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Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

From the Harvard-MIT Division of Health Sciences and Technology (C.-W.H., E.R.E.), Massachusetts Institute of Technology, Cambridge, Mass; Cardiovascular Division, Department of Medicine (E.R.E.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Chao-Wei Hwang, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Room 16-343, 77 Massachusetts Ave, Cambridge, MA 02139. E-mail cwhwang{at}mit.edu

An incomplete understanding of the transport forces and local tissue structures that modulate drug distribution has hampered local pharmacotherapies in many organ systems. These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release. Local delivery produces tremendous drug concentration gradients and although these are in part derived from transport forces, differences in deposition from tissue to tissue imply that tissue ultrastructure also plays an important role. We measured the equilibrium drug uptake and the penetration and diffusivity of dextrans (a model hydrophilic drug similar to heparin) and albumin in orthogonal planes in arteries explanted from different vascular beds. We found significant variations in drug distribution with geometric orientation and arterial connective tissue content. Drug diffusivities parallel to the connective tissue sheaths were one to two orders of magnitude greater than across these sheaths. This diffusivity difference remained relatively constant for drugs up to 70 kDa before decreasing for larger drugs. Drugs also distributed better into elastic arteries, especially at lower molecular weights, with almost 66% greater transfer into the thoracic aorta than into the carotid artery. Arterial drug transport is thus highly anisotropic and dependent on arterial tissue content. The role of the local composition and geometric organization of arterial tissue in influencing vascular pharmacokinetics is likely to become a critical consideration for local vascular drug delivery.

Key Words: drug delivery • stent • ultrastructure • anisotropy • diffusion

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