Plasma Proteins Alter the Vascular Wall Adhesion of Drug Carriers in a Material & Donor Specific Way

Introduction: 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.

Materials and Method:  poly(lactide-co-glycolic-acid) (PLGA) micro and nanospheres were fabricated via the oil-in-water emulsion solvent evaporation method.  Polystyrene and Silica microspheres were obtained commercially.   All particles were conjugated, via carbodimide chemistry, with the sLe^Acarbohydrate ligand that specifically binds to E-selectin on activated endothelial cells (ECs).  The blood flow adhesion of the inflammation-targeted particles to the vascular wall was evaluated in a parallel plate flow chamber consisting of a monolayer of activated ECs at the bottom wall of the chamber. 

Result and Discussion:  We show that the adhesion of vascular-targeted 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 restored PLGA vascular wall adhesion. The observed plasma protein effect on PLGA is likely due to material characteristic 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. Finally, grafting of sLe^Ato the PLGA surface via high density (brush conformation) of polyethylene glycol (PEG) chains did not eliminate the negative adhesion of PLGA particles to ECs in blood flow.

Conclusion: In this work, the adsorption of certain plasma proteins from human blood onto PLGA carriers were found to prevent these particles from effectively adhering to activated endothelial cells in in vitro assays, an effect that was not observed for particles of other material types. Our results also show that the extent of the negative adhesion effect of plasma proteins on PLGA particles is dependent on specific blood donors and the targeting ligand density but not the targeting ligand type. Overall, the presented data suggests that specific knowledge of the plasma protein composition across different humans may be critical to VTC design and their successful clinical use, i.e., highlighting the need for a shift toward personalized medicine in the design of targeted therapeutics. Alternatively, it is possible that with a detailed understanding of the specific proteins that affect particle vascular targeting, novel biomaterials can be designed to resist the adsorption of these proteins in order to achieve enhanced vascular targeting irrespective of the plasma composition of different individuals.