THE PHARMACOKINETICS OF METAL-BASED ENGINEERED NANOMATERIALS, FOCUSING ON THE BLOOD-BRAIN BARRIER

Metal-based engineered nanomaterials (ENMs) have potential to revolutionize diagnosis, drug delivery and manufactured products, leading to greater human ENM exposure. It is crucial to understand ENM pharmacokinetics and their association with biological barriers such as the blood-brain barrier (BBB). Physicochemical parameters such as size and surface modification of ENMs play an important role in ENM fate, including their brain association. Multifunctional ENMs showed advantages across the highly regulated BBB. There are limited reports on ENM distribution among the blood in the brain vasculature, the BBB, and brain parenchyma. In this study, ceria ENM was used to study the effect of size on its pharmacokinetics. Four sizes of ceria ENMs were studied. Five nm ceria showed a longer half-life in the blood and higher brain association compared with other sizes and 15 and 30 nm ceria had a higher blood cell association than 5 or 55 nm ceria. Because of the long circulation and high brain association of 5 nm ceria compared with other sizes, its distribution between the BBB and brain parenchyma was studied. The in situ brain perfusion technique showed 5 nm ceria (99%) on the luminal surface of the BBB rather than the brain parenchyma. For biomedical applications in the central nervous system (CNS), it is vital to develop stable and biocompatible ENMs and enhance their uptake by taking advantage of their unique properties. Cross-linked nanoassemblies entrapping iron oxide nanoparticles (CNA-IONPs) showed controlled particle size in biological conditions and less toxicity in comparison to Citrate-IONPs. CNA-IONPs considerably enhanced MRI T2 relaxivities and generated heat at mild hyperthermic temperatures (40 ~ 42°C) in the presence of alternating magnetic field (AMF). Numerous researchers showed mild whole body hyperthermia can increase BBB permeability for potential brain therapeutic application. Compared to conventional hyperthermia, AMF-induced hyperthermia increased BBB permeability with a shorter duration of hyperthermia and lower temperature, providing the potential to enhance IONP flux across the BBB with reduced toxicity. Overall, ENMs with optimized physicochemical properties can enhance their flux across the BBB into the brain with desirable pharmacokinetics, which provide great potential for diagnosis and therapy in the CNS

Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake and Flux in Blood-Brain Barrier Models

PURPOSE: Superparamagnetic iron oxide nanoparticles (IONPs) are being investigated for brain cancer therapy because alternating magnetic field (AMF) activates them to produce hyperthermia. For central nervous system applications, brain entry of diagnostic and therapeutic agents is usually essential. We hypothesized that AMF-induced hyperthermia significantly increases IONP blood-brain barrier (BBB) association/uptake and flux. METHODS: Cross-linked nanoassemblies loaded with IONPs (CNA-IONPs) and conventional citrate-coated IONPs (citrate-IONPs) were synthesized and characterized in house. CNA-IONP and citrate-IONP BBB cell association/uptake and flux were studied using two BBB Transwell® models (bEnd.3 and MDCKII cells) after conventional and AMF-induced hyperthermia exposure. RESULTS: AMF-induced hyperthermia for 0.5 h did not alter CNA-IONP size but accelerated citrate-IONP agglomeration. AMF-induced hyperthermia for 0.5 h enhanced CNA-IONP and citrate-IONP BBB cell association/uptake. It also enhanced the flux of CNA-IONPs across the two in vitro BBB models compared to conventional hyperthermia and normothermia, in the absence of cell death. Citrate-IONP flux was not observed under these conditions. AMF-induced hyperthermia also significantly enhanced paracellular pathway flux. The mechanism appears to involve more than the increased temperature surrounding the CNA-IONPs. CONCLUSIONS: Hyperthermia induced by AMF activation of CNA-IONPs has potential to increase the BBB permeability of therapeutics for the diagnosis and therapy of various brain diseases

The cost of ending groundwater overdraft on the North China Plain

Overexploitation of groundwater reserves is a major environmental problem around the world. In many river basins, groundwater and surface water are used conjunctively and joint optimization strategies are required. A hydroeconomic modeling approach is used to find cost-optimal sustainable surface water and groundwater allocation strategies for a river basin, given an arbitrary initial groundwater level in the aquifer. A simplified management problem with conjunctive use of scarce surface water and groundwater under inflow and recharge uncertainty is presented. Because of head-dependent groundwater pumping costs the optimization problem is nonlinear and non-convex, and a genetic algorithm is used to solve the one-step-ahead subproblems with the objective of minimizing the sum of immediate and expected future costs. A real-world application in the water-scarce Ziya River basin in northern China is used to demonstrate the model capabilities. Persistent overdraft from the groundwater aquifers on the North China Plain has caused declining groundwater levels. The model maps the marginal cost of water in different scenarios, and the minimum cost of ending groundwater overdraft in the basin is estimated to be CNY 5.58 billion yr−1. The study shows that it is cost-effective to slowly recover the groundwater aquifer to a level close to the surface, while gradually lowering the groundwater value to the equilibrium at CNY 2.15 m−3. The model can be used to guide decision-makers to economic efficient long-term sustainable management of groundwater and surface water resources

Binding, Transcytosis and Biodistribution of Anti-PECAM-1 Iron Oxide Nanoparticles for Brain-Targeted Delivery

OBJECTIVE: Characterize the flux of platelet-endothelial cell adhesion molecule (PECAM-1) antibody-coated superparamagnetic iron oxide nanoparticles (IONPs) across the blood-brain barrier (BBB) and its biodistribution in vitro and in vivo. METHODS: Anti-PECAM-1 IONPs and IgG IONPs were prepared and characterized in house. The binding affinity of these nanoparticles was investigated using human cortical microvascular endothelial cells (hCMEC/D3). Flux assays were performed using a hCMEC/D3 BBB model. To test their immunospecificity index and biodistribution, nanoparticles were given to Sprague Dawley rats by intra-carotid infusion. The capillary depletion method was used to elucidate their distribution between the BBB and brain parenchyma. RESULTS: Anti-PECAM-1 IONPs were ~130 nm. The extent of nanoparticle antibody surface coverage was 63.6 ± 8.4%. Only 6.39 ± 1.22% of labeled antibody dissociated from IONPs in heparin-treated whole blood over 4 h. The binding affinity of PECAM-1 antibody (KD) was 32 nM with a maximal binding (Bmax) of 17 × 10(5) antibody molecules/cell. Anti-PECAM-1 IONP flux across a hCMEC/D3 monolayer was significantly higher than IgG IONP\u27s with 31% of anti-PECAM-1 IONPs in the receiving chamber after 6 h. Anti-PECAM-1 IONPs showed higher concentrations in lung and brain, but not liver or spleen, than IgG IONPs after infusion. The capillary depletion method showed that 17±12% of the anti-PECAM-1 IONPs crossed the BBB into the brain ten minutes after infusion. CONCLUSIONS: PECAM-1 antibody coating significantly increased IONP flux across the hCMEC/D3 monolayer. In vivo results showed that the PECAM-1 antibody enhanced BBB association and brain parenchymal accumulation of IONPs compared to IgG. This research demonstrates the benefit of anti-PECAM-1 IONPs for association and flux across the BBB into the brain in relation to its biodistribution in peripheral organs. The results provide insight into potential application and toxicity concerns of anti-PECAM-1 IONPs in the central nervous system

Magmatic record of India-Asia collision

This work was financially co-supported by Chinese Academy of Sciences (XDB03010301) and other Chinese funding agencies (Project 973: 2011CB403102 and 2015CB452604; NSFC projects: 41225006, 41273044, and 41472061).New geochronological and geochemical data on magmatic activity from the India-Asia collision zone enables recognition of a distinct magmatic flare-up event that we ascribe to slab breakoff. This tie-point in the collisional record can be used to back-date to the time of initial impingement of the Indian continent with the Asian margin. Continental arc magmatism in southern Tibet during 80-40 Ma migrated from south to north and then back to south with significant mantle input at 70-43 Ma. A pronounced flare up in magmatic intensity (including ignimbrite and mafic rock) at ca. 52-51 Ma corresponds to a sudden decrease in the India-Asia convergence rate. Geological and geochemical data are consistent with mantle input controlled by slab rollback from ca. 70 Ma and slab breakoff at ca. 53 Ma. We propose that the slowdown of the Indian plate at ca. 51 Ma is largely the consequence of slab breakoff of the subducting Neo-Tethyan oceanic lithosphere, rather than the onset of the India-Asia collision as traditionally interpreted, implying that the initial India-Asia collision commenced earlier, likely at ca. 55 Ma.Publisher PDFPeer reviewe

Ares 1X Hybrid Modeling with Comparisons to Flight Data

This slide presentation reviews the Ares 1X test flight and compares the resultant flight data with the results of modeled data from siumulations of the flight. It includes: (1) Ares 1X Flight Summary, (2) Ares 1X Data Summary (3) Model Descriptions (4) Model Comparisons to Flight Data in three areas: (a) Liftoff, (b) Transonic and (c) Roll Control Firings (RCS) Firings

Raising the Gangdese Mountains in southern Tibet

This research was financially supported by the MOST of China (No. 2016YFC0600304 and No. 2016YFC0600407), the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB03010301), the National Science Foundation of China (41225006 and 41472061), and the MOST Special Fund from the State Key Laboratory of Geological Processes and Mineral Resources (China University of Geosciences).The surface uplift of mountain belts is in large part controlled by the effects of crustal thickening and mantle dynamic processes (e.g., lithospheric delamination or slab breakoff). Understanding the history and driving mechanism of uplift of the southern Tibetan Plateau requires accurate knowledge on crustal thickening over time. Here we determine spatial and temporal variations in crustal thickness using whole-rock La/Yb ratios of intermediate intrusive rocks from the Gangdese arc. Our results show that the crust was likely of normal thickness prior to ca. 70 Ma (~37 km) but began to thicken locally at ca. 70 − 60 Ma. The crust reached (58 − 50) ± 10 km at 55 − 45 Ma extending over 400 km along the strike of the arc. This thickening was likely due to magmatic underplating as a consequence of rollback and then breakoff of the subducting Neo-Tethyan slab. The crust attained a thickness of 68 ± 12 km at ca. 20 − 10 Ma, as a consequence of underthrusting of India and associated thrust faulting. The Gangdese Mountains in southern Tibet broadly attained an elevation of >4000 m at ca. 55 − 45 Ma as a result of isostatic surface uplift driven by crustal thickening and slab breakoff, and reached their present-day elevation by 20 − 10 Ma. Our paleoelevation estimates are consistent not only with the C − O isotope-based paleoaltimetry but also with the carbonate clumped isotope paleothermometer, exemplifying the promise of reconstructing paleoelevation in time and space for ancient orogens through a combination of magmatic composition and Airy isostatic compensation.Publisher PDFPeer reviewe