Unmodified Rose Bengal photosensitizer conjugated with NaYF4:Yb,Er upconverting nanoparticles for efficient photodynamic therapy.

In photodynamic therapy (PDT), photosensitizer (PS) molecules are irradiated by light to generate reactive oxygen species (ROS), the presence of which subsequently leads to cell death. At present, the modality is limited to the treatment of skin diseases because of the low tissue penetration of visible or ultraviolet light required for producing ROS. To increase tissue penetration and extend the therapeutic possibilities of PDT to the treatment of deep-seated cancer, rare-earth doped nanoparticles capable of up-converting infrared to visible light are investigated. These up-converting nanoparticles (UCNPs) are conjugated with PS molecules to efficiently generate ROS. In this work, we employ hexagonal ß-NaYF4:Yb3 + ,Er3 + as UCNPs and Rose Bengal (RB) as PS molecules and demonstrate efficient in vitro PDT using this nanoformulation. Covalent bonding of the RB molecules is accomplished without their functionalization-an approach which is expected to increase the efficiency of ROS generation by 30%. Spectroscopic studies reveal that our approach results in UCNP surface fully covered with RB molecules. The energy transfer from UCNPs to RB is predominantly non-radiative as evidenced by luminescence lifetime measurements. As a result, ROS are generated as efficiently as under visible light illumination. The in vitro PDT is tested on murine breast 4T1 cancer cells incubated with 250 µg ml-1 of the nanoparticles and irradiated with NIR light under power density of 2 W cm-2 for 10 minutes. After 24 hours, the cell viability decreased to 33% demonstrating a very good treatment efficiency. These results are expected to simplify the protocols for preparation of the PDT agents and lead to improved therapeutic effects.

Cerium and Yttrium Oxide Nanoparticles and Nano-selenium Produce Protective Effects Against H2O2-induced Oxidative Stress in Pancreatic Beta Cells by Modulating Mitochondrial Dysfunction.

BACKGROUND: Type 1 diabetes mellitus is characterized by the destruction of insulin- producing Beta cells in the pancreas. Researchers hope that islet transplantation will help to patients with insulin-dependent diabetes mellitus (IDDM). Oxidative stress is the most important challenge that beta cells face to it after isolation, and mitochondrial dysfunction is a crucial mediator in beta cells death. Hence, therapeutic approaches can shift to antioxidants through the application of nanoparticles such as cerium and yttrium oxide nanoparticles (Cer and Ytt Ox NPs) and nano-selenium (Nan Se). OBJECTIVE: This study evaluates the effects of Cer and Ytt Ox NPs and Nan Se on H2O2- induced oxidative stress in pancreatic beta cells with focus on mitochondrial dysfunction pathway. METHODS: CRI-D2 beta-cell line were pretreated with Cer Ox NPs (200 µM) + Ytt Ox NPs (0.5 µg/mL) for 3 days and/or Nan Se (0.01 µM) for 1 day. Then markers of oxidative stress, mitochondrial dysfunction, insulin and glucagon secretion were measured. RESULTS: We reported a decrease in H2O2-induced reactive oxygen species (ROS) level and glucagon secretion, and an increase in H2O2-reduced ATP/ADP ratio, MMP, as well as UCP2 protein expression, and insulin secretion by pretreatment of CRI-D2 cells with Cer and Ytt Ox NPs and/or Nan Se. CONCLUSION: We found maximum protective effect with Cer and Ytt Ox NPs on CRI-D2 beta-cell line exposed by H2O2 for keeping beta cells alive until transplant whereas combination of Cer and Ytt Ox NPs and Nan Se had very little protective effect in this condition.

Prussian blue-coated lanthanide-doped core/shell/shell nanocrystals for NIR-II image-guided photothermal therapy.

Lanthanide-doped nanoparticles have long been stereotyped for optical luminescence bioimaging. However, they are known to be unable to produce therapeutic abilities. Here, we describe a lanthanide-based theranostic agent, namely, prussian blue (PB)-coated NaErF4@NaYF4@NaNdF4 core/shell/shell nanocrystals encapsulated in a phospholipid PEG micelle (PEG-CSS@PB), which showed switched imaging and hyperthermia abilities under distinct near infrared (NIR) light activation. The erbium (Er3+)-enriched inner core nanocrystals (NaErF4) enabled the emission of tissue-penetrating luminescence (1525 nm) in the second biological window (NIR-II, 1000-1700 nm), which endowed high-resolution optical imaging of the blood vessels and tumors under ∼980 nm excitation. High neodymium (Nd3+) concentrations in the epitaxial outer NaNdF4 shell introduced maximum cross relaxation processes that converted the absorbed NIR light (∼808 nm) into heat at high efficiencies, thus providing abilities for photothermal therapy (PTT). Importantly, the coated Prussian blue (PB) increased light absorption by about 10-fold compared to the composite free of PB, thus entailing a high light-to-heat conversion efficiency of ∼50.5%. This commensurated with that of well-established gold nanorods. As a result, the PEG-CSS@PB nanoparticles with MTT-determined low toxicities resulted in ∼80% death of HeLa cells at a dose of 600 µg mL-1 under 808 nm laser irradiance (1 W cm-2) for 10 min. Moreover, utilizing the same light dose, a single PTT treatment in tumor-bearing BALB/c mice shrunk the tumor size by ∼12-fold compared to the tumors without treatment. Our results, here, constituted a solid step forward to entitle lanthanide-based nanoparticles as theranostic agents in nanomedicine studies.

Y2O3:Yb,Er@mSiO2-Cu(x)S double-shelled hollow spheres for enhanced chemo-/photothermal anti-cancer therapy and dual-modal imaging.

Multifunctional composites have gained significant interest due to their unique properties which show potential in biological imaging and therapeutics. However, the design of an efficient combination of multiple diagnostic and therapeutic modes is still a challenge. In this contribution, Y2O3:Yb,Er@mSiO2 double-shelled hollow spheres (DSHSs) with up-conversion fluorescence have been successfully prepared through a facile integrated sacrifice template method, followed by a calcination process. It is found that the double-shelled structure with large specific surface area and uniform shape is composed of an inner shell of luminescent Y2O3:Yb,Er and an outer mesoporous silica shell. Ultra small Cu(x)S nanoparticles (about 2.5 nm) served as photothermal agents, and a chemotherapeutic agent (doxorubicin, DOX) was then attached onto the surface of mesoporous silica, forming a DOX-DSHS-Cu(x)S composite. The composite exhibits high anti-cancer efficacy due to the synergistic photothermal therapy (PTT) induced by the attached Cu(x)S nanoparticles and the enhanced chemotherapy promoted by the heat from the Cu(x)S-based PTT when irradiated by 980 nm near-infrared (NIR) light. Moreover, the composite shows excellent in vitro and in vivo X-ray computed tomography (CT) and up-conversion fluorescence (UCL) imaging properties owing to the doped rare earth ions, thus making it possible to achieve the target of imaging-guided synergistic therapy.

Water-soluble oxoglaucine-Y(III), Dy(III) complexes: in vitro and in vivo anticancer activities by triggering DNA damage, leading to S phase arrest and apoptosis.

Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.

Effects of fly ash and boric acid on Y2O3-stabilized tetragonal ZrO2 dispersed with MgAl2O4: An experimental study on rat subcutaneous tissue.

The aim of this study was to evaluate the subcutaneous tissue reaction around zirconia-based materials. Forty-eight male Wistar Albino rats were used in this study. Disk-shaped (1mm height and 5mm diameter) samples composed of 67% spinel (MgAl2O4), 27% tetragonal zirconia polycrystal, 4% (m/m) fly ash and 2% (m/m) boric acid were inserted into dorsal muscles of rats. After 1, 4, 8 and 16 weeks, the animals were sacrificed and zirconia materials were removed with the surrounding tissue. Tissue sections were made with a microtome and then stained with hematoxylin and eosin. Sections were evaluated for the intensity of inflammation. Additionally, the somatic and visceral lymph nodes were evaluated. Data were submitted to one-way analysis of variance (ANOVA) and Tukey HSD tests at a significant level of p < 0.05. There were statistically significant differences between mean inflammatory scores in different experimental periods (p <0.05). In addition, the inflammatory reaction decreased over time. The tested materials had no damaging effect on the rat lymph nodes and did not have a toxic action on the internal organs. Therefore, zirconia polycrystal tested in the present study may offer a promising treatment alternative after further mechanical and biological studies are performed.

In vitro evaluation of osteoconductivity and cellular response of zirconia and alumina based ceramics.

Developed ceria/yttria stabilized zirconia and ceria/yttria stabilized zirconia toughened alumina supported formation of apatite layer when immersed in simulated body fluid without any prior surface treatment. The formed mineral layer was confirmed as hydroxyapatite through X-ray diffraction patterns. The calcium/phosphate atomic ratio obtained from energy dispersive X-ray spectroscopy was found to be little less (Ca/P=1.5) than that of pure hydroxyapatite (Ca/P=1.7) which indicates the probability of mixed type calcium-phosphate compound formation. The achieved thickness of apatite layer was estimated through a surface profilometer and as high as ~17 µm thickness was found after 28 days of soaking. The biocompatibility of the developed materials was ensured through in vitro human osteoblast like cell (MG63) culture on ceramic discs. The morphology of attached cells was characterized through scanning electron microscopy and fluorescent microscopy which show multilayered interconnected cell growth within 8 days of culture period. Moreover, differentiation of MG63 cells was evaluated through MTT assay, total protein content and alkaline phosphatase activity.

In vitro evaluation of the effects of yttria-alumina-silica microspheres on human keratinocyte cells.

The behavior of yttria-alumina-silica spray-dried microspheres was investigated in vitro on a human keratinocyte cell line, first to exclude their cytotoxicity. The HaCaT cells were chosen due to their well-characterized phenotype and their phagocytic ability. Microscopic analysis and cell viability tests showed no negative effect of the microspheres on cells morphology and behavior. Scanning electron microscopy and transmission electron microscopy results evidenced the cellular internalization of the microspheres at 48 h after their incubation with cultured cells. The shape, size distribution, structure, composition, and chemical states of the elements on samples surface were analyzed by SEM, transmission electron microscopy, x-ray diffraction, and x-ray photoelectron spectroscopy, because these properties could influence their internalization by cells. The yttrium distribution on the microspheres surface was indicated by fluorescence microscopy imaging. The microspheres dimension and shape inside the cells was in accordance with their dimension and shape before incubation. The microspheres seemed captured and engulfed by the cells in native form and appeared resistant to degradation over the first 48 h. Most of the analyzed cells took up more microspheres, suggesting that the microspheres were actively phagocytosed by the cells and accumulated within the cytoplasm. X-ray photoelectron spectroscopy results on Al and Si atomic environments denoted Al-O-Si crosslinks, which improve the surface protection to corrosion.

Targeted delivery of chemotherapeutic agents using improved radiosensitive liquid core microcapsules and assessment of their antitumor effect.

PURPOSE: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. METHODS AND MATERIALS: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 microg) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl(2) solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy (60)Co gamma-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. RESULTS: Microcapsules that had been polymerized using a 4.34% CaCl(2) solution supplemented with 5.0 x 10(-3)% (10(-3)% meant or 10%(-3)) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. CONCLUSION: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

The role of amino acids in the long-distance transport of La and Y in the xylem sap of tomato.

This study focuses on the role of amino acids in xylem sap of tomato grown in hydroponics in a medium supplemented with a series of concentration of La and Y. Eighteen amino acids in xylem saps were identified and measured by reversed-phase high-performance liquid chromatography. The main amino acids in xylem sap samples of the tomato are histidine, tryptophan, aspartic acid, and glutamic acid. The concentration of glutamic acid in xylem sap significantly increased in the La and Y treatment compared to the control. By analyzing the correlation between concentrations of amino acids and concentrations of La and Y in the xylem saps, we considered that the glutamic acid in xylem saps seemed to participate in the long-distance La and Y translocation processes, and histidine did not relate to xylem La and Y transport of tomato. The role of other amino acids which was excreted by tomato has not been demonstrated in the long-distance transport of La and Y in the xylem.

Cerium and yttrium oxide nanoparticles are neuroprotective.

The responses of cells exposed to nanoparticles have been studied with regard to toxicity, but very little attention has been paid to the possibility that some types of particles can protect cells from various forms of lethal stress. It is shown here that nanoparticles composed of cerium oxide or yttrium oxide protect nerve cells from oxidative stress and that the neuroprotection is independent of particle size. The ceria and yttria nanoparticles act as direct antioxidants to limit the amount of reactive oxygen species required to kill the cells. It follows that this group of nanoparticles could be used to modulate oxidative stress in biological systems.

Effects of MA 956 superalloy and alpha-alumina particles on some markers of human osteoblastic cells in primary culture.

One of the problems associated with the modern biomaterials used in prostheses is osteolysis, which, although its exact origin is unknown, has been associated with wear particles. Osteoblasts seem to participate directly in this phenomenon. This paper investigates in vitro cellular response to the wear particles from the metal substrate and ceramic covering (alpha-alumina) of a new titanium yttrium aluminum alloy, MA 956, that has been proposed as a biomaterial because of its exceptional mechanical and electrochemical properties. The effect of different sizes (10 and 80 microm) of MA 956 and alpha-alumina particles on osteoblast function was studied in primary human bone cell cultures. Cells were harvested from trabecular bone fragments obtained during knee arthroplasty. Osteoblastic cell response to the particles was measured by assaying C-terminal type I procollagen (PICP), alkaline phosphatase, and osteocalcin secretion, with and without 1.25(OH)(2)D(3) stimulation, in the cell-conditioned medium. Both sizes of MA 956 and alpha-alumina particles decreased PICP secretion in nonstimulated osteoblastic cells, but this secretion was not affected in the cultures stimulated with 1.25(OH)(2)D(3). Only the 10 microm alpha-alumina particles inhibited alkaline phosphatase activity in 1.25(OH)(2)D(3)-stimulated and nonstimulated cultures. The rise in osteocalcin levels after 1.25(OH)(2)D(3) stimulation was lower in the presence of the 10 microm MA 956 particles than in the presence of alpha-alumina particles. Although both materials seem to have directly affected in vitro osteoblastic cell function, the increase in osteocalcin levels after 1.25(OH)(2)D(3) stimulation was lower after exposure to MA 956 particles than the increase observed after exposure to alpha-alumina particles. Therefore, it does not seem that osteocalcin stimulated bone resorption, suggesting that MA 956 would be less likely to provoke osteolysis.