Correlation of transarterial transport of various dextrans with their physicochemical properties

Elmalak, Omar; Lovich, Mark A.; Edelman, Elazer R.

doi:10.1016/s0142-9612(00)00152-6

Cited by 21 publications

(17 citation statements)

References 30 publications

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“…Charge, molecular weight, and drug partitioning determine the relative impact of convective versus diffusive forces on drug transport. 13,25 Compounds that partition significantly into tissues will have smaller low-drug regions, because these drugs would be less prone to both diffusive backwash into the endovascular space and convective washout into the perivascular space. Paclitaxel, rapamycin, and other drugs currently being considered for stent-based release partition extremely well into arterial tissues as a result of hydrophobic and vascular wall protein interactions.…”

Section: Concentration Gradients Depend On Drug Physicochemical Propementioning

confidence: 99%

Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery

2001

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Background-The first compounds considered for stent-based delivery, such as heparin, were chosen on the basis of promising tissue culture and animal experiments, and yet they have failed to stop restenosis clinically. More recent compounds, such as paclitaxel, are of a different sort, being hydrophobic in nature, and their effects after local release seem far more profound. This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of differences in biology or differences in physicochemical properties and targeting. Methods and Results-We applied continuum pharmacokinetics to examine the effects of transport forces and device geometry on the distribution of stent-delivered hydrophilic and hydrophobic drugs. We found that stent-based delivery invariably leads to large concentration gradients, with drug concentrations ranging from nil to several times the mean tissue concentration over a few micrometers. Concentration variations were a function of the Peclet number (Pe), the ratio of convective to diffusive forces. Although hydrophobic drugs exhibited greater variability than hydrophilic drugs, they achieved higher mean concentrations and remained closer to the intima. Inhomogeneous strut placement influenced hydrophilic drugs more negatively than hydrophobic drugs, dramatically affecting local concentrations without changing mean concentrations. Conclusions-Because local concentrations and gradients are inextricably linked to biological effect, our results provide a potential explanation for the variable success of stent-based delivery. We conclude that mere proximity of delivery devices to tissues does not ensure adequate targeting, because physiological transport forces cause local concentrations to deviate significantly from mean concentrations. (Circulation. 2001;104:600-605.)

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Section: Concentration Gradients Depend On Drug Physicochemical Propementioning

confidence: 99%

Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery

2001

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“…The endothelial layer was denuded by gently passing a small wire loop through the arterial lumen. 12 Arteries were positioned in a perfusion apparatus, which recirculates PBS 2ϩ with no transmural pressure. 16 A solution of 20 mg/mL 20-kDa FITCdextran was infused at 0.4 mL/h for 20 minutes by a syringe pump (Cole-Palmer 74900) through a blunt 5-L micropipette applied tightly against the external perivascular aspect of the arterial segment.…”

Section: Drug Infusion and Dispersionmentioning

confidence: 99%

“…Albumin is a carrier protein for hydrophobic drugs, 9 and dextran, structurally similar to heparin and readily available in a range of molecular weights, has widely served as a model hydrophilic drug. [12][13][14] We correlated transport properties of the drugs to connective tissue content, in large part elastin, and to geometric organization of the arteries and found significant variation in drug deposition and transport with tissue content and geometric orientation. Drugs distributed to a greater extent into more elastic compared with more muscular arteries, although this preferential distribution was less apparent above 70 kDa.…”

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confidence: 99%

“…4,12 We therefore sought to examine local vascular pharmacokinetics by specifically considering how drugs with defined physical characteristics would distribute in tissues of defined ultrastructural characteristics. We measured the equilibrium drug uptake and the penetration and diffusivity of dextrans (4 to 250 kDa) and albumin in different orthogonal planes in bovine arteries from different vascular beds.…”

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confidence: 99%

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Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

Hwang

Edelman

2002

Circulation Research

110

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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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“…Uptake of therapeutic agents by the arterial wall is dependent on diffusion and transendothelial permeability as well as the molecular weight, hydrophobic/hydrophilic balance, and electrostatic charge of the therapeutic. 37 Gases can be considered small molecules that can readily cross the endothelial barrier. 38 A further advantage of ultrasound-controlled local release is the radiation force effects that can enhance the recruitment of liposomes into the arterial wall.…”

mentioning

confidence: 99%

Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage

Kim¹,

Britton²,

Peng³

et al. 2013

IJN

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Delayed cerebral vasospasm following subarachnoid hemorrhage causes severe ischemic neurologic deficits leading to permanent neurologic dysfunction or death. Reduced intravascular and perivascular nitric oxide (NO) availability is a primary pathophysiology of cerebral vasospasm. In this study, we evaluated NO-loaded echogenic liposomes (NO-ELIP) for ultrasound-facilitated NO delivery to produce vasodilation for treatment of vasospasm following subarachnoid hemorrhage. We investigated the vasodilative effects of NO released from NO-ELIP both ex vivo and in vivo. Liposomes containing phospholipids and cholesterol were prepared, and NO was encapsulated. The encapsulation and release of NO from NO-ELIP were determined by the syringe/vacuum method and ultrasound imaging. The ex vivo vasodilative effect of NO-ELIP was investigated using rabbit carotid arteries. Arterial vasodilation was clearly observed with NO-ELIP exposed to Doppler ultrasound whereas there was little vasodilative effect without exposure to Doppler ultrasound in the presence of red blood cells. Penetration of NO into the arterial wall was determined by fluorescent microscopy. The vasodilative effects of intravenously administered NO-ELIP in vivo were determined in a rat subarachnoid hemorrhage model. NO-ELIP with ultrasound activation over the carotid artery demonstrated effective arterial vasodilation in vivo resulting in improved neurologic function. This novel methodology for ultrasound-controlled delivery of NO has the potential for therapeutic treatment of vasospasm following subarachnoid hemorrhage. This ultrasound-controlled release strategy provides a new avenue for targeted bioactive gas and therapeutic delivery for improved stroke treatment.

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Correlation of transarterial transport of various dextrans with their physicochemical properties

Cited by 21 publications

References 30 publications

Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery

Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery

Arterial Ultrastructure Influences Transport of Locally Delivered Drugs

Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage

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