Targeted nanomedicine holds promise to find clinical use in many medical areas. Endothelial cells that line the luminal surface of blood vessels represent a key target for treatment of inflammation, ischemia, thrombosis, stroke, and other neurological, cardiovascular, pulmonary, and oncological conditions. In other cases, the endothelium is a barrier for tissue penetration or a victim of adverse effects. Several endothelial surface markers including peptidases (e.g., ACE, APP, and APN) and adhesion molecules (e.g., ICAM-1 and PECAM) have been identified as key targets. Binding of nanocarriers to these molecules enables drug targeting and subsequent penetration into or across the endothelium, offering therapeutic effects that are unattainable by their nontargeted counterparts. We analyze diverse aspects of endothelial nanomedicine including (i) circulation and targeting of carriers with diverse geometries, (ii) multivalent interactions of carrier with endothelium, (iii) anchoring to multiple determinants, ...

http://pubs.acs.org/doi/pdf/10.1021/nn500136z

Vascular Targeting of Nanocarriers: Perplexing Aspects of the Seemingly Straightforward Paradigm

Targeting nanoparticles (NPs) loaded with drugs and probes to precise locations in the body may improve the treatment and detection of many diseases. Generally, to achieve targeting, affinity ligands are introduced on the surface of NPs that can bind to molecules present on the cell of interest. Optimization of ligand density is a critical parameter in controlling NP binding to target cells, and a higher ligand density is not always the most effective. In this study, we investigated how NP avidity affects targeting to the pulmonary vasculature, using NPs targeted to ICAM-1. This cell adhesion molecule is expressed by quiescent endothelium at modest levels and is upregulated in a variety of pathological settings. NP avidity was controlled by ligand density, with the expected result that higher avidity NPs demonstrated greater pulmonary uptake than lower avidity NPs in both naive and pathological mice. However, in comparison with high-avidity NPs, low-avidity NPs exhibited several-fold higher selectivity of targeting to pathological endothelium. This finding was translated into a PET imaging platform that was more effective in detecting pulmonary vascular inflammation using low-avidity NPs. Furthermore, computational modeling revealed that elevated expression of ICAM-1 on the endothelium is critical for multivalent anchoring of NPs with low avidity, while high-avidity NPs anchor effectively to both quiescent and activated endothelium. These results provide a paradigm that can be used to optimize NP targeting by manipulating ligand density and may find biomedical utility for increasing detection of pathological vasculature.

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Reduction of Nanoparticle Avidity Enhances the Selectivity of Vascular Targeting and PET Detection of Pulmonary Inflammation

The blood-brain barrier (BBB) limits transport of nanoparticles from the circulation to the brain parenchyma. Angiopep-2, a peptide which functions as a brain transport vector, can be coupled to nanoparticles in order to facilitate binding and internalization by brain endothelial cells (ECs), and subsequent BBB penetration. This multi-step process may be affected by blood flow over brain ECs, as flow influences endothelial cell phenotype as well as interactions of nanoparticles with ECs. In the present study a microfluidic BBB model was constructed to evaluate binding and internalization by brain ECs, as well as BBB penetration of Angiopep-2 coupled liposomes (Ang2-Liposomes) in static and flow conditions. Ang2 conjugation to liposomes markedly improved binding relative to unconjugated liposomes. Ang2-Liposomes bound and were internalized efficiently by brain endothelial cells after static incubation or with 1 dyne/cm2 of fluid shear stress (FSS), while binding was reduced at a FSS of 6 dyne/cm2. Penetration of the model microfluidic BBB by Ang2-Liposomes was higher at a FSS of 1 dyne/cm2 and 6 dyne/cm2 than with static incubation. Analysis of barrier function and control experiments for receptor-mediated penetration provided insight into the magnitude of transcellular versus paracellular transport at each tested FSS. Overall, the results demonstrate that flow impacted the binding and BBB penetration of Ang2-functionalized nanoparticles. This highlights the relevance of the local flow environment for in vitro modeling of the performance of nanoparticles functionalized with BBB penetrating ligands.

/pdf/effect-of-flow-on-targeting-and-penetration-of-angiopep-41er7fe70l.pdf

Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier.

Endothelial cells represent important targets for therapeutic and diagnostic interventions in many cardiovascular, pulmonary, neurological, inflammatory, and metabolic diseases. Targeted delivery of drugs (especially potent and labile biotherapeutics that require specific subcellular addressing) and imaging probes to endothelium holds promise to improve management of these maladies. In order to achieve this goal, drug cargoes or their carriers including liposomes and polymeric nanoparticles are chemically conjugated or fused using recombinant techniques with affinity ligands of endothelial surface molecules. Cell adhesion molecules, constitutively expressed on the endothelial surface and exposed on the surface of pathologically altered endothelium—selectins, VCAM-1, PECAM-1, and ICAM-1—represent good determinants for such a delivery. In particular, PECAM-1 and ICAM-1 meet criteria of accessibility, safety, and relevance to the (patho)physiological context of treatment of inflammation, ischemia, and thrombosis and offer a unique combination of targeting options including surface anchoring as well as intra- and transcellular targeting, modulated by parameters of the design of drug delivery system and local biological factors including flow and endothelial phenotype. This review includes analysis of these factors and examples of targeting selected classes of therapeutics showing promising results in animal studies, supporting translational potential of these interventions.

/pdf/targeted-drug-delivery-to-endothelial-adhesion-molecules-2gas2jzfu7.pdf

Targeted Drug Delivery to Endothelial Adhesion Molecules

Nanoparticles in the bloodstream are subjected to complex fluid forces as they move through the curves and branches of healthy or tumor vasculature. While nanoparticles are known to preferentially accumulate in angiogenic vessels, little is known about the flow conditions in these vessels and how these conditions may influence localization. Here, we report a methodology which combines confocal imaging of nanoparticle-injected transgenic zebrafish embryos, 3D modeling of the vasculature, particle mapping, and computational fluid dynamics, to quantitatively assess the effects of fluid forces on nanoparticle distribution in vivo. Six-fold lower accumulation was found in zebrafish arteries compared to the lower velocity veins. Nanoparticle localization varied inversely with shear stress. Highest accumulation was present in regions of disturbed flow found at branch points and curvatures in the vasculature. To further investigate cell-particle association under flow, human endothelial cells were exposed to nanoparticles under hemodynamic conditions typically found in human vessels. Physiological adaptations of endothelial cells to 20 hours of flow enhanced nanoparticle accumulation in regions of disturbed flow. Overall our results suggest that fluid shear stress magnitude, flow disturbances, and flow-induced changes in endothelial physiology modulate nanoparticle localization in angiogenic vessels.

Nanoparticle localization in blood vessels: dependence on fluid shear stress, flow disturbances, and flow-induced changes in endothelial physiology.

This article reviews experimental and modeling methods for determining the critical roles played by the various factors that control nanocarrier drug delivery to vascular endothelial cells.

https://iubmb.onlinelibrary.wiley.com/doi/pdf/10.1002/iub.475

Dynamic factors controlling carrier anchoring on vascular cells.

Higher order simulation of hydrocarbon flows associated with complex fractures produced in the hydraulic fracturing process in a well system may be used to obtain high fidelity results while minimizing a cost of computation. The higher order simulation of hydrocarbon flows may provide efficient and stable simulation algorithms that avoid any artificial boundary treatment inconsistent with the governing equations, while maintaining a uniform order of accuracy. In particular, a re-normalization technique implements higher-order finite difference/finite volume discretization near the boundary of the complex fractures. The simulation of hydrocarbon flows may be used to determine a production activity for the well system.

Uma Balakrishnan

Papers

Dynamic factors controlling carrier anchoring on vascular cells.

Higher order simulation of hydrocarbon flows of hydraulic fracture treatments