(584e) Hemodynamics-Driven Design of Carriers for Imaging and Drug Delivery In Atherosclerosis

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The development of vascular-targeted carriers (VTC) for the delivery of therapeutics could greatly improve the treatment of many human diseases.  Spherical nanoparticles are commonly used as potential drug carriers due to their ability to easily navigate microvasculature and ease of fabrication/drug loading.  However, recent literature has shown that spherical nanoparticles do not efficiently marginate and adhere to the vascular wall in medium/large blood vessels (M/LBV) compared to larger micron sized particles.¹  Therefore spherical nanoparticles may not be effective in treating diseases which occur in M/LBV, such as atherosclerosis.  Recently, particle shape has received attention as a parameter that can be used to improve the performance of VTCs.  The purpose of this study is to examine the hemodynamics of rod-shaped particles of different aspect ratios relative to spheres of equal volume both in vitro in human blood flow under physiological conditions relevant in M/LBVs and in vivo in a mouse model of atherosclerosis.

Materials and Methods:  Polystyrene rod-shaped particles were fabricated via a polymer film stretch method previously described in literature.²   Selectin-targeted (via Sialyl Lewis ^a) spheres and rods at a fixed concentration were mixed with RBC and saline flow buffer, and allowed to flow over a layer of IL-1β activated human umbilical vein endothelial cells (HUVEC) using a parallel plate flow chamber.  The number of adherent particles under various flow conditions was imaged/quantified using brightfield and fluorescence microscopy.  The particles explored ranged in diameter from 0.5 – 5 μm (equivalent spherical diameter, ESD, for rods).

Results and Discussion:  With in vitro assays we find that rod shaped particles with ESD >2 µm have a higher binding efficiency to HUVEC monolayer at the wall from bulk human blood flow than spheres of equivalent volume and targeting ligand site density.  The folds increase in the adhesion of rods over spheres increased both with increasing blood shear rate and increasing particle aspect ratio. Overall, the observed flow adhesion pattern for micron-sized rods was due to a combination of both a higher affinity (localization) of rods for the vascular wall, as well as an increased ability of rods to resist detachment from the vascular wall due to its streamlined shape.  Interestingly, there appears to be a minimum major axis length requirement for rods with ESD <2µm to display a significant increase in flow adhesion over their equivalent spheres.  Result from in vivo assays in mice show that rods have significantly higher localization to plaque surface in the aorta compare to nanospheres.  

Conclusions:  Our study shows that shape can be a very useful and tunable parameter in the design of vascular-targeted carriers for imaging and treatment of atherosclerosis and other diseases of M/LBVs.   

References: 

¹  Charoenphol et al.  Biomaterials (2010) vol 31, 1392-1402. 

² Ho et al.  Colloid Polym Sci (1993) vol 271 n 5, 469-479.