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.

Due to the role of nitric oxide (NO) in regulating a variety of biological functions in humans, numerous studies on different NO releasing/generating materials have been published over the past two decades. Although NO has been demonstrated to be a strong antimicrobial and potent antithrombotic agent, NO-releasing (NOrel) polymers have not reached the clinical setting. While increasing the concentration of the NO donor in the polymer is a common method to prolong the NO-release, this should not be at the cost of mechanical strength or biocompatibility of the original material. In this work, it was shown that the incorporation of S-nitroso-penicillamine (SNAP), an NO donor molecule, into Elast-eon E2As (a copolymer of mixed soft segments of polydimethylsiloxane and poly(hexamethylene oxide)), does not adversely impact the physical and biological attributes of the base polymer. Incorporating 10 wt % of SNAP into E2As reduces the ultimate tensile strength by only 20%. The inclusion of SNAP did not significantly affect the surface chemistry or roughness of E2As polymer. Ultraviolet radiation, ethylene oxide, and hydrogen peroxide vapor sterilization techniques retained approximately 90% of the active SNAP content, where sterilization of these materials did not affect the NO-release profile over an 18 day period. Furthermore, these NOrel materials were shown to be biocompatible with the host tissues as observed through hemocompatibility and cytotoxicity analysis. In addition, the stability of SNAP in E2As was studied under a variety of storage conditions, as they pertain to translational potential of these materials. SNAP-incorporated E2As stored at room temperature for over 6 months retained 87% of its initial SNAP content. Stored and fresh films exhibited similar NO release kinetics over an 18 day period. Combined, the results from this study suggest that SNAPdoped E2As polymer is suitable for commercial biomedical applications due to the reported physical and biological characteristics that are important for commercial and clinical success.

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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.