Preferential Killing of Cancer Cells and Activated Human T-Cells Using ZnO Nanoparticles

Here we disclose the response of normal human cells to ZnO nanoparticles under different signaling environments and compare it to the response of cancerous cells. ZnO nanoparticles exhibit a strong preferential ability to kill cancerous T cells (-28-35X) compared to normal cells. Interestingly, the activation state of the cell contributes toward nanoparticle toxicity as resting T cells display a relative resistance while cells stimulated through the T cell receptor and CD28 costimulatory pathway show greater toxicity in direct relation to the level of activation. The novel findings of cell selective toxicity towards potential disease causing cells indicate a potential utility of ZnO nanoparticle in the treatment of cancer and/or autoimmunity

Zinc Oxide Nanoparticles for Selective Destruction of Tumor Cells and Potential for Drug Delivery Applications

Importance of the field: Metal oxide nanoparticles, including zinc oxide, are versatile platforms for biomedical applications and therapeutic intervention. There is an urgent need to develop new classes of anticancer agents, and recent studies demonstrate that ZnO nanomaterials hold considerable promise. Areas covered in this review: This review analyzes the biomedical applications of metal oxide and ZnO nanomaterials under development at the experimental, preclinical, and clinical levels. A discussion regarding the advantages, approaches, and limitations surrounding the use of metal oxide nanoparticles for cancer applications and drug delivery is presented. The scope of this article is focused on ZnO, and other metal oxide nanomaterial systems, and their proposed mechanisms of cytotoxic action, as well as current approaches to improve their targeting and cytotoxicity against cancer cells. Take home message: Through a better understanding of the mechanisms of action and cellular consequences resulting from nanoparticles interactions with cells, the inherent toxicity and selectivity of ZnO nanoparticles against cancer may be further improved to make them attractive new anti-cancer agents

Fluorescent Particles Comprising Nanoscale ZnO Layer and Exhibiting Cell-Specific Toxicity

Multifunctional smart nanostructures are disclosed that include fluorescein isothiocyanate (FITC)-encapsulated SiO2 core-shell particles with a nanoscale ZnO finishing layer, wherein an outer ZnO layer is formed on the SiO2-FITC core. These ~200 nm sized particles showed promise toward cell imaging and cellular uptake studies using the bacterium Escherichia coli and Jurkat cancer cells, respectively. The FITC encapsulated ZnO particles demonstrated excellent selectivity in preferentially killing Jurkat cancer cells with minimal toxicity to normal primary immune cells (18% and 75% viability remaining, respectively, after exposure to 60 μg/mL) and inhibited the growth of both gram-positive and gram-negative bacteria at concentrations .gtoreq.250-500 μg/mL (for Staphylococcus aureus and Escherichia coli, respectively). These results indicate that the FITC encapsulated multifunctional particles with nanoscale ZnO surface layer can be used as smart nanostructures for particle tracking, cell imaging, antibacterial treatments and cancer therapy

Serum Proteins Enhance Dispersion Stability and Influence the Cytotoxicity and Dosimetry of ZnO Nanoparticles in Suspension and Adherent Cancer Cell Models

Agglomeration and sedimentation of nanoparticles (NPs) within biological solutions is a major limitation in their use in many downstream applications. It has been proposed that serum proteins associate with the NP surface to form a protein corona that limits agglomeration and sedimentation. Here, we investigate the effect of fetal bovine serum (FBS) proteins on the dispersion stability, dosimetry, and NP-induced cytotoxicity of cationic zinc oxide nanoparticles (nZnO) synthesized via forced hydrolysis with a core size of 10 nm. Two different in vitro cell culture models, suspension and adherent, were evaluated by comparing a phosphate buffered saline (PBS) nZnO dispersion (nZnO/PBS) and an FBS-stabilized PBS nZnO dispersion (nZnO – FBS/PBS). Surface interactions of FBS on nZnO were analyzed via spectroscopic and optical techniques. Fourier transformed infrared spectroscopy (FTIR) confirmed the adsorption of negatively charged protein components on the cationic nZnO surface through the disappearance of surfaced-adsorbed carboxyl functional groups and the subsequent detection of vibrational modes associated with the protein backbone of FBS-associated proteins. Further confirmation of these interactions was noted in the isoelectric point shift of the nZnO from the characteristic pH of 9.5 to a pH of 6.1.In nZnO – FBS/PBS dispersions, the FBS reduced agglomeration and sedimentation behaviors to impart long-term improvements (\u3e24 h) to the nZnO dispersion stability. Furthermore, mathematical dosimetry models indicate that nZnO – FBS/PBS dispersions had consistent NP deposition patterns over time unlike unstable nZnO/PBS dispersions. In suspension cell models, the stable nZnO – FBS/PBS dispersion resulted in a ~33 % increase in the NP-induced cytotoxicity for both Jurkat leukemic and Hut-78 lymphoma cancer cells. In contrast, the nZnO – FBS/PBS dispersion resulted in 49 and 71 % reductions in the cytotoxicity observed towards the adherent breast (T-47D) and prostate (LNCaP) cancer cell lines, respectively. Presence of FBS in the NP dispersions also increased the reactive oxygen species generation. These observations indicate that the improved dispersion stability leads to increased NP bioavailability for suspension cell models and reduced NP sedimentation onto adherent cell layers resulting in more accurate in vitro toxicity assessments

Intensive Care and Invasive Ventilation in the Elderly Patient, Implications of Chronic Lung Disease and Comorbidities

Elderly patients have an increasing prevalence of illness that requires consideration of critical care and invasive ventilatory support. Although critical care of even the very elderly can provide value, with increasing age the potential risks of treatment and diminishing returns with respect to quality and quantity of life result in a need for careful evaluation. Variable combinations of impaired organ function, active disease and residual pathology from past disease and injury all affect critical care, with the consequence that the elderly are a very heterogeneous population. Recognizing that critical care is a limited resource, it is important to identify patients who may be at increased risk or least likely to benefit from treatment. Patients with functional impairments, nutritional deficiencies and multiple comorbidities may be at highest risk of poor outcomes. Those with very severe disease, extreme age and requirements for prolonged ventilatory support have high in-hospital mortality. Functional impairments, comorbidities and severity of illness are usually more important considerations than chronologic age. The objective of this review is to identify how common problems of the elderly affect critical care and decisions concerning use of invasive ventilatory support

Divergence in NK Cell and Cyclic AMP Regulation of T Cell CD40L Expression in Asthmatic Subjects

T cells are central in the pathogenesis of asthma, and the associated ligand, CD40L, plays an important role by increasing production of immunoglobulin E and inflammatory mediators. β-Adrenoceptor agonists are commonly used in asthma, although little is known regarding effects on CD40L expression and T cell activation. Here, we demonstrate that cyclic adenosine monophosphate (cAMP) and β-adrenoceptor agonists differentially regulate CD40L in asthma. cAMP increased naïve T cell CD40L expression in asthmatics (9.8±8.5 increase in percent CD40L-positive cells), and expression in control subjects was inhibited (7.1±6.0 decrease in percent CD40L-positive cells; P\u3c 0.05). Cell depletion and reconstitution experiments were used to determine that cAMP enhancement of CD40L required cell-to-cell contact with an asthma-associated natural killer (NK) cell subset. The NK cell subset expressed elevated levels of CD95, and in vitro-generated CD95+NK2 cells also produced similar effects on CD40L expression. Our findings suggest that a subset of NK cells with elevated CD95 expression is associated with asthma and can reverse cAMP inhibitory effects on T cell CD40L with the potential to increase disease exacerbation

Measuring Aptamer Affinity with Kinexa

Aptamers are nucleic acid or peptide molecules selected to have a high affinity and specificity for their substrates, very often in the sub-nanomolar range. Consequently, precise and reliable determination of their binding constant to the targets using techniques traditionally based on real-time monitoring is extremely challenging. To alleviate these roadblocks, we investigated the usefulness of the Kinetics Exclusion Assay (KinExA) technology to assess the equilibrium when high-affinity aptamers are employed. Although this technology was specifically developed for characterization of antibody-antigen interactions down to the femtomolar range, we adapted it for routine measurements of interactions that employ DNA aptamers