Particle-Blood Dynamics: Adhesion of Vascular-Targeted Pegylated Particles and Blood Cells in Flow.

Abstract

Vascular targeting is a viable strategy for the therapeutic intervention of inflammatory diseases such as cardiovascular disease. The multiple components of blood (red blood cell, leukocytes, platelets, and plasma) create a complex transport process for optimizing tissue specific targeting. Attaching poly(ethylene glycol) (PEG) spacers to a drug carrier’s surface (PEGylation) is often proposed as a strategy for avoiding systemic clearance by minimizing plasma protein adsorption onto the drug carrier. However, it is unclear as to whether PEGylation influences ligand-based tissue targeting in blood flow. Additionally, both platelets and leukocytes localize and interact with the vessel wall during inflammation. Little is known whether the presence of inflammation targeting drug carriers in blood or at the vessel wall influences the homeostatic interaction of leukocytes and platelets with the same targeted tissue. Here, I investigate the dynamics between the non-red cell components of blood and vascular targeted carriers; specifically, how PEGylation influences carrier adhesion in blood and whether inflammation targeting drug carriers affect leukocyte and platelet adhesion to the same targeted tissue. The addition of a 5.5 kDa or 10 kDa PEG spacer to a model drug carrier improved targeting to a model vessel wall in laminar human blood flow, but only for an unfavorable targeting system (aICAM-1/ICAM-1). While PEGylation was unable to neutralize a negative plasma effect on the adhesion of an actual drug delivery system (poly(lactic-co-glycolic) acid spheres) in human blood, a high PEG surface density maintained the adhesiveness of a model drug carrier in pig blood. Also, high blood concentrations of 500 nm-5 µm targeted spheres were found to reduce the adhesion of leukocytes to the same targeted tissue under high shear conditions, with nearly a 100% reduction in leukocyte adhesion with 5 µm and 3 µm targeted spheres. This work contributes to the design and application of targeted drug carriers by recommending a 5.5 kDa or 10 kDa PEG spacer for targeting high shear areas associated with cardiovascular disease and identifying a new application for inflammation targeting particles through reducing leukocyte accumulation to inflammatory tissue.