Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

<p>Abstract</p> <p>Background</p> <p>Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells.</p> <p>Methods</p> <p>Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured <it>in vivo </it>with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed <it>ex vivo </it>with fluorescence imaging.</p> <p>Results</p> <p>We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells.</p> <p>Conclusion</p> <p>The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.</p

Global-Scale Environmental Niche and Habitat of Blue Shark (Prionace glauca) by Size and Sex: A Pivotal Step to Improving Stock Management

Blue shark (Prionace glauca) is amongst the most abundant shark species in international trade, however this highly migratory species has little effective management and the need for spatio-temporal strategies increases, possibly involving the most vulnerable stage or sex classes. We combined 265,595 blue shark observations (capture or satellite tag) with environmental data to present the first global-scale analysis of species' habitat preferences for five size and sex classes (small juveniles, large juvenile males and females, adult males and females). We leveraged the understanding of blue shark biotic environmental associations to develop two indicators of foraging location: productivity fronts in mesotrophic areas and mesopelagic micronekton in oligotrophic environments. Temperature (at surface and mixed layer depth plus 100 m) and sea surface height anomaly were used to exclude unsuitable abiotic environments. To capture the horizontal and vertical extent of thermal habitat for the blue shark, we defined the temperature niche relative to both sea surface temperature (SST) and the temperature 100 m below the mixed layer depth (Tmld+100). We show that the lifetime foraging niche incorporates highly diverse biotic and abiotic conditions: the blue shark tends to shift from mesotrophic and temperate surface waters during juvenile stages to more oligotrophic and warm surface waters for adults. However, low productivity limits all classes of blue shark habitat in the tropical western North Atlantic, and both low productivity and warm temperatures limit habitat in most of the equatorial Indian Ocean (except for the adult males) and tropical eastern Pacific. Large females tend to have greater habitat overlap with small juveniles than large males, more defined by temperature than productivity preferences. In particular, large juvenile females tend to extend their range into higher latitudes than large males, likely due to greater tolerance to relatively cold waters. Large juvenile and adult females also seem to avoid areas with intermediate SST (similar to 21.7-24.0 degrees C), resulting in separation from large males mostly in the tropical and temperate latitudes in the cold and warm seasons, respectively. The habitat requirements of sensitive size- and sex-specific stages to blue shark population dynamics are essential in management to improve conservation of this near-threatened species