Magnetic core-shell nanoparticles for drug delivery by nebulization

Background

Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe₃O₄ magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated.

Results

Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 μg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting.

Conclusion

We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route.     

Simulating the effects of climate change on the distribution of an invasive plant,using a high resolution,local scale,mechanistic approach: challenges and insights

The growing economic and ecological damage associated with biological invasions, which will likely be exacerbated by climate change, necessitates improved projections of invasive spread. Generally, potential changes in species distribution are investigated using climate envelope models; however, the reliability of such models has been questioned and they are not suitable for use at local scales. At this scale, mechanistic models are more appropriate. This paper discusses some key requirements for mechanistic models and utilises a newly developed model (PSS[gt]) that incorporates the influence of habitat type and related features (e.g., roads and rivers), as well as demographic processes and propagule dispersal dynamics, to model climate induced changes in the distribution of an invasive plant (Gunnera tinctoria) at a local scale. A new methodology is introduced, dynamic baseline benchmarking, which distinguishes climate‐induced alterations in species distributions from other potential drivers of change. Using this approach, it was concluded that climate change, based on IPCC and C4i projections, has the potential to increase the spread‐rate and intensity of G. tinctoria invasions. Increases in the number of individuals were primarily due to intensification of invasion in areas already invaded or in areas projected to be invaded in the dynamic baseline scenario. Temperature had the largest influence on changes in plant distributions. Water availability also had a large influence and introduced the most uncertainty in the projections. Additionally, due to the difficulties of parameterising models such as this, the process has been streamlined by utilising methods for estimating unknown variables and selecting only essential parameters.     

Distribution of purinergic P2X receptors in the equine digit, cervical spinal cord and dorsal root ganglia

Purinergic pathways are considered important in pain transmission, and P2X receptors are a key part of this system which has received little attention in the horse. The aim of this study was to identify and characterise the distribution of P2X receptor subtypes in the equine digit and associated vasculature and nervous tissue, including peripheral nerves, dorsal root ganglia and cervical spinal cord, using PCR, Western blot analysis and immunohistochemistry. mRNA signal for most of the tested P2X receptor subunits (P2X_{1–5, 7}) was detected in all sampled equine tissues, whereas P2X₆ receptor subunit was predominantly expressed in the dorsal root ganglia and spinal cord. Western blot analysis validated the specificity of P2X_{1–3, 7} antibodies, and these were used in immunohistochemistry studies. P2X_{1–3, 7} receptor subunits were found in smooth muscle cells in the palmar digital artery and vein with the exception of the P2X₃ subunit that was present only in the vein. However, endothelial cells in the palmar digital artery and vein were positive only for P2X₂ and P2X₃ receptor subunits. Neurons and nerve fibres in the peripheral and central nervous system were positive for P2X_1–3 receptor subunits, whereas glial cells were positive for P2X₇ and P2X_{1 and 2} receptor subunits. This previously unreported distribution of P2X subtypes may suggest important tissue specific roles in physiological and pathological processes.     

The Geometry of Locomotive Behavioral States in C. elegans

We develop a new hidden Markov model-based method to analyze C elegans locomotive behavior and use this method to quantitatively characterize behavioral states. In agreement with previous work, we find states corresponding to roaming, dwelling, and quiescence. However, we also find evidence for a continuum of intermediate states. We suggest that roaming, dwelling, and quiescence may best be thought of as extremes which, mixed in any proportion, define the locomotive repertoire of C elegans foraging and feeding behavior.     

MCHM Acts as a Hydrotrope,Altering the Balance of Metals in Yeast

Biological Trace Element Research - While drugs and other industrial chemicals are routinely studied to assess risks, many widely used chemicals have not been thoroughly evaluated. One such...     

Critical events in the evolutionary history of calcareous Nannoplankton

Calcareous nannofossil diversity, and rates of speciation and extinction are calculated for five million year intervals from their first appearance in the Late Triassic through to the Present Day. Important evolutionary events are as follows: first appearance in the Late Triassic, Triassic‐Jurassic boundary extinctions, Tithonian radiation (and the first occurrence of nannofossil carbonates), Late Cretaceous diversity maximum, Cretaceous‐Tertiary boundary extinctions, Palaeocene radiation, mid Eocene to Oligocene diversity decline, and early Miocene diversity rise. These events are related to possible causal factors of which climate appears to be the most fundamental. Other factors may include biogeographical isolation, sea level change, and the configuration of Mesozoic oceans.     

Searching Responses of a Hunting Spider to Cues Associated with Lepidopteran Eggs

Cheiracanthium inclusum (Hentz), a hunting spider, feeds on eggs of Helicoverpa zea (Boddie) and other moths. This study investigated whether C. inclusum can use chemical compounds present in H. zea scales and egg residues as kairomones to find these non-motile prey items. In a series of no- choice tests, spiders were presented with a piece of florist paper containing scales alone, scales + egg residues, or untreated controls. Next, spiders were presented with solvent extracts of either scales or eggs. Polar and non-polar solvents were used in the extractions. Contact with scales alone, scales + egg residues, and non-polar solvent extracts of both scales and eggs resulted in retention and/or induction of local searching behavior. Extracts made with polar solvents induced no apparent response, indicating that the chemostimulatory compounds are lipophilic. These results show that C. inclusum responds to kairomones left by ovipositing H. zea and use these chemical cues to detect and locate H. zea eggs.     

Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists

High throughput screening led to the identification of a novel series of quinolone α7 nicotinic acetylcholine receptor (nAChR) agonists. Optimization of an HTS hit (1) led to 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one, which was found to be potent and selective. Poor brain penetrance in this series was attributed to transporter-mediated efflux, which was in turn due to high pK_a. A novel 4-fluoroquinuclidine significantly lowered the pK_a of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay.