© 2000 American Heart Association, Inc.
Integrative Physiology |
Arterial Paclitaxel Distribution and Deposition
From the Harvard-MIT Division of Health Sciences and Technology (C.J.C., M.A.L., E.R.E.), Massachusetts Institute of Technology, Cambridge, and Cardiovascular Division, Department of Medicine (E.R.E.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Dr Elazer R. Edelman, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Room 16-343, 77 Massachusetts Ave, Cambridge, MA 02139. E-mail eedelman{at}mit.edu
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Abstract |
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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. The complexity of paclitaxel pharmacokinetics requires in-depth investigation if this drug is to reach its full clinical potential in proliferative vascular diseases.
Key Words: paclitaxel • local drug delivery • artery • pharmacokinetics • polymeric drug delivery
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Introduction |
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Local drug delivery to the arterial wall can be achieved either through catheter-mediated endovascular application or through surgically implanted perivascular release devices.1 2 3 Regardless of the interventional approach, the transfer of drug from a point of release to a target tissue relies on mechanisms of drug transport and binding such as diffusion, convection, and partitioning in and around target tissues.4 5 6 7 8 These mechanisms are heavily dependent on the physicochemical properties of the drug and the surrounding environment. For example, hydrophobicity or absolute charge can regulate transport and distribution of drug in and around arterial tissues. 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.9 Unlike hydrophilic drugs, hydrophobic compounds can possibly remain in and around target arterial tissues for some time after application. Whereas the diffusive and convective forces that drive these drugs across the blood vessel might adequately describe the fate of hydrophilic compounds,4 11 hydrophobic compounds may be subject to associative and dissociative events that evolve over time with fixed arterial elements, resulting in localization of drug in proximity to the delivery source. The complexity of the forces that govern the coupled transport and binding of hydrophobic drugs requires in-depth characterization before they might fully be used to achieve clinical goals.
Paclitaxel is such a hydrophobic compound with tremendous potential in proliferative vascular diseases,12 13 14 15 16 17 and its ultimate clinical use may depend on thorough characterization of these mechanisms.12 13 14 18 We hypothesized that the hydrophobic nature of paclitaxel would drastically alter its transport properties through the arterial parenchyma from that of hydrophilic vasoactive compounds, such as heparin. Furthermore, we hypothesized that hydrophobic interactions between paclitaxel and the arterial wall would result in differential drug distribution patterns dependent on the aspect of drug application. We tested these hypotheses by quantifying the transport of paclitaxel within arterial tissues in an ex vivo preparation that allowed application to either the inner endovascular surface or the outer perivascular aspect of the artery in the presence of a controlled physiological transmural pressure gradient.
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Materials and Methods |
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Equilibrium Deposition
We defined the affinities of different tissues within the arterial wall for paclitaxel by measuring drug distribution at equilibrium. Calf common carotid arteries were harvested and transported in PBS with physiological calcium and magnesium (PBS++, 0.01 mol/L CaCl2 and 0.01 mol/L MgCl2, Sigma) at 0°C. Arteries were opened longitudinally, cut into segments (190 to 260 mg), and placed in centrifuge tubes with 1.2 mL of [3H]paclitaxel (2.11 mCi/mg, dissolved in 100% ethanol, Amersham Life Sciences) in Krebs-Henseleit (KH) buffer (0.017, 0.024, 0.034, 0.065, 0.07, 0.086, and 0.195 mg/L) at 4°C for 72 hours. Preliminary data showed that paclitaxel uptake reaches equilibrium in these arteries in <72 hours (not shown). After incubation, 0.100-mL samples of the bulk fluid around each artery were removed and assayed for [3H]paclitaxel content through liquid scintillation spectroscopy (2500 TR Liquid Scintillation Analyzer, Packard-Canberra).
Transmural Distribution
Transmural arterial paclitaxel distribution was
measured at each concentration through en face cryosectioning in which
the arterial segments were sectioned parallel to the intima
with a refrigerated microtome (Cryotome SME, Shandon,
Inc).19 20 21 Segment length and width were measured with a
caliper, 0.020-mm thick sections were cut parallel to the intima, and
the [3H]paclitaxel content of each sample was
determined by liquid scintillation spectroscopy. Tissue concentration
at each transmural location was calculated as the mass of paclitaxel
normalized by the measured tissue area and slice thickness.
Ex Vivo Perfusion
Calf carotid arteries were perfused ex vivo in an
apparatus that simulated plasma flow and permitted
examination of paclitaxel distribution when applied endovascularly or
perivascularly.4 11 The in vitro perfusion
apparatus allows perfusate from an upper reservoir
to flow through 3 arteries in parallel before emptying into a lower
reservoir. The transmural pressure gradient was set by the relative
height, hydrostatic head (
H), of the upper reservoir. Three arteries
were immersed in a perivascular bath of KH buffer that was stirred and
maintained at 37°C. Arterial paclitaxel distribution with
endovascular or perivascular application of drug in KH buffer was
examined after 15 minutes, 1 hour, or 4 hours. The height of the upper
reservoir (H) was adjusted to 1200 mm, inducing a
physiological transmural pressure differential
(P) of 12 kPa (90 mm Hg). At regular intervals, 0.100 mL was
removed from the perivascular and endovascular compartments for
determination of [3H]paclitaxel concentrations
through liquid scintillation spectroscopy.
After each experiment, the artery between the cannulated ends was divided in 2, with 1 segment used for morphometric analysis and the remaining segment sectioned parallel to the intima, as described above. Total artery deposition was calculated as the sum of drug concentrations in all serial transmural sections normalized by the driving endovascular or perivascular concentration. Average artery deposition was calculated as the total drug deposition normalized by the total arterial volume. These values were compared using a Student t test in which P<0.05 indicated significant differences.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Equilibrium Tissue Incubation
Arterial samples were incubated in [3H]paclitaxel with KH buffer at several bulk concentrations (0.017 to 0.195 mg/L) for 72 hours at 4°C and sectioned en face to determine the equilibrium paclitaxel distribution. Partitioning (
), defined as the tissue concentration
(cT) at equilibrium normalized by the bulk
concentration (cBulk), was determined at
every location for each artery, as follows:
 | (1) |
). At every transmural location, the
tissue concentration of paclitaxel greatly exceeded the applied bulk
concentration, indicating significant partitioning, which
consistently varied with transmural location. By correlating
the spatial distribution with histological
arterial cross sections, we were able to ascribe the
partitioning of paclitaxel to specific tissue elements within the
arterial wall. Partitioning was maximal in the intima and
declined precipitously within the most intimal regions of the
arterial media to less than half the intimal level. At the
outer edge of the media, 
0.450 mm from the lumenal border, the
paclitaxel partitioning increased gradually and peaked within the
adventitia. The gradual decline in partitioning at the outer edge of
the adventitia likely corresponds to the nonuniform radial thickness of
this arterial layer seen on histological
sections.
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Endovascular and Perivascular Application
Arterial samples were perfused ex vivo for 15 minutes,
1 hour, or 4 hours with a physiological transmural
pressure gradient. Paclitaxel was applied to the endovascular or
perivascular aspect of the artery in KH buffer and drug distribution
determined through en face cryosectioning. Because of slight variations
in paclitaxel delivery concentration between experiments, tissue
concentrations were normalized by the applied concentration. Paclitaxel
distribution exhibited several common characteristics in all
experiments conducted. Permeation distance into, and concentration of
paclitaxel within, the artery increased with perfusion time for both
endovascular (Figure 2A) and perivascular
(Figure 2B) modes of delivery. Tissue concentrations were
maximal nearest the intima with endovascular application and in the
adventitia with perivascular application. The peak tissue
concentrations of paclitaxel offset from the perivascular delivery
source are an artifact of the uneven, jagged anatomy of the
adventitia. The distribution of paclitaxel at any location steadily
increased with time as well.
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During endovascular perfusion, paclitaxel was applied to the
arterial wall from the lumenal aspect. Tissue
concentrations in excess of 100-fold above perfusate
concentration were observed (Figure 2A
). Drug permeated
0.700 mm from the intima into the arterial wall
after 4 hours of perfusion. Total artery deposition increased with each
extension of the perfusion time (Figure 3). During perivascular perfusion,
paclitaxel was applied to the arterial wall from the
adventitial aspect. Maximum tissue concentrations 37-fold above
perfusate concentrations were seen (Figure 2B). Drug
permeated 0.580 mm from the outer adventitial border into the
arterial parenchyma after 4 hours of perfusion, and again,
the total tissue deposition increased as perfusion times were extended.
Total arterial deposition with endovascular application was
2.9- and 2.0-fold higher than perivascular delivery at 1 and 4 hours,
with P=0.04 and P=0.02, respectively. There was
no significant difference in whole-artery deposition between
perivascular and endovascular delivery at 15 minutes
(P>0.05).
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Effective Diffusivity Characterizes Arterial Transport
The effective diffusivity (Deff) was
estimated from the paclitaxel distribution data to facilitate
comparison of transport of paclitaxel through arterial
parenchyma with that of other vasoactive agents and to characterize the
disparity between endovascular and perivascular application of
drug.19 22 This transport parameter
describes the motion of drug in tissues given an applied concentration
gradient and includes, in addition to diffusion, the impact of steric
hindrance within the arterial interstitium; nonspecific
binding to arterial elements; and, in the preparation used
here, convective effects from the applied transmural pressure gradient.
For each paclitaxel distribution profile (Figure 2), the
permeation depth (lp) was calculated and
the effective diffusivity was estimated from the
following:19 22
 | (2) |
). These
computations provide a quantitative measure for additional comparison
of perivascular and endovascular application and allow us to contrast
the overall motion of the hydrophobic drug paclitaxel to prior
measurements from hydrophilic compounds.
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Discussion |
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Local delivery has special appeal for vascular diseases such as intimal hyperplasia, but it is rapidly becoming evident that drug potency is not the sole determinant of biological effect. For locally administered compounds to remain locally active, therapeutic drug concentrations at focal target sites must be created and sustained. Issues such as drug transport and binding in and around target tissues therefore become immensely important in local delivery and are to a great degree determined by drug-specific physicochemical properties. Hydrophobic drugs are relatively insoluble in the aqueous phase and bind to hydrophobic sites on fixed tissue elements. Association with tissue binding sites may impede the movement of drug across the arterial wall, localizing drug in arterial regions nearest the delivery source. We now demonstrate that the beneficial effects of paclitaxel at retarding post–vascular interventional intimal hyperplasia may stem in part from the physical properties of this compound and its interaction with tissue elements.
Paclitaxel Partitions Non-Uniformly Into Arteries
To characterize the affinity of different structures of the
arterial wall for paclitaxel, we measured
arterial drug distribution at equilibrium. Tissue
concentration at all locations in the arterial wall greatly
exceeded the applied bulk concentration (>>1, Figure 1), indicating that paclitaxel partitions, or binds to, elements
throughout the blood vessel wall. Partitioning was greatest in the
intima, followed by the adventitia and then the media, likely
reflecting differential densities of nonspecific hydrophobic binding
sites. Furthermore, although one might have anticipated a uniform
distribution of paclitaxel across the media, there was a gradient in
measured tissue paclitaxel and, by extrapolation, of hydrophobic
binding sites, extending inward from both the intima and
adventitia.
Kinetics of Arterial Paclitaxel Distribution
Arterial paclitaxel concentrations and permeation
depth increased with time after both endovascular and perivascular
application in KH buffer (Figure 2). In the absence of binding
or cellular internalization, drug localization should be confined to
interstitial void spaces, and one might expect tissue
concentration to be less than the applied, surrounding bath
concentration. Tissue paclitaxel concentration, however, greatly
exceeded the driving endovascular or perivascular concentration,
indicating that the vast majority of drug at any one instant is bound
to fixed hydrophobic binding sites. The small minority of unbound drug
in the void spaces is subject to transport by diffusive and convective
mechanisms. Each drug molecule that diffuses down its concentration
gradient, and simultaneously convects down the transmural
interstitial pressure gradient, can bind to fixed
arterial elements. In this manner, drug binding competes
with forward motion and distribution. Drug molecules resume diffusive
and convective motion only after dissociation from binding sites.
Hydrophobic drugs such as paclitaxel heavily partition into tissues,
and drug binding significantly slows transport, leading to large,
localized concentrations adjacent to sites of application.
The binding of hydrophobic drug to tissue elements is not
instantaneous. The most intimal slice of arterial media
should be in near-equilibrium with the applied endovascular source of
drug. The tissue concentration nearest the intima, however, increased
with time, indicating that partitioning evolves over hours (Figure 2A). The same phenomenon of slow progression to equilibrium
occurs with tissue concentration peaks in the outer adventitia
resulting from perivascular drug application. Clearly, drug binding and
localization is not only a function of position within the
arterial wall, but also a time-dependent process. Thus, the
distribution of paclitaxel reflects a complex combination of transport
and associative and dissociative events with nonhomogenous hydrophobic
binding sites throughout the arterial parenchyma.
Transport and Localization of Hydrophobic Versus Hydrophilic
Compounds
The important role hydrophobicity plays in
transarterial transport is further demonstrated by
comparing the average deposition of paclitaxel to that of a very
hydrophilic molecule, heparin. The average normalized tissue
concentration of paclitaxel 1 hour after perivascular and endovascular
application is compared with that of heparin obtained from a prior
study (Figure 4).11 The
average deposition for paclitaxel when compared with heparin is
19.4-fold higher after endovascular and 25.6-fold higher after
perivascular application. This increased deposition is the result of
the ability of paclitaxel to bind to many more nonspecific sites than
heparin. This binding allows the tissue concentration of hydrophobic
paclitaxel to exceed the applied concentration and indicates that the
volume of distribution within arteries is very large. In contrast, the
tissue levels of hydrophilic heparin cannot exceed that of the applied
medium, and, as a result, its volume of distribution within arteries is
low. Thus, the degree of hydrophobicity of a vasoactive drug affects
the extent to which it can be loaded into arteries.
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In addition to the maximal loading of tissues, the hydrophobicity of
vasoactive drugs impacts the rate at which compounds move through
tissues. In another previous study, we measured the diffusivity of
heparin in the arterial media to be
7.73x10–6
mm2/s.4 The estimates of the
effective diffusivity of paclitaxel in arteries ranged from
1.26x10–6 to
4.87x10–6 mm2/s in
the current study (Table). Note however, that the heparin
diffusivity measured in the prior study was in the absence of a
transmural pressure gradient, whereas in this study a
physiological pressure gradient was always
used.4 At each ending time point, the effective
diffusivity estimate from endovascular application exceeded that from
perivascular application (Table), as the convective and
diffusive forces are aligned in the former and opposed in the
latter.4 11 Thus, the effective diffusivities obtained
from endovascular application are overestimates and those from
perivascular delivery are underestimates. A reasonable measure of the
effective diffusivities of paclitaxel in the absence of convective
effects would be given by the average at each time (Table).
Thus, the diffusivity of heparin in arterial tissues is
more than double that of paclitaxel, despite the larger size of the
heparin molecule. Heparin has an average molecular weight of
14 000, and in the absence of binding should move almost
6-fold more slowly through tissues than the much smaller paclitaxel
(molecular weight 854).23 The strong, nonspecific binding
of the hydrophobic paclitaxel not only allows for larger concentrations
to amass in tissues when compared with hydrophilic compounds, but also
slows the transport of drug through the tissue as each molecule
repeatedly binds and dissociates in the process of diffusing down its
concentration gradient.
Perivascular Versus Endovascular Application
One of the fascinating aspects of paclitaxel distribution is that
the total tissue deposition (Figure 3) did not adequately
reflect the distribution of applied drug within the
arterial wall (Figures 2A and 2B). Total tissue
deposition was nearly 2-fold greater with endovascular than
perivascular application (Figure 3). This may well reflect the
synchronous effects of diffusive and convective forces when drug is
released from the endovascular space, and their opposition with
perivascular release. At the same time, however, the pattern of drug
deposition varied significantly across the wall, and was itself
dependent on the origin of drug administration (Figure 2).
Whereas drug applied from the endovascular space was principally
localized to the intima and inner media, perivascular release led to
the highest concentrations within the adventitia. These findings may be
of great clinical import. One might conclude endovascular application
to be more efficacious as a result of the physical forces that augment
drug transport through the arterial wall, for example, in
the presence of convective forces that arise from
physiological transmural pressure gradients. If the
preferential distribution of drug is considered, such thinking may need
to be revised. The spatial gradients in cellular and molecular effects
after vascular injury direct or localize specific tissue reactions to
particular vascular subcompartments and may require more tight
regulation of drug transport to or from these areas. Endovascular
delivery for events that are primarily adventitial may be as fruitless
as the perivascular delivery that localizes drug to the adventitia when
control of subendothelial phenomena is desired.
Paclitaxel Pharmacokinetics
Paclitaxel, derived from the bark of Taxus brevifolia
(Pacific yew),24 is a potent inhibitor of
cell proliferation principally because of its action on microtubule
formation.25 26 As paclitaxel is poorly soluble in water
(<0.01 mg/mL) and possesses no side groups that can be ionized in an
acceptable pH range,27 it has been suspended in vehicles
for solubilization. Successful cancer therapy clinical trials
administered paclitaxel suspended in 50% Cremophor EL (polyethoxylated
castor oil surfactant) and 50% dehydrated alcohol
(USP).28 29 30 31 32 33 34 The same physicochemical properties that
complicated systemic delivery of paclitaxel might improve retention of
locally delivered drug. Paclitaxel inhibits vascular smooth muscle cell
migration and proliferation, and it was proposed that this compound
might play role in the prevention of vascular
restenosis.12 14 Local delivery
devices35 36 37 38 can place drugs in direct contact with
target tissues, and yet studies utilizing these forms of paclitaxel
delivery have exhibited mixed results. Porous balloon catheter delivery
and coated stent release of paclitaxel decreased postangioplasty
intimal hyperplasia in rat, rabbit, and porcine
models.13 14 15 16 17 Similar studies initially concluding
prevention of neointima formation in rabbits after balloon
angioplasty12 were later shown to be statistically
unfounded.18 These studies clearly demonstrate that
experimental results from any ex vivo or animal model must be
considered in the context of the experiment in which they were
obtained. Positive results for human in vivo studies with paclitaxel
have yet to be conclusively demonstrated.
Discrepancies between animal model results and the absence of conclusive human in vivo studies compel examination of drug delivery issues. The disparate conclusions regarding the in vivo efficacy of paclitaxel might well be appreciated with an in-depth understanding of the physical forces that govern transport of this drug across the arterial wall. For example, in vivo evidence suggesting that the rate of release impacts the efficacy of paclitaxel16 may also be explained by the rate of intra-arterial binding and subsequent region of deposition rather than an extra-arterial mechanism. By understanding the phenomena behind the transport of paclitaxel across the arterial wall, we may rationally and efficiently approach the local delivery dilemma and perhaps develop fundamental principles applicable to a wide array of local delivery scenarios.
Summary
The common understanding that paclitaxel is an insoluble compound
is only a small part of its pharmacokinetic profile. Our data indicate
that the interaction between this compound and the blood vessel wall,
as governed by the physicochemical characteristics of the drug itself,
impart unique transport qualities to this drug. Paclitaxel moves
through arterial tissue subject to diffusive and convective
forces, but binding to hydrophobic sites within arterial
tissues dominates the localization and transport. Association with
hydrophobic binding sites takes time to evolve and serves to impede
forward movement of drug through the arterial wall. Perhaps
as a byproduct of this impedance, the surface of the blood vessel
from which drug delivery originates determines arterial
distribution. Although we have used paclitaxel as a model hydrophobic
compound, these illuminated principles and mechanisms should be
applicable to other compounds possessing similar physicochemical
properties and may ultimately help in the rational design and clinical
utility of effective local drug delivery systems.
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Acknowledgments |
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This study was supported in part by grants from the NIH (GM/HL 49039 and HL 60407), the Burroughs-Wellcome Fund in Experimental Therapeutics, the Whitaker Foundation in Biomedical Engineering, and the Stanley J. Sarnoff Endowment for Cardiovascular Science. We are grateful for the assistance of Angiotech Pharmaceuticals, Inc, and for the technical help of Kristy Hong. E.R.E. is an Established Investigator of the American Heart Association.
Received January 6, 2000; accepted February 22, 2000.
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  B. E. Stahli, G. G. Camici, and F. C. Tanner Drug-eluting stent thrombosis Therapeutic Advances in Cardiovascular Disease, February 1, 2009; 3(1): 45 - 52. [Abstract] [PDF]
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 N. M M Pires, D. Eefting, M. R de Vries, P. H A Quax, and J W. Jukema Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries Heart, August 1, 2007; 93(8): 922 - 927. [Abstract] [Full Text] [PDF]
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 J.-B. Michel, O. Thaunat, X. Houard, O. Meilhac, G. Caligiuri, and A. Nicoletti Topological Determinants and Consequences of Adventitial Responses to Arterial Wall Injury Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1259 - 1268. [Abstract] [Full Text] [PDF]
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 A. R. Goriely, A. L. Baldwin, and T. W. Secomb Transient diffusion of albumin in aortic walls: effects of binding to medial elastin layers Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2195 - H2201. [Abstract] [Full Text] [PDF]
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 G. J. Murphy, T. W. Johnson, M. H. Chamberlain, S. I. Rizvi, M. Wyatt, S. J. George, G. D. Angelini, K. R. Karsch, M. Oberhoff, and A. C. Newby Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts Cardiovasc Res, February 1, 2007; 73(3): 607 - 617. [Abstract] [Full Text] [PDF]
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 B. Kelly, M. Melhem, J. Zhang, G. Kasting, J. Li, M. Krishnamoorthy, S. Heffelfinger, S. Rudich, P. Desai, and P. Roy-Chaudhury Perivascular paclitaxel wraps block arteriovenous graft stenosis in a pig model Nephrol. Dial. Transplant., September 1, 2006; 21(9): 2425 - 2431. [Abstract] [Full Text] [PDF]
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 B. E. Stahli, G. G. Camici, J. Steffel, A. Akhmedov, K. Shojaati, M. Graber, T. F. Luscher, and F. C. Tanner Paclitaxel Enhances Thrombin-Induced Endothelial Tissue Factor Expression via c-Jun Terminal NH2 Kinase Activation Circ. Res., July 21, 2006; 99(2): 149 - 155. [Abstract] [Full Text] [PDF]
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N. M.M. Pires, A. Schepers, B. L. van der Hoeven, M. R. de Vries, L. S.M. Boesten, J. W. Jukema, and P. H.A. Quax Histopathologic alterations following local delivery of dexamethasone to inhibit restenosis in murine arteries Cardiovasc Res, December 1, 2005; 68(3): 415 - 424. [Abstract] [Full Text] [PDF]
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 J. J. Nawarskas and L. A. Osborn Paclitaxel-eluting stents in coronary artery disease Am. J. Health Syst. Pharm., November 1, 2005; 62(21): 2241 - 2251. [Abstract] [Full Text] [PDF]
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 C.-W. Hwang, A. D. Levin, M. Jonas, P. H. Li, and E. R. Edelman Thrombosis Modulates Arterial Drug Distribution for Drug-Eluting Stents Circulation, April 5, 2005; 111(13): 1619 - 1626. [Abstract] [Full Text] [PDF]
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B. Scheller, U. Speck, C. Abramjuk, U. Bernhardt, M. Bohm, and G. Nickenig Paclitaxel Balloon Coating, a Novel Method for Prevention and Therapy of Restenosis Circulation, August 17, 2004; 110(7): 810 - 814. [Abstract] [Full Text] [PDF]
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 A. D. Levin, N. Vukmirovic, C.-W. Hwang, and E. R. Edelman Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel PNAS, June 22, 2004; 101(25): 9463 - 9467. [Abstract] [Full Text] [PDF]
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 B. Scheller, U. Speck, A. Schmitt, M. Bohm, and G. Nickenig Addition of paclitaxel to contrast media prevents restenosis after coronary stent implantation J. Am. Coll. Cardiol., October 15, 2003; 42(8): 1415 - 1420. [Abstract] [Full Text] [PDF]
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 B. Scheller, U. Speck, B. Romeike, A. Schmitt, M. Sovak, M. Bohm, and H.-P. Stoll Contrast media as carriers for local drug delivery: Successful inhibition of neointimal proliferation in the porcine coronary stent model Eur. Heart J., August 1, 2003; 24(15): 1462 - 1467. [Abstract] [Full Text] [PDF]
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A. Finkelstein, D. McClean, S. Kar, K. Takizawa, K. Varghese, N. Baek, K. Park, M. C. Fishbein, R. Makkar, F. Litvack, et al. Local Drug Delivery via a Coronary Stent With Programmable Release Pharmacokinetics Circulation, February 11, 2003; 107(5): 777 - 784. [Abstract] [Full Text] [PDF]
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R. Virmani, F. Liistro, G. Stankovic, C. Di Mario, M. Montorfano, A. Farb, F. D. Kolodgie, and A. Colombo Mechanism of Late In-Stent Restenosis After Implantation of a Paclitaxel Derivate-Eluting Polymer Stent System in Humans Circulation, November 19, 2002; 106(21): 2649 - 2651. [Abstract] [Full Text] [PDF]
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F. D. Kolodgie, M. John, C. Khurana, A. Farb, P. S. Wilson, E. Acampado, N. Desai, P. Soon-Shiong, and R. Virmani Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel Circulation, September 3, 2002; 106(10): 1195 - 1198. [Abstract] [Full Text] [PDF]
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C.-W. Hwang and E. R. Edelman Arterial Ultrastructure Influences Transport of Locally Delivered Drugs Circ. Res., April 19, 2002; 90(7): 826 - 832. [Abstract] [Full Text] [PDF]
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 D. S. Schrump, S. Zhai, D. M. Nguyen, T. S. Weiser, B. A. Fisher, R. E. Terrill, B. M. Flynn, P. H. Duray, and W. D. Figg Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques J. Thorac. Cardiovasc. Surg., April 1, 2002; 123(4): 686 - 694. [Abstract] [Full Text] [PDF]
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S. Yasuda, T. Noguchi, M. Gohda, T. Arai, N. Tsutsui, Y. Nakayama, T. Matsuda, and H. Nonogi Local delivery of low-dose docetaxel, a novel microtubule polymerizing agent, reduces neointimal hyperplasia in a balloon-injured rabbit iliac artery model Cardiovasc Res, February 1, 2002; 53(2): 481 - 486. [Abstract] [Full Text] [PDF]
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C.-W. Hwang, D. Wu, and E. R. Edelman Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery Circulation, July 31, 2001; 104(5): 600 - 605. [Abstract] [Full Text] [PDF]
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C.-W. Hwang and E. R. Edelman Arterial Ultrastructure Influences Transport of Locally Delivered Drugs Circ. Res., April 19, 2002; 90(7): 826 - 832. [Abstract] [Full Text] [PDF]
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