280060 In Vivo Evaluation of Rod-Shaped Carriers for Vascular Imaging and Targeted Drug Delivery in Large Vessels in Mice

Tuesday, October 30, 2012: 9:24 AM
Westmoreland Central (Westin )
Alex Thompson1, Katawut Namdee2 and Omolola Eniola-Adefeso1, (1)Chemical Engineering, University of Michigan, Ann Arbor, MI, (2)Biomedical Engineering, University of Michigan, Ann Arbor, MI

Introduction: The development of vascular-targeted carriers (VTC) for the delivery of therapeutics could greatly improve the treatment of many human diseases. 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. 

Methods: For in vitro assays, rod-shaped and spherical particles were conjugated with targeting molecules to selectins (via Sialyl Lewis a) at a fixed surface density.  The differently shaped particles were tested for their margination efficiency from human blood flow both via parallel plate flow chambers with human endothelial cellsThe particles explored ranged in diameter from 0.5 – 2 μm (equivalent spherical diameter, ESD, for rods).  For in vivo analysis, particles co-conjugated with sLeA (ligands for selectin) and mouse VCAM-1 antibody (at a fixed surface density for all particle dimension) were injected via the tail vein into ApoE knockout mice with developed atherosclerosis. Particle binding efficiency was quantified along the aorta and biodistribution quantified in internal organs and blood as a function of particle size, particle shape and circulation time.  

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. 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. To further investigate this, nanoparticles (500 nm ESD) is fabricated which have relatively high major axis lengths (major axis≈6 μm). The adhesion of these rods from blood flow is compared to spheres to determine whether a long major axis can significantly improve nanoparticle binding

For in vivo assays, preliminary results suggest that particle size and shape play a significant role in particle binding efficiency in atherosclerotic mice. Specifically, 2 µm spherical particles showed higher adhesion to plaque surface in the aorta over 0.5 µm spheres in agreement with previous in vitro studies. Furthermore, ellipsoidal particles with aspect ratio (AR) 4 yielded higher adhesion in the aorta than 2 µm spheres, especially at the branch and bifurcation area where plaque were preferentially deposited.  However, longer rods with AR 9 displayed minimal adhesion along the aorta while exhibiting significant accumulation in the lung and other internal organs possibly due to the physical entrapment in the capillaries.  The biodistribution of particles after 30 min and 8 hr circulation times will also be discussed.  

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 medium and large blood vessels.

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