stress.

Application of Asymmetrical Flow Field-Flow Fractionation for Characterizing the Size and Drug Release Kinetics of Theranostic Lipid Nanovesicles.

Liposome size and in vitro release of the active substance belong to critical quality attributes of liposomal carriers. Here, we apply asymmetric flow field-flow fractionation (AF4) to characterize theranostic liposomes prepared by thin lipid film hydration/extrusion or microfluidics. The vesicles' size was derived from multi-angle laser light scattering following fractionation (AF4) and compared to sizes derived from dynamic light scattering measurements. Additionally, we adapted a previously developed AF4 method to study zinc phthalocyanine (ZnPc) release/transfer from theranostic liposomes. To this end, theranostic liposomes were incubated with large acceptor liposomes serving as a sink (mimicking biological sinks) and were subsequently separated by AF4. During incubation, ZnPc was transferred from donor to acceptor fraction until reaching equilibrium. The process followed first-order kinetics with half-lives between 119.5-277.3 min, depending on the formulation. The release mechanism was postulated to represent a combination of Fickian diffusion and liposome relaxation. The rate constant of the transfer was proportional to the liposome size and inversely proportional to the ZnPc/POPC molar ratio. Our results confirm the usefulness of AF4 based method to study in vitro release/transfer of lipophilic payload, which may be useful to estimate the unwanted loss of drug from the liposomal carrier in vivo.

Dual Encapsulated Dacarbazine and Zinc Phthalocyanine Polymeric Nanoparticle for Photodynamic Therapy of Melanoma.

PURPOSE: Melanoma is an invasive and very aggressive skin cancer due to its multi-drug resistance that results in poor patient survival. There is a need to test new treatment approaches to improve therapeutic efficacy and reduce side effects of conventional treatments. METHODS: PLA/PVA nanoparticles carrying both Dacarbazine and zinc phthalocyanine was produced by double emulsion technique. The characterization was performed by dynamic light scattering and atomic force microscopy. In vitro photodynamic therapy test assay using MV3 melanoma cells as a model has been performed. In vitro cell viability (MTT) was performed to measure cell toxicity of of nanoparticles with and without drugs using human endothelial cells as a model. The in vivo assay (biodistribution/tissue deposition) has been performed using radiolabeled PLA/PVA NPs. RESULTS: The nanoparticles produced showed a mean diameter of about 259 nm with a spherical shape. The in-vitro photodynamic therapy tests demonstrated that the combination is critical to enhance the therapeutic efficacy and it is dose dependent. The in vitro cell toxicity assay using endothelial cells demonstrated that the drug encapsulated into nanoparticles had no significant toxicity compared to control samples. In-vivo results demonstrated that the drug loading affects the biodistribution of the nanoparticle formulations (NPs). Low accumulation of the NPs into the stomach, heart, brain, and kidneys suggested that common side effects of Dacarbazine could be reduced. CONCLUSION: This work reports a robust nanoparticle formulation with the objective to leveraging the synergistic effects of chemo and photodynamic therapies to potentially suppressing the drug resistance and reducing side effects associated with Dacarbazine. The data corroborates that the dual encapsulated NPs showed better in-vitro efficacy when compared with the both compounds alone. The results support the need to have a dual modality NP formulation for melanoma therapy by combining chemotherapy and photodynamic therapy.

Water dispersible ZnSe/ZnS quantum dots: Assessment of cellular integration, toxicity and bio-distribution.

Quantum dots (QDs) comprise an emerging group of materials with innumerable number of possibilities in biological research including cellular labelling. Among the leading members in this category, ZnSe/ZnS quantum dots (QDs) hold greater attractive possibilities in imaging primarily due to their higher biocompatibility and dispersibility. Nevertheless, the inherent toxicity of ZnSe/ZnS QDs is not yet completely explored which largely compromise most of their biomedical application potential. Strong blue emitting water soluble QDs effectively synthesized by aqueous phase route. Synthesized QDs further subjected to various optical and physicochemical characterization. Approximately 5-6 nm sized ZnSe/ZnS QDs illuminated bluish green fluorescence under UV lamp. Present study addresses possible adverse effects of ZnSe/ZnS QDs in hepatic system using HepG2 cells; which is the routinely employed in vitroliver cell model. A bundle of assays wasperformed out to reveal the cytotoxic nature of ZnSe/ZnS QDs and the mechanism behind it. Herein, absorption, distribution, metabolism, excretion and toxicity (ADME and T) of ZnSe/ZnS in mice were profiled in detail followed by intravenous (i.v.) and intraperitoneal (i.p.) administration at a dose of 10 mg/kg body weight. In a short review, it could be state that ZnSe/ZnS QDs did not exhibit any significant in vivo toxicity outcome in mice.

Nephrotoxicity Evaluation of Indium Phosphide Quantum Dots with Different Surface Modifications in BALB/c Mice.

InP QDs have shown a great potential as cadmium-free QDs alternatives in biomedical applications. It is essential to understand the biological fate and toxicity of InP QDs. In this study, we investigated the in vivo renal toxicity of InP/ZnS QDs terminated with different functional groups-hydroxyl (hQDs), amino (aQDs) and carboxyl (cQDs). After a single intravenous injection into BALB/c mice, blood biochemistry, QDs distribution, histopathology, inflammatory response, oxidative stress and apoptosis genes were evaluated at different predetermined times. The results showed fluorescent signals from QDs could be detected in kidneys during the observation period. No obvious changes were observed in histopathological detection or biochemistry parameters. Inflammatory response and oxidative stress were found in the renal tissues of mice exposed to the three kinds of QDs. A significant increase of KIM-1 expression was observed in hQDs and aQDs groups, suggesting hQDs and aQDs could cause renal involvement. Apoptosis-related genes (Bax, Caspase 3, 7 and 9) were up-regulated in hQDs and aQDs groups. The above results suggested InP/ZnS QDs with different surface chemical properties would cause different biological behaviors and molecular actions in vivo. The surface chemical properties of QDs should be fully considered in the design of InP/ZnS QDs for biomedical applications.

Zinc sulphide nanoparticle (nZnS): A novel nano-modulator for plant growth.

In spite of extraordinary properties of zinc sulphide nanoparticle (nZnS), its role on plant system is not well understood, yet. Therefore, this study was aimed to assess the uptake, translocation and effects of nZnS in mung bean (Vigna radiata) plant at 0, 0.1, 0.5 and 1 mg L-1 concentrations. In this study, nZnS was synthesized by modified reflux method and physicochemical characterizations were conducted. The effects of nZnS on mung bean plant were determined by seed germination, growth parameters, membrane integrity and ROS-antioxidant defense assays. Our results showed that nZnS treatment has significantly increased seed germination, root-shoot length, pigment content and decreased lipid peroxidation. There were increased total antioxidant activity (TAA), DPPH and flavonoid contents found in treated plants. Also, nZnS treatment did not activate oxidative stress determined by SOD, CAT, CPX, APOX and GR activities. The uptake and translocation of nZnS in mung bean plants were determined by Transmission Electron Microscope (TEM) and Scanning Electron Microscope (SEM), revelling that nZnS localized primarily in the vacuoles and chloroplasts. Besides, electron micrographs showed no alteration in cell structures between treated and control plants, further confirming that nZnS treatment has no phytotoxic effects. In vitro and in vivo studies on Zn release from nZnS were also determined using Inductively Coupled Plasma Mass Spectroscopy (ICPMS) and Energy Dispersive X-ray (EDX), which showed that the Zn release and particles uptake were concentration dependent. Overall, results of this study demonstrated the positive role of nZnS on growth and antioxidant defense responses in V. radiata at the experimental concentrations.

Structure, dissolution, and plant uptake of ferrous/zinc phosphates.

Development of slow release fertilizers by tuning dissolution kinetics can reduce the environmental impact of (micro) nutrients added to crops. Mixed metal compounds may have different dissolution kinetics and plant uptake than single metal compounds. In this study, mixed Fe(II)/Zn(II) phosphates (0-100 at% Zn) were prepared by aqueous precipitation and their structural characteristics and dissolution kinetics in a sand column were measured as model for divalent metal and phosphate release in soil. Three minerals were identified, namely vivianite (Fe3(PO4)2·8H2O) at 0-20 at% Zn, phosphophyllite (Zn2Fe(PO4)2·4H2O) at 20-79 at% Zn, and hopeite (Zn3(PO4)2·4H2O) at 79-100 at% Zn. The Fe-rich materials had high SSA of 42-64 m2 g-1, which decreased to ≤4 m2 g-1 for ≥79 at% Zn. The Fe K-edge and Zn K-edge XANES spectroscopy measurements show that the samples had comparable local structure and contained 13-72% of Fe as Fe(III) due to partial oxidation. In the sand column, Zn(II) and Fe(II) phosphates dissolved near-congruently at steady state (>7 h), whereas mixed Fe(II)/Zn(II) phosphates showed preferential release of Zn over P and Fe, likely due to reprecipitation of Fe. Pot experiments demonstrate that Zn from Fe(II)/Zn(II) phosphates is absorbed by bird's eye chili plants (C. annuum), in agreement with the preferential dissolution of Zn(II). These results may provide insight into the dissolution of other divalent metals, which not only aids in the growth of plants and resulting foodstuff but ultimately leads to reductions in environmental contamination.

Different dynamic accumulation and toxicity of ZnO nanoparticles and ionic Zn in the soil sentinel organism Enchytraeus crypticus.

There is still no consensus over the specific effects of metal-based nanoparticles when compared with the conventional metal salts. Here, the accumulation and toxicity of ZnO-NPs and ZnCl2 in Enchytraeus crypticus over time (1-14 d) were investigated using a sand-solution exposure medium and applying a toxicokinetics and toxicodynamics approach. For both Zn forms, body Zn concentration in the organisms was dependent on both the exposure concentration and exposure time, with equilibrium being reached after 7-14 days of exposure. Generally, the uptake and elimination rate constants (Ku and Ke1) were smaller for ZnO-NPs (5.74-12.6 mg kg-1d-1 and 0.17-0.39 d-1) than for ZnCl2 (8.32-40.1 mg kg-1d-1 and 0.31-2.05 d-1), suggesting that ionic Zn was more accessible for E. crypticus than nanoparticulate Zn. Based on external exposure concentrations, LC50s for ZnO-NPs and ZnCl2 decreased with time from 123 to 67 Zn mg L-1 and from 86 to 62 Zn mg L-1, reaching an almost similar ultimate value within 14 d. LC50s based on body Zn concentrations were almost constant over time (except for 1 d) for both ZnO-NPs and ZnCl2, with overall LC50body of Zn being 1720 and 1306 mg kg-1 dry body weight, respectively. Body Zn concentration, which considers all available pathways, was a good predictor of dynamic toxicity of ZnCl2, but not for ZnO-NPs. This may be attributed to the specific internal distribution and detoxification mechanisms of ZnO-NPs. The particles from ZnO-NPs dominated the accumulation (>75%) and toxicity (∼100%). Our results suggest that dynamic aspects should be taken into account when assessing and comparing NPs and metals uptake and consequent patterns of toxicity.

Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008.

BACKGROUND: The discovery of the zinc-sensing receptor, has provided new possibilities for explaining the neurobiology of zinc. Recent studies indicate that the GPR39 zinc receptor may play an important role in the pathogenesis of depression as well as in the antidepressant mechanism of action. METHODS: In this study we evaluated the time-course of the antidepressant response of the GPR39 agonist (TC-G 1008), imipramine, ZnCl2 and MK-801 in the forced swim test in mice 30 min, 3 h, 6 h and 24 h after acute drug administration as well as after 14-day treatment. Zinc level was measured in serum of mice. BDNF protein level was evaluated in hippocampus following both acute and chronic TC-G 1008 treatment. RESULTS: A single administration of the GPR39 agonist caused an antidepressant-like effect lasting up to 24 h following the injection, which is longer than the effect of imipramine, ZnCl2 and MK-801. Chronic treatment with these compounds caused a decrease in immobility time in the FST. Serum zinc concentrations showed an increased level following chronic ZnCl2 administration, but not following administration of TC-G 1008, imipramine or MK-801. We also observed some tendencies for increased BDNF following acute TC-G 1008 treatment. LIMITATIONS: TC-G 1008 is new drug designed to study GPR39 therefore additional pharmacodynamic and pharmacokinetic properties in preclinical studies are required. CONCLUSION: This study shows for the first time the long-lasting antidepressant effect of the GPR39 agonist in comparison with imipramine, ZnCl2 and MK-801. Our findings suggest that GPR39 should be considered as a target in efforts to develop new antidepressant drugs.

Actively Targeted Magnetothermally Responsive Nanocarriers/Doxorubicin for Thermochemotherapy of Hepatoma.

Nanodrug-delivery systems modified with targeting molecules allow antitumor drugs to localize to tumor sites efficiently. CD147 protein is expressed highly on hepatoma cells. Firstly, we synthesized magnetothermally responsive nanocarriers/doxorubicin (MTRN/DOX) which was composed of manganese zinc (Mn-Zn) ferrite magnetic nanoparticles, amphiphilic and thermosensitivity copolymer drug carriers together with DOX. Then CD147-MTRN/DOX was formed with MTRN/DOX and monoclonal antibody that specifically binds to CD147 protein. It could target hepatoma cells actively and improve the DOX concentration in the tumor sites. Subsequently, an external alternating magnetic field elevated the temperature of the thermomagnetic particles, resulting in structural changes in the thermosensitive copolymer drug carriers, thereby releasing DOX. Hence, CD147-MTRN/DOX could enhance the responsiveness of hepatoma cells to the pre-existing chemotherapy drugs owing to active targeting combined synergistically with thermotherapy and chemotherapy, which has more significant anticancer effects than MTRN/DOX.

Matricidal hatching can induce multi-generational effects in nematode Caenorhabditis elegans after dietary exposure to nanoparticles.

In this study, we investigated multi-generational effects and generation particle transfer in Caenorhabditis elegans following maternal food exposure to core-shell quantum dots. We found that that the Bag of Worms (BOW) phenotype in aged worms induces changes in quantum dot distribution in the parental body, which is related to the inter-generation transfer of these nanoparticles and to their effects in the offspring. To confirm these results we examined a variety of endpoints, namely, survival, reproduction, aging phenotype, oxidative stress, and intestinal fat metabolism. We show that worms born to parents at different times after exposure show different phenotypic effects as a consequence of quantum dot transfer. This evidence of trans-generational transfer and the effects of nanoparticles highlights the complex multi-generational effects and potential safety hazards that can occur under real environmental conditions.

[Clinical Application of Basic Research on Mohs' Paste to Meet Medical Needs].

　Mohs' paste (MP), which is widely used in medical services as a specific hospital preparation, has been considered to have demerits, such as increased hardness after preparation and marked adhesiveness. However, factors associated with variations in its physical properties have not yet been clarified. Therefore, we conducted studies to clarify the physicochemical phenomena influencing such variations, and also examined prescription drug designs of MP preparations that are difficult to use clinically due to the above-mentioned demerits, with a view to improving their usability. Furthermore, with cooperation from the director of the Department of Palliative Care and Maintenance Therapy and certified wound ostomy and continence (WOC) nurses of Yokohama Minami Kyousai Hospital, we clinically applied an improved form of MP I. We also examined the effects of an improved MP II (designed as a stable formulation) in mice. This is an example of the clinical application of basic research to design a new clinical formulation in order to meet medical needs.

Effects of Different Sources and Levels of Zinc on Growth Performance, Nutrient Digestibility, and Fur Quality of Growing-Furring Male Mink (Mustela vison).

The objective of this study was to investigate the effects of different sources and levels of zinc (Zn) on growth performance, nutrient digestibility, serum biochemical parameters, and fur quality in growing-furring male mink. Animals in the control group were fed a basal diet with no Zn supplementation. Mink in the other nine treatments were fed the basal diet supplemented with Zn from either grade Zn sulfate (ZnSO4·7H2O), Zn glycinate (ZnGly), or Zn pectin oligosaccharides (ZnPOS) at concentrations of either 100, 300, or 900 mg Zn/kg dry matter. One hundred and fifty healthy 15-week-old male mink were randomly allocated to ten dietary treatments (n = 15/group) for a 60-day trial from mid-September to pelting in December. Mink in the Zn-POS groups had higher average daily gain than those in the control group (P < 0.05). Zn source slightly improved the feed/gain (P = 0.097). N retention was increased by Zn addition (P < 0.05). Mink supplemented with dietary Zn had higher (P < 0.05) pancreas Zn level than the control group. Fur length was greater (P < 0.05) in ZnGly and ZnPOS groups compared with the control. In addition, fur length and fur density increased (linear, P < 0.05) with Zn supplementation in the diet. In conclusion, our data show that dietary Zn addition improves growth performance by increasing nitrogen retention and fat digestibility in growing-furring mink and Z-POS is equally bioavailable to mink compared to ZnGly.

Toxicokinetics of zinc-oxide nanoparticles and zinc ions in the earthworm Eisenia andrei.

The toxicokinetics of zinc in the earthworm Eisenia andrei was investigated following exposure for 21 days to ionic zinc (ZnCl2) or zinc oxide nanoparticles (ZnO-NPs) in Lufa 2.2 soil, followed by 21 days elimination in clean soil. Two concentrations were tested for both ZnCl2 (250 and 500µg Zn g-1) and ZnO-NPs (500 and 1000µg Zn g-1), corresponding to EC25 and EC50 for effects on reproduction. Based on the measured internal Zn concentrations in the earthworms over time of exposure, the kinetics parameters ka - assimilation rate constant (gsoil g-1body weight day-1) and ke - elimination rate constant (day-1) were estimated using a one-compartment model for either total Zn concentrations in the soil or porewater Zn concentrations. In the ZnCl2 treatments, ka was higher for total Zn concentrations in soil, whereas in the ZnO-NP treatments, ka was higher for porewater Zn concentrations. The value of ke did not differ between the two Zn forms (ZnCl2 vs ZnO-NPs) for either EC50 or EC25 when related to total Zn concentrations in soil, but for EC50, ke related to porewater Zn concentrations was significantly higher for ZnCl2 than for ZnO-NPs. It is concluded that differences in kinetic parameters between treatments were connected with exposure concentrations rather than with the form of Zn. Zinc was efficiently regulated by the earthworms in all treatments: a 2-fold increase in exposure concentration resulted in a less than 2-fold increase in internal concentration, and after transfer to uncontaminated soil the internal Zn concentrations in the earthworms returned to ca 111µgg-1 dw in all treatments.

Effects of Zinc and N-Acetylcysteine in Damage Caused by Lead Exposure in Young Rats.

This study investigated the toxicity of rats exposed to lead acetate (AcPb) during the second phase of brain development (8-12 days postnatal) in hematological and cerebral parameters. Moreover, the preventive effect of zinc chloride (ZnCl2) and N-acetylcysteine (NAC) was investigated. Pups were injected subcutaneously with saline (0.9% NaCl solution), ZnCl2 (27 mg/kg/day), NAC (5 mg/kg/day) or ZnCl2 plus NAC for 5 days (3rd-7th postnatal days), and with saline (0.9% NaCl solution) or AcPb (7 mg/kg/day) in the five subsequent days (8th-12th postnatal days). Animals were sacrificed 21 days after the last AcPb exposure. Pups exposed to AcPb presented inhibition of blood porphobilinogen-synthase (PBG-synthase) activity without changes in hemoglobin content. ZnCl2 pre-exposure partially prevented PBG-synthase inhibition. Regarding neurotoxicity biomarkers, animals exposed to AcPb presented a decrease in cerebrum acetylcholinesterase (AChE) activity and an increase in Pb accumulation in blood and cerebrum. These changes were prevented by pre-treatment with ZnCl2, NAC, and ZnCl2 plus NAC. AcPb exposure caused no alteration in behavioral tasks. In short, results show that AcPb inhibited the activity of two important enzymatic biomarkers up to 21 days after the end of the exposure. Moreover, ZnCl2 and NAC prevented the alterations induced by AcPb.

Preparation, properties and anticancer effects of mixed As4S4/ZnS nanoparticles capped by Poloxamer 407.

Arsenic sulfide compounds have a long history of application in a traditional medicine. In recent years, realgar has been studied as a promising drug in cancer treatment. In this study, the arsenic sulfide (As4S4) nanoparticles combined with zinc sulfide (ZnS) ones in different molar ratio have been prepared by a simple mechanochemical route in a planetary mill. The successful synthesis and structural properties were confirmed and followed via X-ray diffraction and high-resolution transmission electron microscopy measurements. The morphology of the particles was studied via scanning electron microscopy and transmission electron microscopy methods and the presence of nanocrystallites was verified. For biological tests, the prepared As4S4/ZnS nanoparticles were further milled in a circulation mill in a water solution of Poloxamer 407 (0.5wt%), in order to cover the particles with this biocompatible copolymer and to obtain stable nanosuspensions with unimodal distribution. The average size of the particles in the nanosuspensions (~120nm) was determined by photon cross-correlation spectroscopy method. Stability of the nanosuspensions was determined via particle size distribution and zeta potential measurements, confirming no physico-chemical changes for several months. Interestingly, with the increasing amount of ZnS in the sample, the stability was improved. The anti-cancer effects were tested on two melanoma cell lines, A375 and Bowes, with promising results, confirming increased efficiency of the samples containing both As4S4 and ZnS nanocrystals.

Inhibitory effect of divalent metal cations on zinc uptake via mouse Zrt-/Irt-like protein 8 (ZIP8).

AIMS: There is controversy regarding the substrate specificity of ZIP8, a ZIP isoform, involved in regulation of extra- and intracellular zinc levels. Here, we investigated the inhibitory effects of divalent metal cations on zinc uptake via mouse ZIP8 (mZIP8). MAIN METHODS: mZIP8 cDNA was transfected into HEK293T cells by a lipofection method, and its functional expression was evaluated by immunocytochemistry, Western blotting and 65Zn (65ZnCl2) uptake measurement. KEY FINDINGS: Transfection of mZIP8 cDNA into HEK293T cells induced expression of mZIP8 in the cells, and increased zinc uptake. mZIP8-mediated zinc uptake depended on extracellular bicarbonate, and the Michaelis constant for the uptake was estimated to be 8.48±2.46µM. In the inhibition study, iron and cadmium competitively, and cobalt, nickel and copper non-competitively inhibited the mZIP8-mediated zinc uptake, the inhibition constants being calculated to be 3.37, 55.5, 80.6, 198 and 48.3µM, respectively. In contrast, magnesium and manganese at concentrations of up to 1500 and 200µM, respectively, had no inhibitory effect on the zinc uptake via mZIP8. SIGNIFICANCE: In this study, we reveal that the inhibition profiles of divalent metal cations as to zinc uptake via mZIP8 apparently differ from those for mZIP1, especially in the affinity and inhibition manner of nickel. These findings should contribute to identification of ZIP isoforms involved in total cellular zinc transport.

Effect of Nanoparticle Surface Coating on Cell Toxicity and Mitochondria Uptake.

We report on the effect of surface charge and the ligand coating composition of CdSe/ZnS core/shell quantum dot (QD) nanoparticles on human keratinocyte toxicity using fluorescent microscopy, flow cytometry, transmission electron microscopy. Two commonly reported positive charged (cysteamine, polyethylenimine) and two negative charged (glutathione, dihydrolipoic acid) ligands were studied. The QDs were fully characterized by UV-vis absorption spectroscopy, fluorescence emission spectroscopy, dynamic light scattering and zeta potential. Differences in surface coatings and charges were evaluated against cellular uptake, ROS generation, cytotoxicity, and mitochondrial targeting. Results show that the negative charged QDs coated with GSH exhibit excellent water solubility, high quantum yield and low cytotoxicity. Ligand composition is more important in ROS generation than surface charge whereas surface charge is an important driver of cytotoxicity. Most importantly we observe the selective accumulation of glutathione coated QDs in vesicles in the mitochondria matrix. This observation suggests a new strategy for developing mitochondria-targeted nanomaterials for drug/gene delivery.

Synthesis and Evaluation of Thermo-Sensitive, Magnetic Fluorescent Nanocomposite as Trifunctional Drug Delivery Carrier.

The thermo-sensitive magnetic fluorescent trifunctional nanocomposite (Fe3O4/ZnS@PNIPAM) has been synthesized via a facile route. The obtained biocompatible nanocomposite was composed of monodisperse heterostructural Fe3O4/ZnS core and a thermo-sensitive poly(N-isopropyl acrylamide) (PNIPAM) shell. Fe3O4/ZnS acted as magnetic response and fluorescence luminous body, PNIPAM acted as drug loaded platform which can adsorb and release drug controllably. Fe3O4/ZnS@PNIPAM was characterized and all of the results showed that it had excellent magnetic response, photostability and thermo-sensitivity. Moreover, the drug release studies in vitro showed that the release rate increased with increasing temperature. MTT assays in model HepG2 cells demonstrated that Fe3O4/ZnS@PNIPAM was practically non-toxic. Thus, our results revealed that Fe3O4/ZnS@PNIPAM would be used in biomedical fields such as targeted drug delivery, as well as cancer diagnosis and treatment in the nearly future.

Physiologically based pharmacokinetic modeling of zinc oxide nanoparticles and zinc nitrate in mice.

Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of (65)ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm (65)ZnO NPs and zinc nitrate ((65)Zn(NO3)2) in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of (65)ZnO NPs were greater than those of (65)Zn(NO3)2, particularly the lung partition coefficient of 10 nm (65)ZnO NPs. Sensitivity analysis revealed that 71 nm (65)ZnO NPs and (65)Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for (65)ZnO NPs and (65)Zn(NO3)2. The simulation of (65)Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of (65)ZnO NPs with those of (65)Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to (65)ZnO NPs <10 nm because those small (65)ZnO NPs tend to accumulate in the body for a relatively longer time than 71 nm (65)ZnO NPs and (65)Zn(NO3)2 do.