Many variants of vascular-targeted carriers (VTCs) have been investigated for therapeutic intervention in several human diseases. However, in order to optimize the functionality of VTC in vivo, carriers' physical properties, such as size and shape, are important considerations for a VTC design that evades the reticuloendothelial system (RES) and successfully interacts with the targeted vessel wall. Nonetheless, little evidence has been presented on the role of size in VTC's interactions with the vascular wall, particularly in the microcirculation. Thus, in this work, we explore how particle size, along with hemodynamics (blood shear rate and vessel size) and hemorheology (blood hematocrit) affect the capacity for spheres to marginate (localize and adhere) to inflamed endothelium in a microfluidic model of human microvessels. Microspheres, particularly the 2 μm spheres, were found to show disproportionately higher margination than nanospheres in all hemodynamic conditions evaluated due to the poor ability of the latter to localize to the wall region from midstream. This work represents the first evidence that nanospheres may not exhibit "near wall excess" in microvessels, e.g., arterioles and venules, and therefore may not be suitable for imaging and drug delivery applications in cancer and other diseases affecting microvessels.
Gold nanoparticles (AuNPs) have been extensively used as nanomaterials for theranostic applications due to their multifunctional characteristics in therapeutics, imaging, and surface modification. In this study, the unique functionalities of exosome-derived membranes were combined with synthetic AuNPs for targeted delivery to brain cells. Here, we report the surface modification of AuNPs with brain-targeted exosomes derived from genetically engineered mammalian cells by using the mechanical method or extrusion to create these novel nanomaterials. The unique targeting properties of the AuNPs after fabrication with the brain-targeted exosomes was demonstrated by their binding to brain cells under laminar flow conditions as well as their enhanced transport across the blood brain barrier. In a further demonstration of their ability to target brain cells,
in vivo
bioluminescence imaging revealed that targeted-exosome coated AuNPs accumulated in the mouse brain after intravenous injection. The surface modification of synthetic AuNPs with the brain-targeted exosome demonstrated in this work represents a highly novel and effective strategy to provide efficient brain targeting and shows promise for the future in using modified AuNPs to penetrate the brain.
The nanoscale plasma protein interaction with intravenously injected particulate carrier systems is known to modulate their organ distribution and clearance from the bloodstream. However, the role of this plasma protein interaction in prescribing the adhesion of carriers to the vascular wall remains relatively unknown. Here, we show that the adhesion of vascular-targeted poly(lactide-co-glycolic-acid) (PLGA) spheres to endothelial cells is significantly inhibited in human blood flow, with up to 90% reduction in adhesion observed relative to adhesion in simple buffer flow, depending on the particle size and the magnitude and pattern of blood flow. This reduced PLGA adhesion in blood flow is linked to the adsorption of certain high molecular weight plasma proteins on PLGA and is donor specific, where large reductions in particle adhesion in blood flow (>80% relative to buffer) is seen with ∼60% of unique donor bloods while others exhibit moderate to no reductions. The depletion of high molecular weight immunoglobulins from plasma is shown to successfully restore PLGA vascular wall adhesion. The observed plasma protein effect on PLGA is likely due to material characteristics since the effect is not replicated with polystyrene or silica spheres. These particles effectively adhere to the endothelium at a higher level in blood over buffer flow. Overall, understanding how distinct plasma proteins modulate the vascular wall interaction of vascular-targeted carriers of different material characteristics would allow for the design of highly functional delivery vehicles for the treatment of many serious human diseases.
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