Computational simulations of local vascular heparin deposition and distribution

Lovich, Mark A.; Edelman, Elazer R.

doi:10.1152/ajpheart.1996.271.5.h2014

Cited by 51 publications

(57 citation statements)

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“…These findings have profound implications for vascular drug delivery because maintaining an appropriate drug distribution in the arterial wall on the scale of microns is requisite for effective delivery. 22 Unfortunately, tremendous drug concentration gradients are invariably established by transport forces such that drug concentrations in adjacent cells can differ significantly. 7 Our data suggest that these gradients might be further amplified by the heterogeneous arterial drug uptake characteristics.…”

Section: Hwang and Edelmanmentioning

confidence: 99%

Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

Hwang

Edelman

2002

Circulation Research

108

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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.

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Section: Hwang and Edelmanmentioning

confidence: 99%

Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

Hwang

Edelman

2002

Circulation Research

108

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“…Water-soluble drugs readily permeate into tissues, 9 and yet, the very processes that enable rapid equilibration and distribution also lead to rapid clearance. 5,10 As a result, there is increasing interest in less soluble, more hydrophobic compounds. Hydrophobic compounds are relatively insoluble in the aqueous phase, and tissue partitioning and retention are achieved by binding to available hydrophobic elements on fixed tissue sites.…”

mentioning

confidence: 99%

Arterial Paclitaxel Distribution and Deposition

Creel

Lovich

Edelman

2000

Circulation Research

242

188

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Abstract-Successful implementation of local arterial drug delivery requires transmural distribution of drug. The physicochemical properties of the applied compound, which govern its transport and tissue binding, become as important as the mode of delivery. Hydrophilic compounds distribute freely but are cleared rapidly. Hydrophobic drugs, insoluble in aqueous solutions, bind to fixed tissue elements, potentially prolonging tissue residence and biological effect. Paclitaxel is such a hydrophobic compound, with tremendous therapeutic potential against proliferative vascular disease. We hypothesized that the recent favorable preclinical data with this compound may derive in part from preferential tissue binding as a result of unique physicochemical properties. The arterial transport of paclitaxel was quantified through application ex vivo and measurement of the subsequent transmural distribution. Arterial paclitaxel deposition at equilibrium varied across the arterial wall and was everywhere greater in concentration than in the applied drug source. Permeation into the wall increased with time, from 15 minutes to 4 hours, and varied with the origin of delivery. In contrast to hydrophilic compounds, the concentration in tissue exceeds the applied concentration and the rate of transport was markedly slower. Furthermore, endovascular and perivascular paclitaxel application led to markedly differential deposition across the blood vessel wall. These data suggest that paclitaxel interacts with arterial tissue elements as it moves under the forces of diffusion and convection and can establish substantial partitioning and spatial gradients across the tissue.

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“…10,[22][23][24][25] Several groups have demonstrated the residence time 10,11 and antirestenotic effects 10,12-14 of particulate therapeutics. However, the local arterial pharmacokinet- …”

Section: Discussionmentioning

confidence: 99%

Formulation and Delivery Mode Affect Disposition and Activity of Tyrphostin-Loaded Nanoparticles in the Rat Carotid Model

Fishbein

Chorny

Banai

et al. 2001

ATVB

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Abstract-Poor drug residence in the arterial wall hinders clinical implementation of local drug delivery strategies for the treatment of restenosis. A rat carotid model of vascular injury and intraluminal delivery of tyrphostin-containing polylactic acid (PLA) nanoparticles (NPs) were used to determine the relationship between residence properties and biological activity of different formulations and administration modes. The effects of delivery modes (denudation and delivery time) and formulation variables (adsorbed vs encapsulated drug, and NP size) on arterial drug/NP retention were examined. Antirestenotic effects of large (160 nm) and small (90 nm) tyrphostin-containing NPs, surface-absorbed tyrphostin, and systemic treatment were compared. Fluorescent NPs were used to study the spatial distribution of the carrier in the arterial wall. The decrease in arterial tyrphostin level over time fitted a biexponential model. Delivery time and pressure, endothelium integrity, particle size, and drug-polymer association affected local pharmacokinetics and the antirestenotic results after 14 days. The PLA-based tyrphostin NP formulation ensured a prolonged drug residence at the angioplasty site after single intraluminal application. Several readily adjustable formulation and procedural factors considerably modified arterial ingress of the drug-loaded NPs and governed their subsequent redistribution, tissue binding, elimination, and ensuing antirestenotic effect.

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Computational simulations of local vascular heparin deposition and distribution

Cited by 51 publications

References 0 publications

Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

Arterial Paclitaxel Distribution and Deposition

Formulation and Delivery Mode Affect Disposition and Activity of Tyrphostin-Loaded Nanoparticles in the Rat Carotid Model

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