Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

Abstract

Abstract-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.

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

“…For hydrophobic compounds, these layers act in a reverse fashion; the movement of paclitaxel and rapamycin is likely impeded by the more water-rich regions of the blood vessel wall and aided by lipid pools or even the protein-studded elastin lamina. In both cases, however, whereas individual layers might be isotropic, the greater composite of alternating layers of the arterial wall provide for planar diffusion that far exceeds transmural flux (3).…”

“…I t now appears that the success of drug-eluting stents is predicated to as great a degree upon the extent of drug deposition and distribution through the arterial wall as virtually any other factor (1)(2)(3)(4)(5). The biological effects of a candidate drug are essential, but, ultimately, tissue residence time will determine effect and toxicity (6,7).…”

Direct visualization of the arterial wall water permeability barrier using CARS microscopy

“…The nature of this water barrier has been an area of intense research interest because increases in arterial wall water permeability are associated with many diseases that affect the vasculature (1,2) such as acute shock (3), inflammatory conditions (4), and the aging process (5) as well as influencing drug pharmacodynamics (6). We have termed the arterial water permeation barrier the arterial hydro-seal.…”

<i>In vivo</i> tomographically diagnosing technique of early cancer using 2-color optical coherence dosigraphy

“…On the other hand, since in PDT three-dimensional distribution of remaining photosensitizer inside the lesion has to be measured, applying 2C-OCD will be contributed to facilitate the treatment effect. In addition to these applications, non-invasive and tomographic detection of photosensitizer accumulated in lesions using 2C-OCD will provide new insights for the mechanisms in expression and advance of the lesion as well as an assessment for drug delivery system (Hwang and Edelman, 2002). The utilities of 2C-OCD will be improved with development of phtosensitizers functional in higher near-infrared waveband based on rapidly developing nanotechnology.…”