Abstract
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.
Highlights
Injectable vascular-targeted carrier (VTC) systems hold great promise for the effective diagnosis and treatment of many human diseases by non-invasively providing localized delivery of imaging agents or potent therapeutics
The evaluation of VTCs for use in human diseases has mostly focused on the development of novel strategies for targeting, e.g. design of unique peptides [2], and formulations that allow for optimal drug release with the general presumption that all VTCs can successfully marginate in blood flow irrespective of size, shape, and material characteristics
We have shown that red blood cells (RBCs) dynamics and white blood cells (WBCs) physical interaction affect the ability of particles to marginate as a function of particle size and shape [3,4,5]
Summary
Injectable vascular-targeted carrier (VTC) systems hold great promise for the effective diagnosis and treatment of many human diseases by non-invasively providing localized delivery of imaging agents or potent therapeutics. To date, only a few VTCs have been effectively translated into the clinics [1]. The evaluation of VTCs for use in human diseases has mostly focused on the development of novel strategies for targeting, e.g. design of unique peptides [2], and formulations that allow for optimal drug release with the general presumption that all VTCs can successfully marginate (localize and adhere to the vascular wall) in blood flow irrespective of size, shape, and material characteristics. To date, little is known about the potential role of plasma protein interactions with VTCs in their vascular wall interaction
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