Effect of variation in hemorheology between human and animal blood on the binding efficacy of vascular-targeted carriers.

K Namdee,M Carrasco-Teja,P Charoenphol,O Eniola-Adefeso,M B Fish

doi:10.1038/srep11631

Abstract

Animal models are extensively used to evaluate the in vivo functionality of novel drug delivery systems (DDS). However, many variations likely exist in vivo between the animals and human physiological environment that significantly alter results obtained with animal models relative to human system. To date, it is not clear if the variation in hemorheology and hemodynamics between common animal and human models affect the functionality of DDS. This study investigates the role of hemorheology of humans and various animal models in dictating the binding efficiency of model vascular-targeted carriers (VTCs) to the wall in physiological blood flows. Specifically, the adhesion of sLeA-coated nano- and micro-spheres to inflamed endothelial cells monolayers were conducted via a parallel plate flow chamber assay with steady and disturbed red blood cells (RBCs)-in-buffer and whole blood flows of common animal models. Our results suggest that the ratio of carrier size to RBC size dictate particle binding in blood flow. Additionally, the presence of white blood cells affects the trend of particle adhesion depending on the animal species. Overall, this work sheds light on some deviation in VTC vascular wall interaction results obtained with in vivo animal experimentation from expected outcome and efficiency in vivo in human.

Highlights

The discrepancy in the physiology between laboratory animals and human is likely in the evaluation of particulate drug delivery systems (DDS) where the identified differences in hemorheology and hemodynamics, including differences in blood shear rates, red blood cell (RBC) aggregation, and RBC geometry, may impact the distribution and performance of these systems/therapy
We evaluate the adhesion of inflammation-targeted polystyrene spheres in a parallel plate flow chamber (PPFC) to inflamed endothelial cells (ECs) from physiological flow of human, rabbit, pig and mouse RBCs-in-buffer and whole blood flow
Due to the many advantages gained from utilizing targeted drug delivery in the treatment of diseases, several research works have been focused on the design and engineering of the optimal vascular-targeted drug carriers (VTCs) for localizing potent therapeutics to a target site in several human diseases, including cancer and cardiovascular diseases

Summary

Introduction

The discrepancy in the physiology between laboratory animals and human is likely in the evaluation of particulate drug delivery systems (DDS) where the identified differences in hemorheology and hemodynamics, including differences in blood shear rates, RBC aggregation, and RBC geometry, may impact the distribution and performance of these systems/therapy. Small microparticles are shown to exhibit a high capacity to marginate (localize) and adhere to inflamed human ECs at the wall from human blood flow, while nanoparticles with sizes in the 100 to 500 nm diameter range exhibit limited margination. This observed size effect on the margination, and the subsequent adhesion, of particles is linked to the well-documented migration of RBCs away from the wall and alignment at the center of the flow, which creates a RBC-free layer, or cell free layer (CFL), near the wall. Our results show that the capacity of VTCs to bind to the vascular wall is significantly influenced by blood flow types and most importantly, RBC size

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