Role of Carrier Size, Hemodynamics and Hemorheology in the Efficacy of Vascular-Targeted Spherical Drug Carriers.

Abstract

Spherical polymeric particles in the submicron down to tens nanometers size range are extensively proposed for use as vascular-targeted drug carriers (VTDCs); however, very limited studies have explored their capacity to efficiently localize and adhere to the vascular wall. The studies presented in this dissertation are focused on characterizing the role of particle size, blood flow dynamics (hemodynamics) and blood cells (hemorheology) on dictating the targeting (localization and binding) efficiency of VTDCs at the vascular wall in physiological human bulk blood flow via in vitro parallel plate flow assays. The presented results show that the binding efficiency of VTDCs is a function of particle size in all flow types (i.e. laminar, pulsatile and recirculating flow) and is strongly modulated by the presence of red blood cells (RBCs). Specifically, the migration of RBCs away from the wall under shear flow creating the RBC-free layer (CFL) at the wall vicinity where leukocytes and microspheres are disproportionally concentrated whereas nanospheres tend to get trapped within the RBC core. The binding of localized particle is either enhanced or hindered depending on the ratio of particle size to the CFL width that can vary with the volume fraction of RBCs (% Hct), blood vessel size and wall shear rate. White blood cells (WBCs) tend to hinder microsphere binding due to their collision with bound particles associated with their tethering on the vascular wall, which increases the drag force on particles leading to particle removal. Overall, the presented results suggest that intermediate-size microspheres, 2–5 micrometers, not nanospheres or large microspheres, are the optimal particle sizes for targeting the wall from human blood flow in medium to large-sized blood vessels relevant in several cardiovascular diseases. The relevance of the presented in vitro results were valid with ex vivo model of mouse blood where it is found that the subtle differences in RBC sizes and hemorheology among various animal models utilized in drug delivery research can differently manipulate the particle dynamics and their eventual adhesion in blood flow; thus, raising the awareness of possible result deviation from animal models to human.Ph.D.Chemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91589/1/phapanin_1.pd