Effect of Circadian Rhythm Modulated Blood Flow on Nanoparticle based Targeted Drug Delivery in Virtual In Vivo Arterial Geometries.

Delivery of drug using nanocarriers tethered with vasculature-targeting epitopes aims to maximize the therapeutic efficacy of the drug while minimizing the drug side effects. Circadian rhythm which is governed by the central nervous system has implications for targeted drug delivery due to sleep-wake cycle changes in blood flow dynamics. This paper presents an advanced fluid dynamics modeling method that is based on viscous incompressible shear-rate fluid (blood) coupled with an advection-diffusion equation to simulate the formation of drug concentration gradients in the blood stream and buildup of concentration at the targeted site. The method is equipped with an experimentally calibrated nanoparticle-endothelial cell adhesion model that employs Robin boundary conditions to describe nanoparticle retention based on probability of adhesion, a friction model accounting for surface roughness of endothelial cell layer, and a dispersion model based on Taylor-Aris expression for effective diffusion in the boundary layer. The computational model is first experimentally validated and then tested on engineered bifurcating arterial systems where impedance boundary conditions are applied at the outflow to account for the downstream resistance at each outlet. It is then applied to a virtual geometric model of an in vivo arterial tree developed through MRI-based image processing techniques. These simulations highlight the potential of the computational model for drug transport, adhesion, and retention at multiple sites in virtual in vivo models. The model provides a virtual platform for exploring circadian rhythm modulated blood flow for targeted drug delivery while minimizing the in vivo experimentation.

Modeling of spatiotemporal dynamics of ligand-coated particle flow in targeted drug delivery processes.

Nanoparticles tethered with vasculature-binding epitopes have been used to deliver the drug into injured or diseased tissues via the bloodstream. However, the extent that blood flow dynamics affects nanoparticle retention at the target site after adhesion needs to be better understood. This knowledge gap potentially underlies significantly different therapeutic efficacies between animal models and humans. An experimentally validated mathematical model that accurately simulates the effects of blood flow on nanoparticle adhesion and retention, thus circumventing the limitations of conventional trial-and-error-based drug design in animal models, is lacking. This paper addresses this technical bottleneck and presents an integrated mathematical method that derives heavily from a unique combination of a mechanics-based dispersion model for nanoparticle transport and diffusion in the boundary layers, an asperity model to account for surface roughness of endothelium, and an experimentally calibrated stochastic nanoparticle-cell adhesion model to describe nanoparticle adhesion and subsequent retention at the target site under external flow. PLGA-b-HA nanoparticles tethered with VHSPNKK peptides that specifically bind to vascular cell adhesion molecules on the inflamed vascular wall were investigated. The computational model revealed that larger particles perform better in adhesion and retention at the endothelium for the particle sizes suitable for drug delivery applications and within physiologically relevant shear rates. The computational model corresponded closely to the in vitro experiments which demonstrates the impact that model-based simulations can have on optimizing nanocarriers in vascular microenvironments, thereby substantially reducing in vivo experimentation as well as the development costs.

Delivery-mediated exosomal therapeutics in ischemia-reperfusion injury: advances, mechanisms, and future directions.

Ischemia-reperfusion injury (IRI) poses significant challenges across various organ systems, including the heart, brain, and kidneys. Exosomes have shown great potentials and applications in mitigating IRI-induced cell and tissue damage through modulating inflammatory responses, enhancing angiogenesis, and promoting tissue repair. Despite these advances, a more systematic understanding of exosomes from different sources and their biotransport is critical for optimizing therapeutic efficacy and accelerating the clinical adoption of exosomes for IRI therapies. Therefore, this review article overviews the administration routes of exosomes from different sources, such as mesenchymal stem cells and other somatic cells, in the context of IRI treatment. Furthermore, this article covers how the delivered exosomes modulate molecular pathways of recipient cells, aiding in the prevention of cell death and the promotions of regeneration in IRI models. In the end, this article discusses the ongoing research efforts and propose future research directions of exosome-based therapies.

High Gas Permeability in Aged Superglassy Membranes with Nanosized UiO-66-NH2 /cPIM-1 Network Fillers.

Superglassy membranes synthesised by polymers of intrinsic microporosity (PIMs) suffer from physical aging and show poor gas permeance over time, especially thin membranes, due to the fast rearrangement of nonequilibrium polymer chains. Herein, we constructed a novel PIM-1 thin film nanocomposite membrane (TFN) using nanosized UiO-66-NH2 (≈10 nm)/carboxylated PIM-1 (cPIM-1) as the composite filler. Unlike conventional fillers, which interact with the polymer only via the surface, the UiO-66-NH2 /cPIM-1 forms a stable three-dimensional (3D) network intertwining with the polymer chains, being very effective to impede chain relaxation, and thus physical aging. Nanosizing of UiO-66-NH2 was achieved by regulating the nucleation kinetics using carbon quantum dots (CQD) during the synthesis. This led to increased surface area, and hence more functional groups to bond with cPIM-1 (via hydrogen bonding between -NH2 and -COOH groups), which also improved interfacial compatibility between the 3D network and polymer chains avoiding defect formation. As a result, the novel TFN showed significantly improved performance in gas separation along with reduced aging (i.e. ≈6 % loss in CO2 permeability over 63 days); the aged membranes had a CO2 permeance of 2504 GPU and ideal selectivity values of 37.2 and 23.8 for CO2 /N2 and CO2 /CH4 , respectively.

A Facile Synthesis Route to AuPd Alloys for the Selective Oxidation of 5-Hydroxymethylfurfural to 2,5-Furandicarboxylic Acid.

Synthesis of 2,5-furandicarboxylic acid (FDCA) can be achieved via catalytic oxidation of 5-hydroxymethylfurfural (5-HMF), in which both base and catalyst play important roles. This work presents the development of a simple synthesis method (based on a commercial parent 10 wt.% Pd/C catalyst) to prepare the bimetallic AuPd alloy catalysts (i. e., AuPd/C) for selective 5-HMF oxidation to FDCA. When using the strong base of NaOH, Pd and Au cooperate to promote FDCA formation when deployed either separately (as a physical mixture of the monometallic Au/C and Pd/C catalysts) or ideally alloyed (AuPd/C), with complete 5-HMF conversion and FDCA yields of 66 % vs 77 %, respectively. However, NaOH also promoted the formation of undesired by-products, leading to poor mass balances (<81 %). Comparatively, under weak base conditions (using NaHCO3 ), an increase in Au loading in the AuPd/C catalysts enhances 5-HMF conversion and FDCA productivity (due to the enhanced carbonyl oxidation capacity) which coincides with a superior mass balances of >97 %. Yet, the excessive Pd content in the AuPd/C catalysts was not beneficial in promoting FDCA formation.

Intracerebral Nanoparticle Transport Facilitated by Alzheimer Pathology and Age.

Nanoparticles have emerged as potential transporters of drugs targeting Alzheimer's disease (AD), but their design should consider the blood-brain barrier (BBB) integrity and neuroinflammation of the AD brain. This study presents that aging is a significant factor for the brain localization and retention of nanoparticles, which we engineered to bind with reactive astrocytes and activated microglia. We assembled 200 nm-diameter particles using a block copolymer of poly(lactic-co-glycolic acid) (PLGA) and CD44-binding hyaluronic acid (HA). The resulting PLGA-b-HA nanoparticles displayed increased binding to CD44-expressing reactive astrocytes and activated microglia. Upon intravascular injection, nanoparticles were localized to the hippocampi of both APP/PS1 AD model mice and their control littermates at 13-16 months of age due to enhanced transvascular transport through the leaky BBB. No particles were found in the hippocampi of young adult mice. These findings demonstrate the brain localization of nanoparticles due to aging-induced BBB breakdown regardless of AD pathology.

Finned hierarchical MOFs supported on cellulose for the selective adsorption of n-hexane and 1-hexene.

Finned hierarchical MOF particles (Cu(BDC) nanosheets as fins grown perpendicularly on Ni2(BDC)2(DABCO) hexagonal prisms) were synthesized on modified cellulose support. The hierarchical MOF particles exposed the open Cu(II) sites on Cu(BDC) to enable selective 1-hexene/n-hexane separation.

Palladium-doped hierarchical ZSM-5 for catalytic selective oxidation of allylic and benzylic alcohols.

Hierarchical zeolites have the potential to provide a breakthrough in transport limitation, which hinders pristine microporous zeolites and thus may broaden their range of applications. We have explored the use of Pd-doped hierarchical ZSM-5 zeolites for aerobic selective oxidation (selox) of cinnamyl alcohol and benzyl alcohol to their corresponding aldehydes. Hierarchical ZSM-5 with differing acidity (H-form and Na-form) were employed and compared with two microporous ZSM-5 equivalents. Characterization of the four catalysts by X-ray diffraction, nitrogen porosimetry, NH3 temperature-programmed desorption, CO chemisorption, high-resolution scanning transmission electron microscopy, X-ray photoelectron spectroscopy and X-ray absorption spectroscopy allowed investigation of their porosity, acidity, as well as Pd active sites. The incorporation of complementary mesoporosity, within the hierarchical zeolites, enhances both active site dispersion and PdO active site generation. Likewise, alcohol conversion was also improved with the presence of secondary mesoporosity, while strong Brønsted acidity, present solely within the H-form systems, negatively impacted overall selectivity through undesirable self-etherification. Therefore, tuning support porosity and acidity alongside active site dispersion is paramount for optimal aldehyde production.