© 2001 American Heart Association, Inc.
Vascular Biology |
Polylysine as a Vehicle for Extracellular Matrix–Targeted Local Drug Delivery, Providing High Accumulation and Long-Term Retention Within the Vascular Wall
From the Gaubius Laboratory (D.V.S., A.F.H.J., M.E.A.B., J.J.E., D.C.R.), TNO Prevention and Health, Leiden, and the Institute for Cardiovascular Research (D.V.S.), Vrije Universiteit, Amsterdam, the Netherlands.
Correspondence to Dr D.V. Sakharov, Gaubius Laboratory, TNO Prevention and Health, PO Box 2215, 2301 CE Leiden, Netherlands. E-mail DV.Sakharov@pg.tno.nl or DC.Rijken{at}pg.tno.nl
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Abstract—We present the first steps in the elaboration of an approach of extracellular matrix–targeted local drug delivery (ECM-LDD), designed to provide a high concentration, ubiquitous distribution, and long-term retention of a drug within the vessel wall after local intravascular delivery. The approach is based on the concept of a bifunctional drug comprising a "therapeutic effector" and an "affinity vehicle," which should bind to an abundant component of the vessel wall. The aim of the present study was to select molecules suitable for the role of affinity vehicles for ECM-LDD and to study their intravascular delivery and retention ex vivo and in an animal model. By use of fluorescence microscopy, the following molecules were selected on the basis of strong binding to cross sections of human vessels: protamine, polylysine, polyarginine, a glycosaminoglycan-binding peptide from vitronectin, and a synthetic dendrimer. With polylysine as a prototypic affinity vehicle, we showed that after intravascular delivery, polylysine was concentrated throughout a luminal layer of the vascular wall to an extremely high concentration of 20 g/L and was retained therein for at least 72 hours of perfusion without noticeable losses. Low molecular weight (fluorescein) and high molecular weight (hirudin) compounds could be chemically conjugated to polylysine and were retained in the vessel wall after intravascular delivery of the conjugates. In conclusion, by use of the ECM-LDD method, an extremely high concentration and long-term retention of locally delivered drug can be reached. Polycationic molecules can be considered as potential affinity vehicles for ECM-LDD.
Key Words: local drug delivery • restenosis • polylysine • hirudin • extracellular matrix
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Introduction |
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Local drug delivery (LDD) is a useful approach for treating many localized pathologies. The concentration of systemically administered drugs is often limited by side effects of the drug. With LDD, a much higher local concentration of a drug in the site of pathology can be achieved. Treatment/prevention of restenosis after coronary angioplasty is currently one of the most tantalizing targets for intravascular LDD. A number of sophisticated catheter-based devices have been developed to maximize the efficiency of intravascular LDD; some of these devices do not obstruct the blood flow and, therefore, allow prolonged local delivery.1 The major problem of the intravascular drug delivery is that after being delivered to the site of pathology, the drug may be washed out from the site of delivery rather rapidly, over minutes to hours.1 2 Even if the drug interacts with the cells within the vascular wall, only a small fraction of the locally delivered drug would be caught up by the cells; the rest would be rapidly washed away. The fraction of the drug taken up by the cells may be either internalized or shed from the cellular membrane within hours or, at most, days. It would be desirable to keep a drug at the site of potential restenosis for a longer period of time, because restenosis is a long process, the initial phase of which takes a few weeks, and final changes develop after a few months.1 3
Incorporation of the drug into microparticles or hydrogels with slow (controlled) drug release is suggested as an approach for prolonging drug retention. However, the vessel wall appears to be an anatomic barrier to microparticle delivery; the particles penetrate poorly into the vascular wall and are found mostly in the vasa vasorum and dissections within the intima after angioplasty.4 A variant of controlled drug release is endoluminal paving with a drug-containing hydrogel.5 In this technique, the storage of the drug (hydrogel coating) is also located next to the target tissue but is not in it; thus, the drug, after being released from the hydrogel compartment, must penetrate the neighboring vascular tissue. Simulations show that this technique prolongs the intravascular presence of the drugs from minutes to hours, but not longer.6
Besides LDD, another alternative to systemic drug treatment is cell-targeted drug delivery. In this approach, focused mostly on the treatment of cancer,7 a systemically administered drug, endowed with an affinity to a pathology-specific epitope exposed on the cells, is supposed to find the site of pathology and concentrate there as a result of binding to these epitopes. The approach is most attractive for the cases in which the location of pathology is not precisely known and the local delivery of the drug is not possible. Normally, a highly specific antibody should be generated to ensure the specific delivery of the drug to the targeted cell population in the presence of a great excess of irrelevant tissue epitopes. No reliable restenosis-specific epitopes have been identified as yet, so nowadays, this approach is not applicable to the prevention/treatment of restenosis.
In the present study, we report a novel approach of extracellular matrix (ECM)-directed local drug delivery (ECM-LDD), designed to provide a long-term retention of a highly concentrated drug within the target tissue after local delivery. The method is based on a concept of local delivery of a bifunctional drug comprising an anti-restenotic effector moiety and an "affinity vehicle" moiety capable of anchoring and retaining the drug within the ECM of the vessel wall. A principal feature of the approach, which distinguishes it from other drug-targeting and LDD systems, is that not pathology-specific epitopes but abundant structural components of tissue are used as a molecular target. Because such components are present throughout the tissue at high concentrations, the tissue would be used as a high capacity support for accumulating a high concentration of the drug.
In the present study, we describe a selection of molecules potentially suitable for the role of affinity vehicle within the aforementioned ECM-LDD approach.
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Methods |
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Materials
Fluorescein isothiocyanate (FITC), fluorescein-5-maleimide, tetramethylrhodamine-5(6)-isothiocyanate (TRITC), N-succinimidyl S-acetylthioacetate (SATA), and N-(
-maleimidocaproyloxy)-
succinimide ester (EMCS) were from Pierce.
Poly-L-lysine and
poly-L-arginine of
different molecular weights, ranging from 3000 to 99 000, as well as
lactoferrin and bovine albumin were obtained from Sigma
Chemical Co. Protamine was from Kabi, and Starburst (PAMAM) dendrimer
(generation 4) was from Aldrich. A peptide GRRRGGGRG-amide
containing a consensus sequence for binding to
glycosaminoglycans
(GAGs)8 9 and the
GAG-binding 14-mer peptide from vitronectin with the
sequence KKQRFRHRNRKGYR (kindly provided by Dr K. Preissner, Institute
of Biochemistry,
Germany)10 were both
synthesized with an additional cysteine on the N-terminus. The
fluorescence-labeled GAG-binding peptide from Aß-amyloid
(1-40) was kindly supplied by Dr C. Glabe, University of California,
Irvine,11 and lipoprotein
lipase from bovine milk was provided by Dr L. Havekes, Gaubius
Laboratory, Leiden, The Netherlands. Hirudin (Refludan) was purchased
from Hoechst Marion Roussel; bovine thrombin was from
Akzo.
Labeling of Proteins and Peptides With
Fluorescein Derivatives
The candidate affinity vehicles (except for the
GAG-binding peptide from vitronectin and the peptide
containing the consensus sequence for GAG binding) at concentrations of
2 to 4 mg/mL in a buffer containing 30 mmol/L sodium bicarbonate
and 140 mmol/L NaCl, pH 9.2, were incubated for 1 hour in the dark
with FITC at a final concentration of 60 µmol/L. The preparations
were then gel-filtered into saline buffered with 20 mmol/L
Tris-HCl (TBS), pH 7.5. Thrombin was labeled with TRITC in a similar
manner. The GAG-binding peptide from vitronectin and the
consensus peptide were synthesized with an additional cysteine at the
N-terminus for labeling with fluorescein-5-maleimide. The
peptides at 0.5 mmol/L in TBS, containing 1 mmol/L EDTA, were
incubated with fluorescein-5-maleimide at 0.5 mmol/L
for 1 hour, blocked with 5 mmol/L
N-ethylmaleimide, and separated
from unbound fluorescein by gel filtration into
TBS.
Selection of Candidate Affinity Vehicles:
Binding to Cross Sections of Blood Vessels
The fluorescein-labeled candidate
affinity vehicles at a concentration of 30 µg/mL in human citrated
plasma were incubated with 8 µm fresh-frozen sections of human aorta
for 1 hour at room temperature, and binding was assessed by using a
fluorescence microscope.
Ex Vivo Intravascular Delivery of
FITC-Polylysine Into Human Umbilical Artery
One end of a 2-cm piece of human umbilical artery was
secured on a plastic tube connected to a syringe equipped with a
manometer. To remove any remaining blood, the vessel was rinsed with a
few milliliters of TBS and pumped through with a few milliliters of
air. Then it was rinsed with 200 µL of human citrated plasma
containing 0.5 mg/mL FITC-polylysine. The open end of the vessel was
ligated, and the same plasma with FITC-polylysine was pumped in with a
syringe and kept under pressure of 0.35 atm for 30 minutes. Then the
ligation was removed, and the vessel was perfused with TBS at 10
mL/min. After the desired time periods, pieces of the distal part of
the vessel (
0.7 cm long) were cut off and snap-frozen in liquid
nitrogen. A similar experiment was performed with FITC-labeled BSA.
Cross sections (8 µm) of the vessel were dried and viewed under a
fluorescence microscope.
In order to quantify the local concentration of FITC-polylysine bound within the luminal layer, 20-µm cross sections of the umbilical artery were prepared, and the bound FITC-polylysine was eluted from it with TBS, to which NaCl had been added to a final concentration of 2 mol/L. The amount of fluorescence in the eluate was measured with an LS50B spectrofluorometer (Perkin-Elmer), and the amount of eluted FITC-polylysine was determined by using a calibration curve obtained with dilutions of FITC-polylysine. The local concentration of bound FITC-polylysine was calculated as the ratio of the amount of eluted FITC-polylysine and the volume of the saturated layer of the section. The volume was calculated as a product of the thickness of the section, the perimeter of the vessel, and the depth of the layer saturated with polylysine. The experiment was performed in triplicate. At least 4 sections from each of the 3 vessels were used for FITC-polylysine quantification.
In Vivo Intravascular Delivery of
FITC-Polylysine Into a Segment of Rat Carotid Artery
Male Wistar rats were anesthetized with
pentobarbital sodium (Nembutal) and Hypnorm (0.315 mg fentanyl
citrate and 10 mg fluanisone per milliliter), and a 1-cm segment of a
common carotid artery was separated with atraumatic vascular clamps,
freed of blood through a catheter introduced via the inner carotid
artery, and washed with saline buffered with 20 mmol/L HEPES, pH
7.5. Then the segment was filled with either FITC-polylysine (99 kDa)
or FITC-albumin, both at a concentration of 1 mg/mL in the same
buffer, and incubated for 20 minutes under a pressure of 0.35 atm (the
pressure was limited by the strength of the clamps and was severalfold
lower than the pressure achievable in intravascular
catheters12 ). Then the tip
of the catheter was removed, and the bloodstream was restored. The rats
were euthanized after timed intervals ranging from 15 minutes to 72
hours. The treated segments of the carotid arteries were removed and
snap-frozen. The fluorescence retained was assessed with a
fluorescence microscope and 8-µm frozen cross sections. Some
of the frozen pieces of the vessels were thawed and fixed in ice-cold
10% formalin, paraffinized, and sectioned for
histological staining with
hematoxylin-phloxine-saffron.
Conjugation of Polylysine With Hirudin
The heterobifunctional cross-linking agent EMCS was
used for conjugation of polylysine with recombinant hirudin. Hirudin
(Mr
7000) at 1 mg/mL was first incubated with 1.5 mmol/L SATA for 1
hour to introduce protected sulfhydryl (SH) groups into the
hirudin molecule, and unreacted SATA was removed by gel filtration.
Polylysine (99 kDa) at 1 mg/mL was incubated for 1 hour with 1.5
mmol/L EMCS to introduce SH-reactive maleimide groups into polylysine.
After removal of free EMCS from the polylysine solution (gel
filtration) and deprotection of SH groups in SATA-hirudin (incubation
with 0.5 mol/L hydroxylamine HCl for 2 hours, according to a Pierce
protocol), the 2 solutions were mixed at a molar ratio of 10:1
(hirudin:polylysine) and incubated for 1.5 hours, and cysteine was
added to a final concentration of 30 mmol/L to block reactive
groups. The hirudin-polylysine conjugate was separated from free
hirudin on a column with CM-Sepharose, which was equilibrated with a
50 mmol/L phosphate buffer containing 50 mmol/L NaCl, pH 7.5.
Free hirudin passed through, whereas the conjugate was eluted with a
phosphate buffer containing 1.3 mol/L NaCl and dialyzed into saline
buffered with 20 mmol/L HEPES, pH 7.5. The hirudin activity test
showed that 30% of hirudin was conjugated with polylysine. Thus,
3 hirudin molecules were conjugated to each polylysine
molecule.
Ex Vivo Intravascular Delivery of
Hirudin-Polylysine Into Rat Carotid Artery
A segment (1.5 cm) of the common carotid artery
was removed from an anesthetized rat and kept for 12 to 18
hours in cell culture medium at 4°C before the experiment. The
polylysine-hirudin conjugate at a concentration 1 mg/mL was delivered
into such a segment by using the technique and conditions described
above for human umbilical arteries. The segments of the arteries were
then perfused with TBS for 20 minutes and frozen, and 8-µm cross
sections were prepared. The sections were washed for 20 minutes with
several changes of TBS containing 20 mg/mL BSA (TBS-BSA) and incubated
with TRITC-thrombin at 10 µg/mL in TBS-BSA for 30 minutes. After the
unbound fluorescence was washed away, the distribution of bound
TRITC-thrombin was documented with the fluorescence
microscope.
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Results |
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Selection of Potential Affinity Vehicles: Binding to Cross Sections of Human Aorta
To select molecules suitable for the role of affinity vehicle for ECM-targeted LDD, we studied the binding of a number of candidate molecules to fresh-frozen sections of human aorta. Incubation with the sections was performed in the presence of human plasma to imitate the conditions of delivery in vivo. The following molecules were included in the study on the basis of their known GAG-binding properties: protamine sulfate, a peptide with a consensus sequence for binding to glycosaminoglycans,8 lactoferrin,13 lipoprotein lipase,14 a GAG-binding peptide from Aß-amyloid,15 and a GAG-binding peptide from vitronectin.10 Polylysine and polyarginine of various molecular weights and Starburst dendrimer were included in the screening as well, because their strong positive charge suggests that they could also bind to vascular GAGs. Of the molecules tested, only a few showed a strong binding: namely, protamine sulfate, Figure 1A
; polylysine (29, 52, and 99 kDa), shown in
Figure 1B for polylysine 99 kDa; polyarginine (11 kDa), not
shown; a GAG-binding peptide from vitronectin,
Figure 1C; and the Starburst dendrimer,
Figure 1D. These molecules bound to all parts of the vessel
wall, although the patterns of their staining showed certain
difference. Polylysine of 10 kDa showed a somewhat weaker binding (not
shown), whereas high molecular weight polyarginine (92 kDa) caused
protein aggregation in plasma. The other molecules tested did not bind
to the sections: namely, the peptide with a consensus sequence for
binding to glycosaminoglycans, lactoferrin,
lipoprotein lipase, a GAG-binding peptide from Aß-amyloid, polylysine
with a molecular weight of 3000 (not shown), and albumin
(Figure 1E).
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Further experiments reported in the present study were performed with polylysine with a molecular weight of 99 000, because this molecule showed the most uniform staining of the sections.
Delivery and Retention of Affinity Vehicle
Within Human Umbilical Artery Wall Ex Vivo
Human umbilical artery was used as a simple ex vivo
model of a middle-sized human artery to study intravascular delivery
and retention of polylysine. After 30 minutes of delivery under
pressure, FITC-polylysine was accumulated in a sharply visible luminal
layer of 80 µm depth
(Figure 2A). The bound material was not washed out noticeably
after 72 hours of perfusion
(Figure 2B). In contrast, FITC-BSA did not accumulate
significantly in the vessel wall and was completely washed out after 1
hour
(Figure 2C).
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To estimate the local concentration of FITC-polylysine bound within the luminal layer, the bound material was eluted from 20-µm-thick sections with a buffer containing 2 mol/L NaCl. The greater part of the fluorescence was removed from the cross section as a result of such elution. Amounts of FITC-polylysine in the range of 140 to 260 ng were eluted from the sections with a standard variation between different sections within the same vessel not >6% (n=4). The volumes of the fluorescence-bearing areas ranged from 7 to 10 nL. On the basis of 3 independent experiments, the concentration of the bound polylysine within the stained area was calculated as 21.9±3.8 g/L (n=3).
Delivery and Retention of Affinity Vehicle in
Wall of Rat Carotid Artery In Vivo
After intravascular delivery in vivo into a rat carotid
artery and restoration of the blood flow through the vessel, bound
FITC-polylysine was found throughout the vessel wall
(Figure 3A). After 24 hours and 72 hours
(Figure 3B and 3C, respectively), a significant part of
originally bound fluorescence could still be found throughout
the vessel wall. In contrast, FITC-albumin was mostly washed
away in 90 minutes
(Figure 3D). Histological examination of the
sections of rat carotid arteries removed 24 hours
(Figure 3E and 3F) and 72 hours (not shown) after delivery of
FITC-polylysine or FITC-albumin revealed neither significant
changes in the morphology of the vessel wall nor signs of inflammation,
immune response, or thrombosis. The state of the
endothelium was not ideal in either
FITC-polylysine–treated or FITC-albumin–treated vessels,
probably as a consequence of the intravascular intervention or of the
freezing and thawing of the vessels before they were embedded in
paraffin.
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Delivery of Hirudin Into Rat Carotid Artery
Ex Vivo
Figure 4 shows that hirudin coupled to polylysine can be
found within a luminal layer of the artery after intravascular delivery
ex vivo. Staining with TRITC-labeled thrombin was used to visualize the
distribution of the bound hirudin within the vessel wall and to
demonstrate that bound hirudin was still functional. The penetration of
the conjugate into the vascular wall was somewhat restricted compared
with that of polylysine
(Figure 3A
), supposedly because of the larger molecular size
of the conjugate. If a mixture of the 2 unconjugated components
(hirudin and polylysine) was delivered into the vessel wall in a
similar manner, almost no binding of TRITC-thrombin to the cross
sections was observed (not shown).
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Discussion |
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In the present study, we describe a novel approach in drug delivery, ECM-LDD. The major idea behind this approach, distinguishing it from other drug-targeting and LDD methods, is that structural extracellular components of tissue are used as a high-capacity support capable of accumulating a high concentration of the drug. The bifunctional drug, comprising an affinity vehicle and a "therapeutic effector" moiety, is delivered under pressure into a target tissue and is retained by binding of the affinity vehicle to an abundant and ubiquitous component(s) of the ECM, providing long-term retention of the drug in the locus of pathology. The most interesting application of the approach is, obviously, prevention/treatment of restenosis. Therefore, the present study is focused on the application of ECM-LDD to intravascular delivery.
An important feature of the ECM-LDD is that the affinity vehicle does not have to show pathology-specific binding, because the drug would be directed to the desired site not by site/pathology-specific molecular recognition but by local delivery under pressure via an intravascular catheter. Strong binding of the affinity vehicle to the target component(s) and also the abundant and ubiquitous presence of the target component(s) within the vascular wall are seen as essential requirements for the successful realization of the ECM-LDD approach.
The present study is focused on a selection of potential affinity vehicles that meet these requirements and on a characterization of their local intravascular delivery and retention. Molecular targets for ECM-directed delivery are the major proteins of the vascular ECM (eg, collagen, laminin, elastin, and fibronectin) and GAGs. Vascular GAGs are distributed throughout all layers of the vessel wall rather ubiquitously16 and, therefore, represent an attractive target for drug delivery. We screened a number of molecules with known GAG-binding properties, as well as a few positively charged molecules, which might bind to the negatively charged GAGs.
Selection
Of a number of compounds screened, a few showed
significant binding to cross sections of human aorta in the presence of
plasma. Polylysine with an
Mr of
29 000 showed the most even and ubiquitous binding in this assay
and, therefore, was used in further experiments. A number of other
molecules, such as protamine, the GAG-binding peptide from
vitronectin, and a Starburst dendrimer, were also positive
in the selection assay and are currently being studied in more detail.
The rest of the molecules did not bind to the sections, although on the
basis of the data from the literature, binding might have been
expected. Among them are the short peptide with a consensus sequence
for GAG binding.8 The lack of
binding of such peptides is consistent with the recent data by
Verrecchio et al,17 who
report that 3- and 4-mers of such peptides, but not monomers and
dimers, show strong binding to GAGs.
Characterization
With polylysine as a model affinity vehicle, we made
the following observations, important for characterizing this method of
drug delivery: (1) After intravascular delivery under pressure, bound
polylysine is found in a luminal layer at a depth of a few 10s of
micrometers. In small vessels (as rat carotid artery), this
results in saturation of the whole depth of the vessel wall; in larger
vessels (as human umbilical artery), only a part of the vessel is
saturated with bound polylysine. (2) Within the said layer, bound
polylysine is distributed evenly and ubiquitously, showing no
preferential staining of any particular structures. Such distribution
is consistent with the hypothesis that polylysine binds mostly
to GAGs, which are present throughout the vascular wall. (3) On
binding within the luminal layer, polylysine concentrates up to 20 g/L.
This gives an estimate of the concentration of the drug that can be
delivered and retained in the vascular wall using the method of
ECM-LDD. (4) Polylysine bound within the luminal layer of the vessel
wall is retained for at least days ex vivo under perfusion conditions
and in vivo after restoration of the blood flow.
All these observations are consistent with the idea that the binding sites within the luminal layer of the vascular wall become saturated with polylysine as a result of strong binding and that the layer, saturated with polylysine, slowly extends along with pressure/diffusion-driven influx of polylysine from the lumen. Polylysine concentrates within this layer because of a high concentration of the binding sites.
An important implication of the aforementioned observations is that in addition to increased retention, the ECM-LDD method may increase the efficiency of local delivery, ie, the fraction of the substance that leaves the catheter and is deposited in the vessel wall. In practice, this value is generally <1%.1 Because of strong binding to the ECM, polylysine molecules entering the vascular wall appear to be captured therein and, therefore, are prevented from escaping to the systemic circulation. It has been shown recently that the efficiency of intramural delivery of platelet-derived growth factor18 and tissue factor pathway inhibitor,12 which both have moderate binding properties toward the extracellular matrix, is somewhat higher than that of nonbinding proteins. However, the saturation-like profile has not been observed in the case of platelet-derived growth factor, probably because the binding was not strong enough. Tissue factor pathway inhibitor was mostly found next to the luminal surface. How strong binding to ECM (eg, in the case of polylysine) affects the efficiency of catheter-based intravascular delivery is a subject of our further study. We are also studying in a greater detail how the concentration of bound affinity vehicle, the depth of its penetration into the vascular wall, and retention are affected by properties of the affinity vehicle (size, charge, and affinity) and those of the target component (concentration and accessibility of the binding sites) as well as by the variables of local delivery (pressure and duration) and the state of endothelium.
Accessibility of the subendothelial ECM is an important condition for realization of the ECM-LDD. In the case of anti-restenosis treatment, the method is supposed to be used in situations in which the endothelium is either destroyed or damaged by ballooning and preexisting atherosclerosis. In the present study, we did not physically remove the endothelium (although it could be damaged, because in all experiments a certain amount of air was bubbled through the vessels, and the vessels used in ex vivo experiments were stored for certain time at 4°C before the experiments). Still, this did not prevent accumulation of polylysine within the vessel wall, suggesting that the method can potentially be used also in situations in which the endothelium is not fully removed. This is consistent with the data showing that endothelium represents only a relative barrier for the transport of macromolecules,19 reducing transmural transport of middle-sized proteins 4- to 7-fold12 20 and that the transendothelial transport of proteins increases severalfold as a result of pressure application.21
In the present study, we have demonstrated that the example affinity vehicle (polylysine) can deliver either a small molecule (fluorescein) or a relatively large biologically active polypeptide (hirudin) to the ECM of the vascular wall. Thus, in general, low molecular weight compounds and proteins/enzymes can be tested in the future as therapeutic effectors within the ECM-LDD approach. The list of potential therapeutic effectors includes anticoagulants, antiplatelet drugs, cytostatics, cytoskeletal inhibitors, proapoptotic effectors, vasorelaxants, and other substances considered as potential anti-restenotic drugs for systemic or local administration. Depending on the desirable mode of action (eg, extracellular or intracellular), the therapeutic effector may be attached to the affinity vehicle either through a stable or an unstable link, respectively, providing, in the latter case, a controlled release of the drug inside the vascular wall.
The
Table
summarizes important features of the existing variants of drug
administration compared with the ECM-LDD method. It is to be hoped that
this method will open new perspectives in intravascular drug delivery,
because it provides a combination of extremely high local
concentration, uniform and ubiquitous distribution, and long-term
intravascular retention of the drug, apparently unachievable with other
methods.
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Acknowledgments |
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This study was supported by grant 98.134 from the Netherlands Heart Foundation.
Received December 27, 2000; accepted February 1, 2001.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Brieger D,
Topol E. Local delivery systems and prevention of restenosis.
Cardiovasc Res. 1997;35:405–413.
[Free Full Text] - Fram DB, Aretz T, Azrin MA, Mitchel JF, Samady H, Gillam LD, Sahatijan R, Waters D, McKay RG. Localized intramural drug delivery during balloon angioplasty using hydrogel-coated balloons and pressure-augmented diffusion. J Am Coll Cardiol. 1994;23:1570–1577.[Abstract]
- Lefkovits J, Topol EJ. Pharmacological approaches for prevention of restenosis after percutaneous coronary intervention. Prog Cardiovasc Dis. 1997;40:141–158.[Medline] [Order article via Infotrieve]
- Nasser TK, Wilensky RL, Mehdi K, March KL. Microparticle deposition in periarterial microvasculature and intraluminal dissections after porous balloon delivery into atherosclerotic vessels. Am Heart J. 1996;131:892–898.[Medline] [Order article via Infotrieve]
- Slepian MJ. Polymeric endoluminal gel paving: therapeutic hydrogel barriers and sustained drug delivery depots for local arterial wall biomanipulation. Semin Interv Cardiol. 1996;1:103–116.[Medline] [Order article via Infotrieve]
-
Lovich MA, Edelman
ER. Computational simulations of local vascular heparin deposition and
distribution. Am J
Physiol. 1996;271:H2014–H2024.
[Abstract/Free Full Text] - Hudson PJ. Recombinant antibody constructs in cancer therapy. Curr Opin Immunol. 1999;11:548–557.[Medline] [Order article via Infotrieve]
-
Cardin AD,
Weintraub HIR. Molecular modeling of
protein-glycosaminoglycans interactions.
Arteriosclerosis. 1989;9:21–32.
[Abstract/Free Full Text] - Fromm JM, Hileman RE, Caldwell EEO, Weiler JM, Linhardt RJ. Pattern and spacing of basic amino acids in heparin-binding sites. Arch Biochem Biophys. 1997;343:92–100.[Medline] [Order article via Infotrieve]
- Rosenblatt S, Bassuk JA, Alpers CE, Sage EH, Timpl R, Preissner KT. Differential modulation of cell adhesion by interaction between adhesive and counter-adhesive proteins: characterization of the binding of vitronectin to osteonectin (BM40, SPARC). Biochem J. 1997;324:311–319.
-
Garzon-Rodriguez
W, Sepulveda-Becerra M, Milton S, Glabe CG. Soluble amyloid Aß-(1-40)
exists as a stable dimer at low concentrations.
J Biol Chem. 1997;272:21037–21044.
[Abstract/Free Full Text] - Yang L,-Y, St Pierre J, Scherrer DE, Lasala JM, Walsh RG, Abendschein DR. Comparison of methods of local delivery of tissue factor pathway inhibitor to balloon-injured arteries in rabbits. Coron Artery Dis. 1999;10:327–333.[Medline] [Order article via Infotrieve]
-
Mann DM, Romm E,
Migliorini M. Delineation of
glycosaminoglycan-binding site in the human
inflammatory response protein lactoferrin.
J Biol Chem. 1994;269:23661–23667.
[Abstract/Free Full Text] - Margelin D, Pigier AM, Gardette J, Bertrand J, Vu-Dac N, Picard J. Evidence for an interaction of lipoprotein lipase with artery wall proteoglycans. Int J Biochem. 1989;21:761–768.[Medline] [Order article via Infotrieve]
- Snow AD, Kinsella MD, Parks E, Sekiguchi RT, Miller JD, Kimata K, Wight TN. Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin, and versican) to the beta-amyloid protein of Alzheimer’s disease. Arch Biochem Biophys. 1995;320:84–95.[Medline] [Order article via Infotrieve]
-
Wight TN. Cell
biology of arterial proteoglycans.
Arteriosclerosis. 1989;9:1–20.
[Abstract/Free Full Text] -
Verrecchio A,
Germann MW, Schick BP, Kung B, Twardowski T, San Antonio JD. Design of
peptides with high affinities for heparin and
endothelial cell proteoglycans.
J Biol Chem. 2000;275:7701–7707.
[Abstract/Free Full Text] - Wilensky RL, Mehdi K, Sowinski KM, Baek SH, March KL. Increased intramural retention after local delivery of molecules with increased binding properties. J Cardiovasc Pharmacol Ther. 1999;4:103–112.
-
Chobanian AV,
Menzoian JO, Shipman J, Heath K, Haudenschild CC. Effects of
endothelial denudation and cholesterol
feeding on in vivo transport of albumin, glucose, and water
across rabbit carotid artery. Circ
Res. 1983;53:805–814.
[Abstract/Free Full Text] -
Fry DL, Haupt MW,
Pap JM. Effect of endothelial integrity, transmural
pressure, and time on the intimal-medial uptake of serum
125I-albumin and
125I-LDL in an in vitro porcine
arterial organ-support system.
Arterioscler Thromb. 1992;12:1313–1328.
[Abstract/Free Full Text] -
Curmi PA, Juan L,
Tedgui A. Effect of transmural pressure on low density lipoprotein and
albumin transport and distribution across the intact
arterial wall. Circ
Res. 1990;66:1692–1702.
[Abstract/Free Full Text]
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