U.S. patent application number 10/718580 was filed with the patent office on 2007-02-08 for stents with a radioactive surface coating, processes for their production and their use for restenosis prophylaxis.
Invention is credited to Friedhelm Blume, Ludger Dinkelborg, Stephan Duda, Heidemarie Goerner, Dieter Heldmann, Christoph-Stephan Hilger, Heribert Miklautz, Ulrich Niedballa, Bernhard Noll, Johannes Platzek, Ulrich Speck, Gunnar Tepe.
Application Number | 20070032694 10/718580 |
Document ID | / |
Family ID | 27545066 |
Filed Date | 2007-02-08 |
United States Patent
Application |
20070032694 |
Kind Code |
A1 |
Dinkelborg; Ludger ; et
al. |
February 8, 2007 |
STENTS WITH A RADIOACTIVE SURFACE COATING, PROCESSES FOR THEIR
PRODUCTION AND THEIR USE FOR RESTENOSIS PROPHYLAXIS
Abstract
The invention relates to radioactive stents, characterized in
that the stent is coated on the surface with the radioactive
isotope, as well as processes for their production.
Inventors: |
Dinkelborg; Ludger; (Berlin,
DE) ; Blume; Friedhelm; (Berlin, DE) ; Hilger;
Christoph-Stephan; (Berlin, DE) ; Heldmann;
Dieter; (Berlin, DE) ; Platzek; Johannes;
(Berlin, DE) ; Niedballa; Ulrich; (Berlin, DE)
; Miklautz; Heribert; (Berlin, DE) ; Speck;
Ulrich; (Berlin, DE) ; Duda; Stephan;
(Tuebingen, DE) ; Tepe; Gunnar; (Wankheim, DE)
; Noll; Bernhard; (Freital, DE) ; Goerner;
Heidemarie; (Dresden, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
27545066 |
Appl. No.: |
10/718580 |
Filed: |
November 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09627321 |
Jul 27, 2000 |
6709693 |
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10718580 |
Nov 24, 2003 |
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09403924 |
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PCT/EP98/02527 |
Apr 29, 1998 |
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09627321 |
Jul 27, 2000 |
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Current U.S.
Class: |
600/3 ;
427/2.24 |
Current CPC
Class: |
A61F 2/82 20130101; A61L
31/16 20130101; A61L 2300/44 20130101; A61N 5/1002 20130101; A61L
2300/416 20130101; A61L 31/14 20130101; A61L 31/18 20130101; A61L
31/082 20130101; A61K 51/1282 20130101; A61L 2300/606 20130101;
A61F 2210/0095 20130101 |
Class at
Publication: |
600/003 ;
427/002.24 |
International
Class: |
A61N 5/00 20060101
A61N005/00; A61L 33/00 20060101 A61L033/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 30, 1997 |
DE |
197 18 342.5 |
Apr 30, 1997 |
DE |
197 18 341.7 |
Apr 30, 1997 |
DE |
197 18 340.9 |
Jun 3, 1997 |
DE |
197 24 223.5 |
Jun 3, 1997 |
DE |
197 24 229.4 |
Jun 3, 1997 |
DE |
197 24 230.8 |
Claims
1-9. (canceled)
10. A radioactive stent comprising a radioactive isotope that is
fixed on the surface of the stent by an adhesive that is solely a
peptide, or a peptide bound to a radioactive isotope complexing
agent, a fat bound to a radioactive isotope complexing agent, or
gold bound to a thiol-group-containing radioactive isotope
complexing agent.
11. A radioactive stent according to claim 10, wherein the
radioactive isotope is one or more of Ag, Au, Ba, Bi, C, Co, Cr,
Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh,
Ru, S, Sb, Sc, Sm, Th, Tc or Y.
12. A radioactive stent according to claim 10, wherein the adhesive
is a peptide.
13. A radioactive stent according to claim 10, wherein the adhesive
is a peptide bound to a radioactive isotope complexing agent.
14-28. (canceled)
29. A radioactive stent according to claim 10, wherein the adhesive
is gold bound to a thiol-group-containing radioactive isotope
complexing agent.
30. A radioactive stent according to claim 10, wherein the adhesive
is a fat bound to a radioactive isotope complexing agent.
31. A radioactive stent comprising a radioactive isotope that is
fixed on the surface of the stent by an adhesive consisting
essentially of a peptide, or a peptide bound to a radioactive
isotope complexing agent, a fat bound to a radioactive isotope
complexing agent, or gold bound to a thiol-group-containing
radioactive isotope complexing agent.
Description
[0001] The invention relates to stents with a radioactive surface
coating, processes for their production and their use for
restenosis prophylaxis.
PRIOR ART
[0002] Radioactive stents are prior art (EP 0433011, WO 94/26205,
U.S. Pat. No. 5,176,617). Stents are endoprostheses that make it
possible to keep open duct-like structures in the bodies of humans
or animals (e.g., vascular, esophageal, tracheal and bile duct
stents). They are used as palliative measures in the case of
stenoses by obstruction (e.g., arteriosclerosis) or external
pressure (e.g., in the case of tumors). Radioactive stents are
used, for example, after vascular-surgery interventions or
radiological interventions (e.g., balloon angioplasty) for
restenosis prophylaxis. Such radioactive stents can be produced,
for example, by activation of a non-radioactive stent using
irradiation with protons or deuterons from a cyclotron (WO
94/26205). This process for the production of radioactive stents is
named ion implantation.
[0003] There is now the problem that, on the one hand, generally no
cyclotron is available at the site of the use of the stent to
undertake an activation of the stent, and, on the other hand, the
activated stent cannot be stored indefinitely or transported in any
arbitrary way due to the sometimes short half-life of the activated
isotope and for reasons of protection against radiation.
[0004] The object of this invention is therefore to make available
stents and new processes for their production, and said stents can
be activated independently by a cyclotron. In particular, the
object of the invention is to make available stents that can be
coated independently by a cyclotron with a preselected radioactive
isotope.
[0005] This object is achieved by the stents that are described
below and the processes for their production, as they are
characterized in the claims.
DESCRIPTION OF THE INVENTION
[0006] The above-described object is achieved by the production
processes for radioactive stents that are described below. In
contrast to ion implantation, the processes according to the
invention for the production of radioactive stents are based on
chemical or electrochemical methods.
[0007] Within the framework of this application, the notations
.sup.nnX and X-nn (X: element symbol, nn: mass number) are to be
regarded as synonymous for radioactive isotopes (Example:
.sup.110Ag corresponds to Ag-110).
[0008] The above-described object is achieved in a first variant by
a process for the production of a radioactive stent, in which a
chemical deposition of the radioactive isotope is carried out on
the stent.
[0009] To this end, the selected stent is immersed in a solution
that contains the radioactive isotope. The radioactive isotope is
then chemically deposited on the stent. Depending on the selected
material of the stent, on the one hand, and the radioactive isotope
that is to be deposited, on the other hand, two possible types of
deposition are considered:
1) Chemical Reduction
[0010] During chemical reduction, a reducing agent (e.g.,
SnCl.sub.2, KBH.sub.4, dimethylborane, formaldehyde, sodium
hypophosphite) is added to the solution that contains the
radioactive isotope in dissolved form as well as the stent.
[0011] Survey: M.sup.2++2e.sup.- (from the reducing
agent).fwdarw.catalytic surface.fwdarw.M.sup.0
[0012] Reducing Agent Hypophosphite (with Ni)
H.sub.2PO.sub.2.sup.-+H.sub.2O.fwdarw.catalytic
surface.fwdarw.HPO.sub.3.sup.2-+2H.sup.++H.sup.-
2H.sup.-+Ni.sup.2+.fwdarw.Ni H.sub.2 [0013] Addition of citrate,
acetate, fluoride, succinate, lactate, propionate [0014]
pH=4-11
[0015] Reducing Agent NaBH.sub.4 (with Au, Ni)
BH.sub.4.sup.-+H.sub.2O.fwdarw.BH.sub.3OH.sup.-+H.sub.2
BH.sub.3OH.sup.-+3Au(CN).sub.2.sup.-+3OH.sup.-.fwdarw.catalytic
surface.fwdarw.BO.sub.2.sup.-+1.5H.sub.2+3
Au.sup.0+6CN.sup.-+2H.sub.2O
2Ni.sup.2++NaBH.sub.4+2H.sub.2O.fwdarw.catalytic
surface.fwdarw.2Ni.sup.0+2H.sub.2+4H.sup.++NaBO.sub.2 [0016]
Additions of dimethylammonium borane, boric acid, citric acid,
malonic acid, glycine, pyrophosphate, malic acid, [0017]
pH=4-10
[0018] Reducing Agent Formaldehyde: (with Cu) Cu.sup.2++2
HCOH+4OH.sup.-.fwdarw.catalytic
surface.fwdarw.Cu.sup.0+H.sub.2+2H.sub.2O+2HCOO.sup.- [0019] with
the addition of NaKtartrate, NaOH
[0020] Reducing Agent Hydrazine: (with Pd, Pt) [0021] Pd, Pt with
the addition of NH.sub.4OH, EDTA,
[0022] Reducing Agent Dimethylaminoborane
(CH.sub.3).sub.2NH--BH.sub.3 (with Au, Ag)
(CH.sub.3).sub.2NH--BH.sub.3+OH--.fwdarw.catalytic
surface.fwdarw.BH.sub.3OH.sup.-+(CH.sub.3).sub.2NH [0023] Au and Ag
from cyanidic baths
[0024] After 1 minute to 10 hours, the stent is removed from the
respective solution and washed. The stent is coated on the surface
with the radioactive isotope.
[0025] In this way, for example, radioisotopes of elements Ag, Au,
Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm,
Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal
stents (e.g., steel, nitinol).
[0026] 2) Chemical Precipitation
[0027] During chemical precipitation, a precipitating agent (e.g.,
oxalic acid, phosphoric acid or salts thereof or Na.sub.2CO.sub.3)
is added to the solution that contains the radioactive isotope in
dissolved form as well as the stent.
[0028] In this way, for example, radioisotopes of elements Ag, Au,
Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt,
Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal stents
(e.g., steel, nitinol).
[0029] The above-described object is achieved in a second variant,
in that the radioactive isotope is secured by means of an adhesive
to the surface of the stent.
[0030] The device according to the invention thus consists of the
metal parent substance of the stent, an adhesive on the surface of
the stent and an adhesive radioactive isotope.
[0031] As a parent substance, the commercially available vascular
implants can be used, e.g., a Wiktor stent, a Strecker stent or a
Palmaz-Schatz stent.
[0032] As adhesives, peptides, fats or gold in combination with a
thiol-group-containing complexing agent are used.
[0033] It is thus possible, for example, to use modified
polyurethanes that in turn contain complexing agents.
[0034] As adhesives, however, peptides can also be used that on the
one hand carry a complexing agent and on the other hand bind
specifically to the metal of the stent. Examples of these compounds
are labeled endothelin derivatives, as they are described in, e.g.,
EP 606683, DE 4425778, DE 43 37 600, DE 4337599 and DE 19652374
(e.g.,
Tc-99m-Asp-Gly-Gly-Cys-Gly-Cys-Phe-(Dr-Trp)-Leu-Asp-Ile-Ile-Trp).
[0035] As adhesives, fats that carry a complexing agent can also be
used. Examples of this are the complexing agents that carry
lipophilic radicals and that are mentioned in DE 43 40 809, EP
450742, EP 438206, EP 413405 or WO 96/26182.
[0036] Moreover, gold in combination with a thiol-group-containing
complexing agent can also be used as an adhesive. It is known that
thiol-group-containing compounds show an increased affinity to
gold-coated surfaces (H. Schonherr et al. J. Am. Chem. Soc. 118
(1996), 13051-13057). Surprisingly enough, elementary gold that is
on the surface of the stent is also able to secure specific
complexing agents, if they have thiol groups. The complexing agents
in turn secure the radioactive isotopes.
[0037] For the purposes of this document, complexing agents are,
e.g., DTPA, DOTA, DO3A, EDTA, TTHA, MAG.sub.2-amides,
MAG.sub.3-amides and derivatives thereof.
[0038] As radioactive isotopes, the radioactive isotopes of
elements Ag, Au, Ba, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu,
Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, S, Sb, Sc, Sm, Tb, Tc or Y
can be used.
[0039] The invention therefore relates to radioactive stents,
characterized in that the radioactive isotope is secured to the
surface of the stent by means of an adhesive.
[0040] The stents according to the invention can be produced as
follows by way of example:
[0041] A. Peptide as an Adhesive [0042] A.1 First, a peptide is
selected that for its part is able to complex heavy metal ions. The
latter is activated by reaction with the radioactive isotope (e.g.,
.sup.186Re or .sup.188Re) optionally together with a reducing
agent. The radiolabled peptide is dissolved in a solvent (e.g.,
water, phosphate buffer), and the stent is immersed in the peptide
solution. After the stent is removed from the peptide solution, it
is dried in a drying chamber at room temperature. After the stent
is washed, the latter is ready for use. [0043] A.2 In a variant of
the process, the uncoated stent is first coated with the
non-activated peptide. The thus coated stent is then immersed in a
solution that contains the radioactive metal (e.g., .sup.186Re or
.sup.188Re) optionally together with a reducing agent (e.g.,
SnCl.sub.2) and thus is charged with this isotope. After the stent
is washed, the latter is ready for use.
[0044] B. Fat as an Adhesive [0045] B.1 An uncoated stent is first
coated with a lipophilic compound (e.g.,
3,9-bis(carboxymethyl)-6-bis(octadecyl)-aminocarbonylmethyl-3,6,9-triazau-
ndecanedioic acid, WO 96/26182) as an adhesive. This lipophilic
compound carries a DTPA radical as a complexing agent. The stent
can be directly immersed in the compound or a solution thereof.
After the stent is coated with the compound, it is mixed with a
solution of the radioactive metal (e.g. .sup.90YCl.sub.3). After
the stent is washed, the latter is ready for use. [0046] B.2 In a
variant of this process, the coating of the stent is carried out in
two stages. In this regard, the stent is first treated with a
lipophilic compound that carries amino groups. The amino groups are
then reacted with DTPA-monoanhydride, as it is described in the
literature. The stent now has a coating that carries the complexing
agents (here: DTPA). The stent that is coated in this way is then
mixed with a solution of radioactive metal (e.g. .sup.90YCl.sub.3).
After the stent is washed, the latter is ready for use.
[0047] C. Gold/Thiol-Group-Containing Complexing Agents as
Adhesives [0048] C.1. An uncoated stent is first coated
electrochemically with elementary gold (by internal electrolysis,
cementation). The gold-coated stent is then immersed in an aqueous
solution of a thiol-group-containing complexing agent (e.g.,
N,N-dimethyl-2-(3,3,5,11,13,13-hexamethyl-1,2-dithia-5,8,11-triazacyclotr-
idecan-8-yl)-ethylamine or the coupling product of
11-amino-undecyl-1-thiol with DTPA-bis-anhydride). The
thiol-group-containing complexing agent adheres to the gold-coated
stent. The stent that is prepared in such a way is now mixed with a
solution of the radioactive metal (e.g., .sup.67CuSO.sub.4). After
the stent is washed, the latter is ready for use. [0049] The
complexing agent can be synthesized on the surface of the stent. It
is possible to apply first only one component of the complexing
agent to the gold-coated stent and then to couple this component
with additional partial units. This procedure is described in
detail in the examples. [0050] C.2 In a variant of this process,
the gold-coated stent is mixed with a solution of the
thiol-group-containing complexing agent, which for its part already
complexes a radioactive isotope. After the stent is washed, the
latter is ready for use. [0051] C.3 In a variant of this process,
the gold-coated stent is mixed with a solution of the
thiol-group-containing compound, which in turn contains .sup.35S.
After the stent is washed, the latter is ready for use. [0052] C.4
In another variant of this process, the gold-coated stent is mixed
with a solution of the thiol-group-containing complexing agent,
whereby the thiol group is labeled with .sup.35S, and the
complexing agent already complexes a radioactive isotope (e.g.,
.sup.67Cu). After the stent is washed, the latter is ready for
use.
[0053] The above-described processes are generally performed at
temperatures of 0-100.degree. C. In the coating of the stent with
the adhesive, solvents can be used on the basis of the respective
adhesive. When a non-aqueous solvent is used, the latter is to be
removed before the implantation.
[0054] The stents can also be coated with two or more different
isotopes. It is possible in particular to apply short-lived or
long-lived isotopes together on a stent (for example, .sup.55Co
with .sup.55Fe, .sup.35S with .sup.67Cu or .sup.99Mo with
.sup.57Co).
[0055] The operations that are necessary for implementing the above
process that is described in principle are known to one skilled in
the art. Special embodiments are described in detail in the
examples.
[0056] In a third variant, the invention also relates to a process
for the production of radioactive stents, which is characterized in
that a non-radioactive stent is immersed in a solution that
contains at least one radioactive isotope in ionic form, and the
isotope is then chemically deposited on the stent.
[0057] The above-described object is achieved according to the
invention by an electrochemical deposition of the radioactive metal
isotope on the stent.
[0058] To this end, the selected stent is immersed in a solution
that contains the radioactive metal isotope. The radioactive
isotope is then electrochemically deposited. On the basis of the
selected materials of the stent, on the one hand, and the
radioactive isotope that is to be deposited, on the other hand, two
possible types of deposition are considered: [0059] I)
Electroplating (external electrolysis) During electroplating, the
dissolved radioactive isotope is deposited reductively by applying
electrical direct current to the stent that is connected as a
cathode. In this way, for example, copper, technetium, rhenium,
silver or indium can be deposited on electrically conducting stents
(e.g., steel, nitinol). [0060] II) Cementation (internal
electrolysis) During cementation, the dissolved noble radioactive
isotope is deposited on the non-noble stent material without
applying electrical current due to the position of the materials in
the voltage sequence of the metals. In this way, for example, gold,
silver or copper can be deposited on metal stents (e.g., steel,
nitinol).
DETAILED DESCRIPTION OF THE INVENTION
[0061] For the coating of metal stents, two electrochemical
processes have proven especially suitable: electroplating
(electrolytic coating) and cementation (internal electrolysis). The
process with the broader range of application is the
electroplating, since it also makes possible the coating with an
electrochemically more negative material than that of the stent.
The coating also makes possible chemical reactions--for example
reductive processes.
[0062] From the user-friendly operation, it can be seen that the
cementation is the better process: the stent is added to the
solution of an electrochemically more positive element, and the
coating is carried out without a parasitic current.
[0063] By suitable cell shape, the excess coating material can be
kept small. The necessary stirring can be done by a magnetic
stirrer or by moving the stent manually. Since only small amounts
of substance are applied in this process, manual stirring is
reasonable. The same also holds true for reactions at elevated
temperature: because of the short time available, thermostating is
not necessary; preheating is all that is required.
[0064] The coating of cells (FIGS. 1, 2) can be carried out with
hypodermic syringes or--in the case of larger stents--with the aid
of metering pumps. With these larger cells, it is useful to
separate used electrolyte solution (active) and washing liquid
(inactive) to keep the volume of active liquid small.
[0065] In the cells that are described in FIGS. 1, 2, the stent is
placed with its carrier in the vessel, whereby an elevated location
with a trough provides for the positioning. In the case of a
galvanization cell, this trough contains a Pt sheet as a contact
for the stent that is connected as a cathode. A Pt network is
located on the cell wall as an anode. By using one of the
ring-shaped sheets which is connected in an electrically conducting
manner with the anode and that is made of another metal, the
operation can also be done with tin, zinc or copper anodes.
[0066] The use of the stent with its carrier has the advantage that
the inside of the stent is shielded, and thus no coating is carried
out there. The coating is carried out only at the locations that
are directed against the vessel.
[0067] Since a restenosis is suppressed by the coating, an
electropolishing of the crude stent may be omitted--especially in
the case of high-grade steel.
Possible Types of Electrochemical Labeling of Stents:
Galvanostatic Deposition
[0068] For this purpose, a battery (1.5-12 V) that is connected
with a variable resistor and 2 electrode terminals is sufficient.
The metal that is to be coated is connected as a cathode. As an
anode, a noble metal, preferably platinum, should be used. The
electrolysis period is 20 seconds to 30 minutes. The operation is
performed at temperatures of 0.degree.-80.degree. C., but
preferably at room temperature.
[0069] Cu: (e.g., Cu-67, .beta. and .gamma. Str., t.sub.1/2=61.9 h)
from pyrophosphate baths of the composition below: [0070]
Cu.sup.2+: 20-40 g [0071] (P.sub.2O.sub.7).sup.4-: 15-250 g [0072]
NO.sub.3--: 5-10 g [0073] NH.sub.3: 1-3 g [0074]
(HPO.sub.4).sup.2-: <110 g [0075] pH: 8-9 [0076] I: 1-8
A/dm.sup.2 [0077] from alkaline CuCN baths at pH 12.2-12.8 [0078]
from acid baths of [0079] sulfate-oxalate-boric acid [0080]
CuCl/Na-thiosulfate [0081] fluoroborate, fluorosilicate, formate
[0082] Cu.sup.11/gluconate, lactate, maleate, tartrate [0083]
I=1-2.5 A/dm.sup.2 [0084] U=0.2-6 V [0085] pH=1.2
[0086] Au: (Au-199, t.sub.1/2=3 d, .beta. and .gamma. Str.) [0087]
from cyanidic baths with the addition of phosphate and citrate at
pH 5-12, [0088] from baths of NH.sub.4ClKAuCN.sub.2 with the
addition of thiourea at pH 6.5-7 [0089] I=0.1-0.6 A/dm.sup.2
[0090] In: from cyanidic baths at pH=0-1 [0091] from fluoroborate
baths with the addition of tartaric acid at pH 1 [0092]
In.sub.2(SO.sub.4).sub.3 pH 2-3/or sulfamate and tartrate
[0093] Re: from perrhenate Re-186 [0094] citrate+H.sub.2SO.sub.4,
pH 1-5 [0095] I=1-15 A/dm.sup.2
[0096] Ni: from NiSO.sub.4/boric acid or from acetate, fluoroborate
or sulfamate baths, [0097] pH=1-5 [0098] I=2-30 A/dm.sup.2
[0099] Pt, Rh, Pd, Ru: [0100] (Pt-197, t.sub.1/2=.beta. Str.)
[0101] I=1-4 A/dm.sup.2 [0102] Ru from
(NH.sub.3).sub.4(Ru.sub.2NC.sub.18(H.sub.2O).sub.2) or sulfamate
[0103] Rh from the sulfate or phosphate with the addition of
H.sub.2SO.sub.4 [0104] pH=1-2 [0105] Pd from
Pd(NH.sub.3).sub.4Br.sub.2, ETDA, [0106] Pt from
H.sub.2Pt(NO.sub.2).sub.2SO.sub.4 with the addition of
NH.sub.4NO.sub.2, NH.sub.3 sulfamate [0107]
H.sub.2Pt(NO.sub.2).sub.2SO.sub.4 with the addition of
H.sub.2SO.sub.4 [0108] K.sub.2Pt(OH).sub.6 with the addition of KOH
and/or ethylamine [0109] H.sub.2PtCl.sub.6 in acid baths with the
addition of HCl
[0110] Ag: (Ag-110, t.sub.1/2=250 d) [0111] from cyanidic baths
with the addition of KOH Electrochemical Deposition
[0112] The labeling of the stent is done by electrochemical
deposition of radioactive metal corresponding to its
electrochemical potential in terms of the potential of the stent
metal. The deposition is performed in a suitable electrolyte and
under selected reaction conditions. An especially suitable
electrolyte is hydrochloric acid at the concentrations of 0.75N and
1N. In this way, all radioisotopes of metals, whose electrochemical
potential is more positive than that of the stent metal, can be
deposited.
[0113] It has been shown that after the electrochemical deposition
of the radioactive metal, nonspecifically-bonded activity still
adheres to the stent to some extent. To remove the latter, the
stent is treated with a solution that contains an electrolyte
(e.g., NaCl), a reducing agent and a hydroxycarboxylic acid (e.g.,
SnCl.sub.2 and gentisic acid) or an alcohol and lipophilic cations
(e.g., alcoholic tetrabutylammonium bromide solution).
[0114] Then, the thus produced stent can still be sealed with a
polymer. As a polymer, e.g., a polyacrylate is suitable.
[0115] All stents can also be coated with two or more different
isotopes. In particular, it is possible to apply short-lived and
long-lived isotopes together on a stent (for example, .sup.55Co
with .sup.55Fe or .sup.99Mo with .sup.57Co).
[0116] With the described process, it is possible to produce
radioactive stents that contain on the surface at least one
radioisotope of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho,
In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or
Y.
[0117] The invention therefore relates to such stents, as well as
the processes for their production. The operations that are
necessary for implementing the above processes that are described
in principle are known to one skilled in the art. Special
embodiments are described in detail in the examples.
[0118] The stents according to the invention achieve the
above-described object. Stents can be radiolabled easily by the
disclosed processes and metered precisely. The stents according to
the invention are readily physiologically compatible. As it was
possible to show in the animal model, the restenosis is
significantly inhibited after balloon denudation by implantation of
the stent according to the invention.
[0119] The special advantage of the stent according to the
invention is that the physician can select on the spot a
(non-radioactive) stent according to his needs and can then
activate the selected stent by the described process. The few
substances and solutions that are required for this purpose can be
supplied prepared accordingly, so that the corresponding physician
need only immerse the uncoated stent in the individual solutions in
the specific sequence. The invention thus also relates to those
substances, solutions and preparations (kits) that are prepared for
the processes according to the invention.
Embodiments
[0120] The following examples are to explain the subject of the
invention, without intending that it be limited to these
examples.
EXAMPLE 1
Y-90-Direct Labeling of a Wiktor Stent
[0121] A Wiktor stent (22.85 mg, model 6570, Medtronic) is covered
with a layer of 2 ml of saturated sodium oxalate solution. 37 MBq
of yttrium-90-trichloride solution is added and heated for 30
minutes to 60.degree. C. Then, the stent is removed and washed
three times with 5 ml of 0.9% sodium chloride solution. The thus
labeled Wiktor stent carries an activity of 0.88 MBq of Y-90.
EXAMPLE 2
Tc-99m-Coating of Strecker Stents
[0122] A strecker stent (6.51 mg, SS/5-4, Boston Scientific) is
covered with a layer of 726 .mu.l of sodium pertechnetate solution
(231.9 MBq). 100 .mu.l of tin(II)-chloride dihydrate solution (5 mg
of SnCl.2H.sub.2O/1 ml of 0.01 M HCl) is added, the reaction
mixture is put into an ultrasound bath for 5 minutes and finally
incubated for 25 minutes at room temperature. The stent is dried
and washed three times for 15 minutes with 726 .mu.l of 0.9% sodium
chloride solution. Finally, it is again covered with a layer of 726
.mu.l of 0.9% sodium chloride solution, and the reaction mixture is
put into an ultrasound bath for 5 minutes. The dried Strecker stent
caries an activity of 1.1 MBq-Tc-99m/6.51 mg (.apprxeq.29.7
.mu.Ci/6.51 mg.apprxeq.4.6 .mu.Ci/1 mg).
EXAMPLE 3
Re-186 Coating of Strecker Stents
[0123] A Strecker stent (6.60 mg, SS/5-4, Boston Scientific) is
covered with a layer of 736 .mu.l of sodium perrhenate solution
(240.2 MBq). 100 .mu.l of tin(II)-chloride-dihydrate solution (5 mg
of SnCl2.2H.sub.2O/1 ml of 0.01 M HCl) is added, the reaction
mixture is put into an ultrasound bath for 5 minutes and finally
incubated for 25 minutes at room temperature. The stent is dried
and washed three times for 15 minutes with 736 .mu.l of 0.9% sodium
chloride solution. Finally, it is again covered with a layer of 736
.mu.l of 0.9% sodium chloride solution, and the reaction mixture is
put into an ultrasound bath for 5 minutes. The dried Strecker stent
carries an activity of 1.0 MBq-Re-186/6.6 mg (.apprxeq.27
.mu.Ci/6.6 mg.apprxeq.4.1 .mu.Ci/1 mg).
EXAMPLE 4
Tc-99m Coating of Strecker Stents
[0124] A Wiktor stent (22.92 mg, model 6570, Medtronic) is covered
with a layer of 2.56 ml of sodium pertechnetate solution (911.5
MBq). 256 .mu.l of tin(II)-chloride-dihydrate solution (5 mg of
SnCl.sub.2.2H.sub.2O/1 ml of 0.01 M HCl) is added, the reaction
mixture is put into an ultrasound bath for 5 minutes and then
incubated for 25 minutes at room temperature. The stent is dried
and washed three times for 15 minutes with 2.56 ml of 0.9% sodium
chloride solution. Finally, it is again covered with a layer of
2.56 ml of 0.9% sodium chloride solution, and the reaction mixture
is put into an ultrasound bath for 5 minutes. The dried Wiktor
stent carries an activity of 5.9 MBq-Tc-99m/22.92 mg
(.apprxeq.159.5 .mu.Ci/22.92 mg.apprxeq.6.9 .mu..mu.Ci/1 mg).
EXAMPLE 5
Re-186 Coating of Wiktor Stents
[0125] A Wiktor stent (22.31 mg, model 6570, Medtronic) is covered
with a layer of 2.5 ml of sodium perrhenate solution (884.1 MBq).
249 .mu.l of tin(II) chloride dihydrate solution (5 mg of
SnCl2.2H.sub.2O/1 ml of 0.01 M HCl) is added, the reaction mixture
is put into an ultrasound bath for 5 minutes and finally incubated
for 25 minutes at room temperature. The stent is dried and washed
three times for 15 minutes with 2.5 ml of 0.9% sodium chloride
solution. Finally, it is again covered with a layer of 2.5 ml of
0.9% sodium chloride solution, and the reaction mixture is put into
an ultrasound bath for 5 minutes. The dried Wiktor stent carries an
activity of 5.2 MBq-Re-186/22.31 mg (.apprxeq.140.5 .mu.Ci/22.31
mg.apprxeq.6.3 .mu.Ci/1 mg).
EXAMPLE 6
Administration of a Wiktor Stent that is Coated with Tc-99m in the
Abdominal Aorta of Rabbits
[0126] The Wiktor stent (model 6570, Medtronic) was coated with
Tc-99m as described in Example 4. In an anesthetized
(Rompun/Ketavet 1:2) white New Zealand rabbit (3.2 kg of body
weight), the femoral artery was exposed. The labeled Wiktor stent
was inserted into the vessel via a 5 F sluice and secured in the
infrarenal aorta by inflating the balloon catheter. The catheter
was then removed, and both the femoral artery and the wound were
sutured. Over a period of 8 hours after administration of the
stent, whole-body scintigrams were prepared with the aid of a
commercially available gamma camera. Five hours after
administration of the stent, a scintigram was prepared. Activity
could only be located in the area of the stent that is in the
infrarenal aorta of the animal. During the entire examination
period, no detectable activity was rinsed from the stent. After 8
hours, the rabbit was killed, the stent was removed, and the
activity was measured in the gamma counter. The activity that
adheres to the stent was equally as high as at the beginning of the
test, taking into consideration the radioactive decomposition of
.sup.99mT into .sup.99Tc.
EXAMPLE 7
Labeling of a Strecker Stent with Cu-67
[0127] A Strecker stent (1993 mg) in an alkaline copper
sulfate/potassium-sodium tartrate solution with an activity of 47.3
MBq is added to a cementation cell (FIG. 2a). After formaldehyde
solution is added, the deposition of elementary copper is carried
out. The active solution is removed, and the stent is washed four
times with physiological common salt solution. It shows an activity
of 1.63 MBq. TABLE-US-00001 CuSO.sub.4.5H.sub.2O 500 mg/100 ml
KNaC.sub.4H.sub.4O.sub.6.4H.sub.2O 2500 mg/100 ml NaOH 700 mg/100
ml HCOH (37%) 1 ml/100 ml T 20.degree. C.
EXAMPLE 8
Labeling of a Nitinol Stent with Au-199
[0128] A nitinol stent (496 mg) in a solution that consists of
potassium-gold cyanide (K[.sup.99Au(CN).sub.4]) with an activity of
137.8 MBq, potassium cyanide and potassium hydroxide is added to a
cementation cell (FIG. 2b). After being heated to 75.degree. C.,
potassium borohydride is added and stirred for 3 minutes. After 4
minutes, the solution is drained off, and the stent is washed four
times with physiological common salt solution. Its activity is 1.31
MBq. TABLE-US-00002 K[Au(CN).sub.2] 580 mg/100 ml KCN 1300 mg/100
ml KOH 1120 mg/100 ml KBH.sub.4 2160 mg/100 ml
EXAMPLE 9
Labeling of a Strecker Stent with Ag-110
[0129] A Strecker stent (997 mg) in a solution that consists of
sodium-silver cyanide (NaAg(CN).sub.2) with an activity of 40
MBq/mg of stent, sodium cyanide, sodium hydroxide and is added to a
cementation cell. After being heated to 55.degree. C.,
dimethylborane is added. It is stirred for 4 minutes at 55.degree.
C., then the solution is drained off, the stent is washed four
times with physiological common salt solution, and the activity is
determined. It is 1.34 MBq. TABLE-US-00003 Na[Ag(CN).sub.2] 183
mg/100 ml NaCN 100 mg/100 ml NaOH 75 mg/100 ml KBH.sub.4 200 mg/100
ml Na[Ag(CN).sub.2]: 134 mg of AgCN + 49 mg of NaCN
EXAMPLE 10
Labeling of a Strecker Stent with Pd/P-32
[0130] A Strecker stent (1996 mg) in a solution that consists of
palladium chloride, hydrochloric acid, ammonia and ammonium
chloride is added to a cementation cell (FIG. 2a). The solution has
a temperature of 55.degree. C. and is stirred. 9 mg of sodium
hypophosphite-monohydrate, which has an activity of 36.4 MBq, is
stirred into the solution. A palladium-phosphorus alloy, which has
an activity of 1.31 MBq, is deposited on the stent. TABLE-US-00004
PdCl.sub.2 200 mg/100 ml HCl (38%) 0.4 ml/100 ml NH.sub.4OH (28%)
16 ml/100 ml NH.sub.4Cl 2.7 g/100 ml NaH.sub.2PO.sub.2.H.sub.2O 1
g/100 ml T 55.degree. C.
[0131] 3 g of hypophosphite yields 1 g of Pd alloy with 1.5% P
EXAMPLE 11
Labeling of a High-Grade Steel Stent with Pd/P-32
[0132] A high-grade steel stent (498 mg) in a solution that
consists of palladium chloride, hydrochloric acid, ammonia and
ammonium chloride is added to a cementation cell (FIG. 2b). The
solution has a temperature of 55.degree. C. and is stirred. 6 mg of
sodium hypophosphite-monohydrate, which has an activity of 37.8
MBq, is stirred into the solution. A palladium-phosphorus alloy,
which has an activity of 1.16 MBq, is deposited on the stent.
TABLE-US-00005 PdCl.sub.2 200 mg/100 ml HCl (38%) 0.4 ml/100 ml
NH.sub.4OH (28%) 16 ml/100 ml NH.sub.4Cl 2.7 g/100 ml
NaH.sub.2PO.sub.2.H.sub.2O 1 g/100 ml T 55.degree. C. 3 g of
hypophosphite yields 1 g of Pd alloy with 1.5% P
EXAMPLE 12
Labeling of a Nitinol Stent with Pd/P-32
[0133] A nitinol stent (96 mg) in a solution that consists of
palladium chloride, hydrochloric acid, ammonia and ammonium
chloride is brought into a cementation cell (FIG. 2b). The solution
has a temperature of 55.degree. C. and is stirred. 3 mg of sodium
hypophosphite-monohydrate, which has an activity of 39.4 MBq, is
stirred into the solution. A palladium-phosphorus alloy, which has
an activity of 1.37 MBq, is deposited on the stent. TABLE-US-00006
PdCl.sub.2 200 mg/100 ml HCl (38%) 0.4 ml/100 ml NH.sub.4OH (28%)
16 ml/100 ml NH.sub.4Cl 2.7 g/100 ml NaH.sub.2PO.sub.2.H.sub.2O 1
g/100 ml T 55.degree. C. 3 g of hypophosphite yields 1 g of
Pd-alloy with 1.5% P
EXAMPLE 13
Labeling of a High-Grade Steel Stent with P-32
[0134] A high-grade steel stent (1992 mg) in a solution of
phosphoric acid that is heated to 50.degree. C. with a .sup.32P
activity of 41.4 MBq is brought into a galvanization cell (FIG. 1).
The stent is operated as an anode, and electrolysis is done for 2
minutes at 2 V. Then, the solution is drained off, the stent is
rinsed four times with physiological common salt solution, and the
activity of the stent is measured. It is 0.93 MBq.
EXAMPLE 14a
Coating of a Wiktor stent with
1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane
[0135] 50 mg of
1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced
according to DE 43 40 809.5) is dissolved in 1 ml of ethanol. The
Wiktor stent (22.82 mg, model 6570, Medtronic) is covered with a
layer of the solution that is thus produced. Then, 2 ml of water is
added and incubated for 15 minutes in an ultrasound bath. The
Wiktor stent is removed and dried.
EXAMPLE 14b
In-111 Labeling of a Wiktor Stent that is Coated with
1-{3-[N-(2-Methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane
[0136] A Wiktor stent that is coated as under Example 14a with
1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced
according to DE 43 40 809.5) is covered with a layer of 2 ml of
0.9% sodium chloride solution. After 37 MBq of indium-trichloride
solution is added, the reaction mixture is put into an ultrasound
bath for 15 minutes. The stent is removed, the latter is washed
three times with 5 ml of 0.9% sodium chloride solution and dried.
The Wiktor stent that is thus labeled carries an activity of 1.49
MBq of In-111.
EXAMPLE 14c
Y-90 Labeling of a Wiktor Stent that is Coated with
1-{3-[N-(2-Methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane
[0137] A Wiktor stent that is coated with
1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced
according to DE 43 40 809.5) as under Example 14a is covered with a
layer of 2 ml of 0.9% sodium chloride solution. After 37 MBq of
yttrium-90-trichloride solution is added, the reaction mixture is
put into an ultrasound bath for 15 minutes. The stent is removed,
the latter is washed three times with 5 ml of 0.9% sodium chloride
solution and dried. The Wiktor stent that is thus labeled carries
an activity of 1.12 MBq of Y-90.
EXAMPLE 15a
1-{3-[N-(2-Methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris--
(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane, Y-90
complex
[0138] 50 mg of
1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced
according to DE 4340809.5) is dissolved in 1 ml of ethanol. After
37 MBq of yttrium-90-trichloride solution is added, the reaction
mixture is refluxed for 10 minutes. The Y-90 complex solution that
is thus prepared can be used without further purification for
coating a Wiktor stent.
EXAMPLE 15b
Y-90-Labeling of a Wiktor Stent with the Y-90 Complex of
1-{3-[N-(2-Methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane
[0139] A Wiktor stent (22.89 mg, model 6570, Medtronic) is added to
900 .mu.l of the solution, produced under Example 15a, of
1-{3-[N-(2-methoxyethyl)-octadecylsulfamoyl]-2-hydroxypropyl}-4,7,10-tris-
-(hydroxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-Y-90-complex.
After 2 ml of water is added, the reaction mixture is put into an
ultrasound bath for 15 minutes. Then, the Wiktor stent is removed
and washed three times with 5 ml of 0.9% sodium chloride solution.
The Wiktor stent that is thus labeled carries an activity of 0.98
MBq of Y-90.
EXAMPLE 16a
N,N'-Bisundecyl-Diethylene-Triamine-Pentaacetic Acid-Diamide
[0140] 3.57 g (10 mmol) of diethylene-triamine-pentaacetic
acid-bisanhydride is suspended together with 4.05 g (40 mmol) of
triethylamine in 100 ml of absolute dimethylformamide. Then, a
solution of 3.42 g (20 mmol) of undecylamine, dissolved in 50 ml of
absolute dichloromethane, is added in drops to the reaction mixture
at room temperature. The reaction batch is stirred for 6 hours at
room temperature, filtered and concentrated by evaporation in a
medium-high vacuum. The residue is dissolved three times in 100 ml
of dimethylformamide and in each case concentrated by evaporation
in a medium-high vacuum. 50 ml of absolute diethyl ether is poured
over the foamy reaction product and stirred overnight. It is
filtered and dried in a medium-high vacuum. TABLE-US-00007 Yield:
6.3 g (90%), white powder. Elementary analysis: Cld: C 61.77 H 9.94
N 10.01 O 18.86 Fnd: C 61.52 H 9.63 N 9.91 O
EXAMPLE 16b
Coating of a Wiktor Stent with
N,N'-Bisundecyl-diethylene-triamine-pentaacetic acid-diamide
[0141] 50 mg of N,N'-bisundecyl-diethylene-triamine-pentaacetic
acid-diamide (produced according to Example 16a) is dissolved in 1
ml of ethanol. The Wiktor stent (22.93 mg, model 6570, Medtronic)
is covered with a layer of the solution that is thus produced.
Then, 2 ml of water is added, and it is incubated for 15 minutes in
an ultrasound bath. The Wiktor stent is removed and dried.
EXAMPLE 16c
In-111-Labeling of a Wiktor Stent that is Coated with
N,N'-Bisundecyl-diethylene-triamine-pentaacetic acid-diamide
[0142] A Wiktor stent that is coated with
N,N'-bisundecyl-diethylene-triamine-pentaacetic acid-diamide as
under Example 16b is covered with a layer of 2 ml of 0.9% sodium
chloride solution. After 37 MBq of indium-trichloride solution is
added, the reaction mixture is put into an ultrasound bath for 15
minutes. The stent is removed, the latter is washed three times
with 5 ml of 0.9% sodium chloride solution and dried. The Wiktor
stent that is thus labeled carries an activity of 1.34 MBq of
In-111.
EXAMPLE 16d
Y-90-Labeling of a Wiktor Stent that is Coated with
N,N'-Bisundecyl-diethylene-triamine-pentaacetic acid-diamide
[0143] A Wiktor stent that is coated with
N,N'-bisundecyl-diethylene-triamine-pentaacetic acid-diamide as
under Example 16b is covered with a layer of 2 ml of 0.9% sodium
chloride solution. After 37 MBq of yttrium-trichloride solution is
added, the reaction mixture is put into an ultrasound bath for 15
minutes. The stent is removed, the latter is washed three times
with 5 ml of 0.9% sodium chloride solution and dried. The Wiktor
stent that is thus labeled carries an activity of 1.11 MBq of
Y-90.
EXAMPLE 17a
N,N'-Bisundecyl-diethylene-triamine-pentaacetic acid-diamide, Y-90
Complex
[0144] 50 mg of N,N'-bisundecyl-diethylene-triamine-pentaacetic
acid-diamide (Example 4a) is dissolved in 1 ml of ethanol. After 37
MBq of yttrium-90-trichloride solution is added, the reaction
mixture is heated for 10 minutes to 60.degree. C. The Y-90-complex
solution that is thus prepared can be used without further
purification for coating a Wiktor stent.
EXAMPLE 17b
Y-90-Labeling of a Wiktor Stent with the Y-90 Complex of
N,N'-Bisundecyl-diethylene-triamine-pentaacetic acid-diamide
[0145] A Wiktor stent (22.87 mg, model 6570, Medtronic) is added to
900 .mu.l of the solution, produced under Example 17a, of the Y-90
complex of N,N'-bisundecyl-diethylene-triamine-pentaacetic
acid-diamide. After 2 ml of water is added, the reaction mixture is
put into an ultrasound bath for 15 minutes. Then, the Wiktor stent
is removed and washed three times with 5 ml of 0.9% sodium chloride
solution. The Wiktor stent that is thus labeled carries an activity
of 0.99 MBq of Y-90.
EXAMPLE 18a
N-Benzyloxycarbonyl-glycyl-N'-undecyl-glycinamide
[0146] 3.63 g (10 mmol) of
N-benzyloxycarbonyl-glycyl-glycine-N-hydroxysuccinimide ester and
1.71 g (10 mmol) of undecylamine are dissolved in 100 ml of
absolute dichloromethane. The reaction mixture is stirred for 6
hours at room temperature. Then, it is diluted with 100 ml of
dichloromethane, the organic phase is washed twice with 50 ml of
saturated sodium bicarbonate solution and once with 50 ml of water.
It is dried on magnesium sulfate, and the solvent is evaporated in
a vacuum. The crude product is purified by chromatography on silica
gel (eluant: dichloromethane/methanol 95:5). TABLE-US-00008 Yield:
3.8 g (90.6%), white powder Elementary analysis: Cld: C 65.84 H
8.89 N 10.01 O 15.25 Fnd: C 65.71 H 9.02 N 10.10 O
EXAMPLE 18b
Glycyl-N'-undecyl-glycinamide
[0147] 3 g (7.15 mmol) of
N-benzyloxycarbonyl-glycyl-N'-undecyl-glycinamide (Example 18a) is
dissolved in 100 ml of absolute ethanol. After 300 mg of palladium
is added to carbon (10%), it is hydrogenated for 2 hours at room
temperature (1 atmosphere of hydrogen). It is filtered and
concentrated by evaporation in a vacuum. The resulting amine is
used without further purification for the subsequent reaction.
TABLE-US-00009 Yield: 1.92 g (94.1%), white foam. Elementary
analysis: Cld: C 63.12 H 10.95 N 14.72 O 11.21 Fnd: C 63.03 H 11.04
N 14.57 O
EXAMPLE 18c
N-(S-Acetyl-mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
[0148] 285.4 mg (1 mmol) of glycyl-N'-undecyl-glycinamide (Example
18b) and 231.2 mg (1 mmol) of S-acetyl-mercapto-acetic
acid-N-hydroxy-succinimide ester are dissolved together in 20 ml of
absolute dichloromethane. The reaction mixture is stirred for 6
hours at room temperature. Then, it is diluted with 20 ml of
dichloromethane, the organic phase is washed twice with 5 ml of
semisaturated sodium bicarbonate solution and washed once with 5 ml
of water. It is dried on magnesium sulfate, and the solvent is
evaporated in a vacuum. The crude product is purified by
chromatography on silica gel (eluant: dichloromethane/methanol
93:7). TABLE-US-00010 Yield: 362 mg (90.1%), white powder. EA: Cld:
C 56.83 H 8.79 N 10.46 O 15.94 S 7.98 Fnd: C 56.67 H 8.93 N 10.18 O
S 7.72
EXAMPL 18d
N-(Mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
[0149] 201 mg (0.5 mmol) of
N-(S-acetyl-mercaptoacetyl-glycyl-N'-undecyl-glycinamide (Example
18c) is dissolved in 15 ml of absolute ethanol. It is saturated
with argon, and an ammonia stream is directed through the solution
for 30 minutes. Then, it is concentrated by evaporation, and the
residue is taken up in 20 ml of dichloromethane. The organic phase
is shaken once with 2% aqueous citric acid and dried on sodium
sulfate. The solvent is evaporated in a vacuum, and the residue is
chromatographed on silica gel (eluant: dichloromethane/methanol
9:1). TABLE-US-00011 Yield: 153 mg (85.1%), white powder. EA: Cld:
C 56.79 H 9.25 N 11.69 O 13.35 S 8.92 Fnd: C 56.67 H 9.43 N 11.48 O
S 8.71
EXAMPLE 18e
Coating of a Wiktor Stent with
N-(Mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
[0150] 50 mg of N-(mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
(Example 18d) is dissolved in 1 ml of ethanol. The Wiktor stent
(22.89 mg, model 6570, Medtronic) is covered with a layer of the
solution that is thus produced. Then, 2 ml of water is added, and
it is incubated for 15 minutes in an ultrasound bath. The Wiktor
stent is removed and dried.
EXAMPL 18f
Re-186-Labeling of a Wiktor Stent that is Coated with
N-(Mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
[0151] A Wiktor stent that is coated with
N-(mercaptoacetyl)-glycyl-N'-undecyl-glycinamide, as under Example
18e, is covered with a layer of 2 ml of disodium hydrogen phosphate
buffer (0.1M, pH=8.5). After 37 MBq of perrhenate solution is
added, 100 .mu.l of tin dichloride-dihydrate solution (5 mg of
SnCl2.times.2H2O/1 ml of 0.1M HCl) is added to the reaction batch.
The reaction mixture is put into an ultrasound bath for 15 minutes.
The stent is removed, the latter is washed three times with 5 ml of
0.9% sodium chloride solution and dried. The Wiktor stent that is
thus labeled carries an activity of 1.31 MBq of Re-186.
EXAMPLE 18g
N-(Mercaptoacetyl)-glycyl-N'-undecyl-glycinamide, Re-186
Complex
[0152] 5 mg of N-(mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
(Example 18d) is dissolved in 800 .mu.l of ethanol. After 5 mg of
disodium-L-tartrate and 50 .mu.l of 0.1M sodium hydrogen phosphate
buffer (pH=8.5) are added, 37 MBq of perrhenate and 100 .mu.l of
tin dichloride-dihydrate solution (5 mg of SnCl2.times.2H2O/1 ml of
0.1M HCl) are added. The reaction mixture is heated for 5 minutes
to 60.degree. C. The solution of the Re-186 complex of
N-(mercaptoacetyl)-glycyl-N'-undecyl-glycinamide that is thus
prepared can be used directly for labeling a Wiktor stent.
EXAMPLE 18h
Labeling of a Wiktor Stent with the Re-186 Complex of
N-(Mercaptoacetyl)-glycyl-N'-undecyl-glycinamide
[0153] A Wiktor stent (22.99 mg, model 6570, Medtronic) is added to
900 .mu.l of the solution, produced under Example 18g, of the
Re-186 complex of N-(mercaptoacetyl)-glycyl-N'-undecyl-glycinamide.
After 2 ml of water is added, the reaction mixture is put into an
ultrasound bath for 15 minutes. Then, the Wiktor stent is removed
and washed three times with 5 ml of 0.9% sodium chloride solution.
The Wiktor stent that is thus labeled carries an activity of 1.13
MBq of Re-186.
EXAMPLE 19
Y-90-Direct Labeling of a Wiktor Stent
[0154] A Wiktor stent (22.85 mg, model 6570, Medtronic) is covered
with a layer of 2 ml of saturated sodium oxalate solution. 37 MBq
of yttrium-90-trichloride solution is added and heated for 30
minutes to 60.degree. C. Then, the stent is removed and washed
three times with 5 ml of 0.9% sodium chloride solution. The Wiktor
stent that is thus labeled carries an activity of 0.88 MBq of
Y-90.
EXAMPLE 20
Use of Bisdecyloylhydrazino-diethylenetriamine-pentaacetate for
Coating Stents
EXAMPLE 20a
Production of
Bisdecyloylhydrazino-diethylenetriamine-pentaacetate
[0155] 17.5 g of decanoic acid methyl ester is dissolved in 1 l of
absolute ethanol and mixed with 350 ml of hydrazine hydrate. It is
refluxed for 3 hours and then stirred overnight at room
temperature. The solution is concentrated by evaporation to about
300 ml and allowed to stand until the product is crystallized out.
After it is filtered off and dried, 16.6 g (=94% of theory) of
decanoic acid hydrazide is obtained. TABLE-US-00012 Elementary
analysis: C H N O Calculated: 64.5% 11.9% 15.0% 8.6% Found: 65.4%
11.9% 14.5%
[0156] 3.6 g of diethylenetriamine-pentaacetic acid-bisanhydride is
dissolved in 500 ml of DMF and mixed under nitrogen atmosphere with
4.2 ml of triethylamine and 3.7 g of decanoic acid hydrazide. It is
stirred for 24 hours at room temperature and then undissolved
components are filtered off. The solution is concentrated by
evaporation, and the oily residue is taken up in 500 ml of ether.
After 500 ml of hexane is added and stirring is continued, the
product precipitates in crystalline form. After drying, 7.2 g (=95%
of theory) of bisdecyloylhydrazino-diethylene-triamine-pentaacetate
is obtained.
EXAMPLE 20b
Coating of the Strecker Stent with
Bisdecyloylhydrazino-diethylenetriamine-pentaacetate
[0157] 2 mg of bisdecyloylhydrazino-diethylenetriamine-pentaacetate
is dissolved in 1 ml of methanol and precipitated with the addition
of 2 ml of hexane. In this suspension, a Strecker stent 0.5 cm in
length (SS/5-4, Boston Scientific) is immersed and incubated for 15
minutes by means of ultrasound. The stent is then taken out and
dried. This process is repeated five times, and finally excess
coating material is removed by washing with physiological common
salt solution in an ultrasound bath.
EXAMPLE 20c
Labeling of Strecker Stents that are Coated with
Bisdecyloylhydrazino-diethylenetriamine-Pentaacetate
[0158] The thus treated stent was immersed for labeling in a
commercially acquired solution of the radioactive metal isotope
(In-111, Y-90, 74 MBq each) and incubated for 15 minutes in an
ultrasound bath. Finally, it was washed in physiological saline for
20 minutes in an ultrasound bath. 0.3 MBq of residual activity
remains on the stent.
EXAMPLE 20d
Coating of Strecker Stents with Labeled
Bisdecyloylhydrazino-diethylenetriamine-pentaacetate
[0159] 2 mg of bisdecyloylhydrazino-diethylenetriamine-pentaacetate
is dissolved in 1 ml of methanol and labeled with a commercially
acquired solution of the radioactive metal isotope (In-111, Y-90,
74 MBq each). In this solution, a Strecker stent 0.5 cm in length
(SS/5-4, Boston Scientific) is immersed and incubated for 15
minutes by means of ultrasound. Then, the stent was taken out and
dried. This process was repeated 5 times, and finally soluble
activity was removed by washing with physiological common salt
solution in an ultrasound bath. 0.1 MBq of residual activity
remains on the stent.
EXAMPLE 21a
Use of Thioacetyl-Gly-Gly-amidoethyl-PEG-methylether for Coating
Stents
Production of Thioacetyl-Gly-Gly-amidoethyl-PEG-methylether
[0160] 50 g of aminoethyl-polyethyleneglycol-methylether with a
molecular weight of about 5000 is stirred with 3.6 g of
N-benzyloxycarbonyl-glycylglycine-N-hydroxysuccinimide ester
(Z-Gly-Gly-OSu) in 100 ml of DMF for 24 hours at room temperature.
The solution is concentrated by evaporation, and the residue is
further reacted without further purification.
[0161] The residue is dissolved in a mixture of methanol/water 1:1,
mixed with 2 g of palladium on activated carbon and hydrogenated
under hydrogen atmosphere (pressure 1 bar) until about 230 ml of
hydrogen is taken up. Then, the catalyst is filtered off, and the
remaining mixture is purified after concentration by evaporation
with a gel filtration. After drying, 49 g (=96% of theory) of
glycyl-glycyl-amidoethyl-PEG-methylether is obtained.
[0162] This product is dissolved in 100 ml of DMF and stirred with
2.2 g of S-acetyl-thioglycolic acid-N-hydroxysuccinimide ester for
24 hours at room temperature. Then, the mixture is mixed with 20 ml
of aqueous ammonia solution and stirred for 2 more hours. The
product is acidified to pH 4 with aqueous 6N hydrochloric acid and
concentrated by evaporation. The purification is carried out on a
gel filtration column. 42 g (=85% of theory) of
thioacetyl-glycyl-glycyl-amidoethyl-polyethyleneglycol-methyl ester
is obtained.
EXAMPLE 21b
Coating of Strecker Stents with
Thioacetyl-Gly-Gly-amidoethyl-PEG-methylether and Subsequent
Radiolabeling
[0163] 2 mg of thioacetyl-Gly-Gly-amidoethyl-PEG-methylether with a
molecular weight of about 5300 was dissolved in 2 ml of methanol,
precipitated with the addition of 1 ml of hexane, a Strecker stent
0.5 cm in length (SS/5-4, Boston Scientific) was immersed in this
suspension and incubated by means of ultrasound for 15 minutes.
Then, the stent was taken out and dried. This process was repeated
five times, and finally excess coating material was removed by
washing with physiological common salt solution in an ultrasound
bath.
[0164] The thus treated stent was immersed for labeling in a
solution of the radioactive metal isotope (Tc-99m, Re-186) that
consists of 5 ml of the solution (Tc-99m from the generator, Re-186
that was acquired commercially and contained about 3 MBq of
activity), 200 .mu.l of phosphate buffer (Na.sub.2HPO.sub.4, 0.5
mol/l, pH 8.5), 50 .mu.l of a 0.15 molar disodium tartrate solution
and 2.5 .mu.l of a 0.2 molar SnCl.sub.2 solution and incubated for
15 minutes in an ultrasound bath. Finally, it was washed in
physiological saline for 20 minutes in an ultrasound bath. 0.1 MBq
of residual activity remains on the stent.
EXAMPLE 21c
Coating of Strecker Stents with Radiolabeled
Thioacetyl-Gly-Gly-amidoethyl-PEG-methylether
[0165] 0.5 mg of thioacetyl-Gly-Gly-amidoethyl-PEG-methylether with
a molecular weight of about 5300 was dissolved in 300 .mu.l of
phosphate buffer (Na.sub.2HPO.sub.4, 0.5 mol/l, pH 8.5), and 50
.mu.l of a 0.15 molar disodium tartrate solution and 2.5 .mu.l of a
0.2 molar SnCl.sub.2 solution were added. The mixture was mixed
with a pertechnetate solution (2 MBq) from a Tc-99m generator and
incubated for 15 minutes at 60.degree. C. A solution of
polyethylene glycols that are labeled with Re-186 could be produced
analogously.
[0166] A Strecker stent 0.5 cm in length (SS/5-4, Boston
Scientific) was immersed in this solution and incubated for 15
minutes by means of ultrasound. Then, the stent was taken out and
dried. This process was repeated several times in succession, until
the adhering activity had reached 0.3 MBq. Then, it was washed
twice for 60 minutes in physiological saline. A residual activity
of 100 KBq remained.
EXAMPLE 22
Coating of Strecker Stents with
Tc-99m-Asp-Gly-Gly-Cys-Gly-Cys-Phe-(Dr-Trp)-Leu-Asp-Ile-Ile-Trp
[0167] 0.5 mg of the
Asp-Gly-Gly-Cys-Gly-Cys-Phe-(D-Trp)-Leu-Asp-Ile-Ile-Trp that was
produced analogously to Barany and Marrifield, The Peptides;
Analysis, Biology, Academic Press, New York, 1990; Stewart and
Young, Solid-Phase Peptide Synthesis, 2nd Edition, Pierce Chemical
Co., Rockford, Ill., 1984 is dissolved in 300 ml of phosphate
buffer (Na.sub.2HPO.sub.4, 0.5 mol/l, pH 8.5) and mixed with 50
.mu.l of a 0.15 molar disodium-L-tartrate solution, 2.5 .mu.l, of a
0.2 molar tin(II) chloride-dihydrate solution. The reaction mixture
is mixed with a pertechnetate solution (50 mCi=1.85 GBq) from an
Mo-99/Tc-99m-generator and incubated for 10 minutes at room
temperature.
[0168] A Strecker stent 0.5 cm in length (SS/5-4, Boston
Scientific) was incubated five times in succession for 15 minutes
each in the Tc-99m-peptide solution. After each incubation, the
activity that adheres to the stent was determined with the aid of a
commercially available gamma counter. As the figure shows, an
activity of 230 .mu.Ci on the Strecker stent remained even after
one-time incubation.
[0169] The repetitions of this incubation do not result in any
significantly higher activity that remains on the stent. The stent
that was coated with the Tc-99m-peptide solution was then washed
four times every minute and twice for 60 minutes in physiological
saline. After the first rinsing, 81 .mu.Ci still remains on the
stent. The additional rinsing processes did not result in any
significant reduction of the activity that is bonded to the
stent.
EXAMPLE 23
Tc-99m-Coating of Strecker Stents
[0170] A Wiktor stent (22.92 mg, model 6570, Medtronic) is covered
with a layer of 2.56 ml of sodium-pertechnetate solution (911.5
MBq). 256 .mu.l of tin(II) chloride-dihydrate solution (5 mg of
SnCl.sub.2.2H.sub.2O/1 ml of 0.01 M HCl) is added, the reaction
mixture is put into an ultrasound bath for 5 minutes and finally
incubated for 25 minutes at room temperature. The stent is dried
and washed three times for 15 minutes with 2.56 ml of 0.9% sodium
chloride solution. Finally, it is again covered with a layer of
2.56 ml of 0.9% sodium chloride solution, and the reaction mixture
is put into an ultrasound bath for 5 minutes. The dried Wiktor
stent carries an activity of 5.9 MBq-Tc-99m/22.92 mg
(.apprxeq.159.5 .mu.Ci/22.92 mg.apprxeq.6.9 .mu.Ci/1 mg).
EXAMPLE 24
Re-186 Coating of Wiktor Stents
[0171] A Wiktor stent (22.31 mg, model 6570, Medtronic) is covered
with a layer of 2.5 ml of sodium pertechnetate solution (884.1
MBq). 249 .mu.l of tin(II) chloride-dihydrate solution (5 mg of
SnCl2.2H.sub.2O/1 ml of 0.01 M HCl) is added, the reaction mixture
is put into an ultrasound bath for 5 minutes and finally incubated
for 25 minutes at room temperature. The stent is dried and washed
three times for 15 minutes with 2.5 ml of 0.9% sodium chloride
solution. Finally, it is again covered with a layer of 2.5 ml of
0.9% sodium chloride solution, and the reaction mixture is put into
an ultrasound bath for 5 minutes. The dried Wiktor stent carries an
activity of 5.2 MBq-Re-186/22.31 mg (.apprxeq.140.5 .mu.Ci/22.31
mg.apprxeq.6.3 .mu.Ci/1 mg).
EXAMPLE 25
Administration of a Wiktor Stent that is Coated with Tc-99m in the
Abdominal Aorta of Rabbits
[0172] The Wiktor stent (model 6570, Medtronic) was coated with
Tc-99m as described in Example 10. In an anesthetized
(Rompun/Ketavet 1:2) white New Zealand rabbit (3.2 kg of body
weight), the femoral artery was exposed. The labeled Wiktor stent
was inserted into the vessel via a 5 F sluice and secured in the
infrarenal aorta by inflating the balloon catheter. The catheter
was then removed, and both the femoral artery and the wound were
sutured. Over a period of 8 hours after administration of the
stent, whole-body scintigrams were prepared with the aid of a
commercially available gamma camera. Figure XI shows a scintigram
that was prepared five hours after administration of the stent.
Activity could only be located in the area of the stent that is in
the infrarenal aorta of the animal. During the entire examination
period, no detectable activity was rinsed from the stent. After 8
hours, the rabbit was killed, the stent was removed, and the
activity was measured in a gamma counter. The activity that adheres
to the stent was equally as high as at the beginning of the
test.
EXAMPLE 26a
Cementation of a Strecker Stent with Gold
[0173] A Strecker stent (about 200 mg) is coated with gold (2
minutes of 30 mg of gold(III)-chloride in 30 ml of 5% aqueous
solution) in a cementation vessel (FIG. 2a). The stent that is thus
obtained is washed three times with 10% aqueous nitric acid and
twice with water. Then, it is [washed] twice with acetonitrile and
dried.
EXAMPLE 26b
Linkage of 11-Amino-undecyl-1-thiol to the Surface
[0174] 500 mg of 11-aminoundecyl-1-thiol is dissolved in a solution
that consists of 10 ml of 7.5% aqueous nitric acid/5 ml of
tetrahydrofuran/3 ml of 1,2-dichloromethane. The Strecker stent
that is produced from Example 26a is immersed in this solution
under protective gas (in an ultrasound bath/37.degree. C.). It is
irradiated for about 15 minutes. The stent is washed three times
with ethanol, then twice with acetonitrile.
EXAMPLE 26c
Coupling with DTPA-bis-anhydride
[0175] The stent that is described in Example 26b is immersed in a
7.5% aqueous sodium carbonate solution, and 500 mg of
DTPA-bis-anhydride in 5 portions per 100 mg each is added at
0.degree. C. while being stirred. It is stirred for 10 minutes at
0.degree. C. The stent is washed twice with 5% aqueous hydrochloric
acid, then three times with water and twice with acetonitrile.
EXAMPLE 26d
Indium-111-Labeling of the Stent that is Derivatized from
DTPA-Amide
[0176] The stent that is described in Example 26c is immersed in a
solution of acetate buffer (0.001 mol, pH 5.5), and In-111 solution
(starting activity: 48.8 MBq) is added. It is stirred for 5 minutes
at room temperature. The stent is washed three times with 3%
aqueous sodium carbonate solution, then twice with physiological
common salt solution. The stent can be used directly for
implantation. The stent showed a radioactivity of 1.2 MBq.
EXAMPLE 27a
Coupling of DOTA to the Stent of Example 26b
[0177] The stent that is obtained from Example 26b is immersed in a
solution of phosphate buffer (0.1 mol/l, pH 7.4), and 150 mg of
1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA)
is added. It is cooled to 0.degree. C., and 200 mg of
N-hydroxysulfosuccinimide (Sulfo-NHS) and 200 mg of
1-ethyl-3-(dimethylaminopropyl)-carbodiimide HCl (EDC) are added.
It is stirred for 30 minutes at 0.degree. C. The stent is washed
twice with water and twice with physiological common salt
solution.
EXAMPLE 27b
Labeling with In-111
[0178] The stent that is described in Example 27a is immersed in a
solution of acetate buffer (0.01 mol, pH 5), and In-111 solution
(starting activity: 37.3 MBq) is added. It is heated for 30 minutes
to 50.degree. C. The stent is washed twice with 3% aqueous sodium
carbonate solution, then three times with physiological common salt
solution. The stent showed a radioactivity of 1.45 MBq.
EXAMPLE 28a
Coupling of 4-Isothiocyanato-benzyl-DTPA to the Stent of Example
26b
[0179] A stent that is prepared in Example 26b is immersed in a
solution of sodium carbonate buffer (0.1 mol/l, pH 9), and 100 mg
of 4-isothiocyanato-benzyl-DTPA (Gansow, O. WO 91/14459) is added.
It is stirred for 30 minutes at room temperature. The stent is
washed twice with 3% sodium carbonate solution, then three times
with physiological common salt solution.
EXAMPLE 28b
Labeling with Cu-67
[0180] The stent that is described in Example 28a is immersed in a
solution of acetate buffer (0.01 mol, pH 5), and Cu-67 solution
(starting activity: 34.5 MBq) is added. It is stirred for 5 minutes
at room temperature. The stent is washed twice with 3% aqueous
sodium carbonate solution, then three times with physiological
common salt solution. The stent showed a radioactivity of 0.98
MBq.
EXAMPLE 29a
Coupling of 4-Isothiocyanato-benzyl-DOTA to the Stent of Example
26b
[0181] A stent that is prepared in Example 26b is immersed in a
solution of sodium carbonate buffer (0.1 mol/l, pH 9), and 100 mg
of 4-isothiocyanato-benzyl-DOTA (Gansow, O. U.S. Pat. No.
4,923,985) is added. It is stirred for 30 minutes at room
temperature. The stent is washed twice with 3% sodium carbonate
solution, then three times with physiological common salt
solution.
EXAMPLE 29b
Labeling with Cu-67
[0182] The stent that is described in Example 29a is immersed in a
solution of acetate buffer (0.01 mol, pH 5), and Cu-67 solution
(starting activity: 28.6 MBq) is added. It is stirred for 15
minutes at 40.degree. C. The stent is washed twice with 3% aqueous
sodium carbonate solution, then three times with physiological
common salt solution. The stent showed a radioactivity of 0.77
MBq.
EXAMPLE 30a
Bisamide of Cystamine with DTPA
[0183] 10 g (28 mmol) of DTPA-bis-anhydride is suspended in 100 ml
of dimethyl sulfoxide. It is cooled to 0.degree. C., and 5.7 g (56
mmol) of triethylamine is added. Then, 1.58 g (7 mmol) of cystamine
dihydrochloride is added, and it is stirred for 24 hours at room
temperature. 20 ml of formic acid and 1000 ml of diethyl ether are
added. The precipitated solid is filtered off and chromatographed
on RP18 (mobile solvent: gradient that consists of
acetonitrile/THF/water). Th product that is obtained after the main
fractions are concentrated by evaporation is recrystallized from a
little methanol. TABLE-US-00013 Yield: 1.96 g (31% of theory
relative to cystamine) of a colorless, hygroscopic solid. Water
Content: 6.8% Elementary analysis (relative to anhydrous
substance): Cld: C 42.57 H 6.03 N 12.41 S 7.10 Fnd: C 42.39 H 5.97
N 12.53 S 7.03
EXAMPLE 30b
Coupling of DTPA-Cysteamine Amide to a Gold-Cemented Strecker Stent
(26a)
[0184] The Strecker stent that is described in Example 26a is fixed
in an electrolysis cell (FIG. 1), and a solution of phosphate
buffer (0.1 mol/l, pH 5) is added. 100 mg of the title compound of
Example 126a is added to the solution, and a voltage of 3 V is
applied. Electrolysis is done for 15 minutes at room temperature.
The stent is washed four times with water and can be used directly
for labeling.
EXAMPLE 30c
Labeling with In-111
[0185] The stent that is described in Example 30b is immersed in a
solution of acetate buffer (0.01 mol, pH 5), and In-111 solution
(starting activity: 34.7 MBq) is added. It is stirred for 5 minutes
at room temperature. The stent is washed twice with 3% aqueous
sodium carbonate solution, then three times with physiological
common salt solution. The stent showed a radioactivity of 1.11
MBq.
EXAMPLE 31
Labeling with Cu-67
[0186] The stent that is described in Example 30b is immersed in a
solution of acetate buffer (0.01 mol, pH 5), and Cu-67 solution
(starting activity: 41.2 MBq) is added. It is stirred for 3 minutes
at room temperature. The stent is washed twice with 3% aqueous
sodium carbonate solution, then three times with physiological
common salt solution. The stent showed a radioactivity of 0.97
MBq.
EXAMPLE 32a
Coupling of
N,N-dimethyl-2-(3,3,5,11,13,13-hexamethyl-1,2-dithia-5,8,11-triaza-cyclot-
ridecan-8-yl)-ethylamine to a Gold-Cemented Strecker Stent
[0187] The Strecker stent that is described in Example 26a is fixed
in an electrolysis cell (FIG. 1), and a solution of phosphate
buffer (0.1 mol/l, pH 5) is added. 100 mg of
N,N-dimethyl-2-(3,3,5,11,13,13-hexamethyl-1,2-dithia-5,8,11-triaza-cyclot-
ridecan-8-yl)-ethylamine (produced according to WO 96/11918,
Example 27) is added to the solution, and a voltage of 3.5 V is
applied. Electrolysis is done for 15 minutes at room temperature.
The stent is washed four times with water and can be used directly
for labeling.
EXAMPLE 32b
Labeling with Re-186
[0188] The stent that is described in Example 32a is immersed in a
solution that consists of 30 ml of acetate buffer (0.01 mol, pH 5
and 100 mg of tin(II)-chloride), and Re-186 solution (starting
activity: 48.3 MBq) is added. It is stirred for 3 minutes at room
temperature. The stent is washed twice with 3% aqueous sodium
carbonate solution, then three times with physiological common salt
solution. The stent showed a radioactivity of 1.44 MBq.
EXAMPLE 33
Labeling of a Gold-Cemented Stent with In-111 With In-Situ Coupling
of the Title Compound of Example 30a Using Electrochemical
Reduction
[0189] The Strecker stent that is described in Example 26a is fixed
in an electrolysis cell (FIG. 1), and a solution of phosphate
buffer (0.1 mol/l, pH 5) is added. 10 mg of the title compound of
Example 30a, In-111 solution (starting activity: 34.6 MBq) is added
to the solution, and a voltage of 3 V is applied. Electrolysis is
done for 15 minutes at room temperature. The stent is washed twice
with 3% aqueous sodium carbonate solution, twice with water and can
be implanted directly. The stent showed a radioactivity of 0.77
MBq.
EXAMPLE 34
Labeling of a Gold-Cemented Stent with Cu-67 with In-Situ Coupling
of the Title Compound of Example 30a Electrochemical Reduction
[0190] The Strecker stent that is described in Example 26a is fixed
in an electrolysis cell (FIG. 1), and a solution of citric acid
buffer (0.1 mol/l, pH 5) is added. 10 mg of the title compound of
Example 30a, Cu-67 solution (starting activity: 36.7 MBq) is added
to the solution, and a voltage of 1.8 V is applied. Electrolysis is
done for 15 minutes at room temperature. The stent is washed twice
with 3% aqueous sodium carbonate solution, twice with water and can
be implanted directly. The stent showed a radioactivity of 0.98
MBq.
EXAMPLE 35
Labeling with S-35
[0191] A stent that is produced according to 26a is put into a
solution that consists of 5% aqueous hydrochloric acid, and a
solution of S-35-cysteine (initial activity 37.5 MBq) is added. It
is stirred for 5 minutes at room temperature. The stent is washed
four times with physiological common salt solution. A radioactivity
of 1.35 MBq is measured.
EXAMPLE 36
Labeling of a Strecker Stent with Cu-67
[0192] A Strecker stent (93 mg) is fixed in an electrolysis cell as
described in FIG. 1. Then, the cell is made up with a 5% aqueous
hydrochloric acid solution, and a Cu-67 solution is added (starting
activity 47.4 MBq). Then, a voltage of 2 V is applied. Electrolysis
is done for 5 minutes at room temperature. The radioactive solution
is drained off via a valve, and the stent is washed four times with
physiological common salt solution. A Strecker stent whose surface
is labeled in this way contains a radioactivity of 1.56 MBq and can
be used directly as an implant.
EXAMPLE 37
Labeling of a Nitinol Stent with Cu-67
[0193] A nitinol stent (about 500 mg) was labeled analogously as
described in Example 1. Electrolysis is done for 10 minutes at 1.5
V, however. The stent showed a radioactivity of 3.21 MBq.
EXAMPLE 38
Labeling of a Nitinol Stent with Re-186
[0194] A nitinol stent (about 1000 mg) is fixed in an electrolysis
cell as described in FIG. 1. Then, phosphate buffer (0.01 mol/l, pH
5) is added. Then, an Re-186 solution (starting activity 51.4 MBq)
is added, and a voltage of 2.5 V is applied. Electrolysis is done
for 10 minutes at room temperature. The radioactive solution is
removed, and the stent is washed four times with physiological
common salt solution. The stent showed a radioactivity of 2.44
MBq.
EXAMPLE 39
Labeling of a Palmaz-Schatz Stent (316 Stainless Steel) with
Re-186
[0195] A Palmaz stent (about 200 mg) is fixed in an electrolysis
cell (FIG. 1), and a solution that consists of 5% aqueous nitric
acid, in which 150 mg of sodium chloride/ml is dissolved, is added.
An Re-186 solution (starting activity: 37.4 MBq) is added, and a
voltage of 2.3 V is applied. Electrolysis is done for 5 minutes at
room temperature. The radioactive solution is removed, and the
stent is washed four times with physiological common salt solution.
The stent showed a radioactivity of 1.98 MBq.
EXAMPLE 40
Labeling of a Strecker Stent with Au-199
[0196] A Strecker stent (about 150 mg) is in an electrolysis cell
(FIG. 1), and a solution of 7.5% aqueous hydrochloric acid is
added. Then, an Au-199 solution (starting activity: 45.2 Mbq) is
added, and a voltage of 1.5 V is applied. Electrolysis is done for
5 minutes at room temperature. The radioactive solution is removed,
and the stent is washed four times with physiological common salt
solution. The stent showed a radioactivity of 2.13 MBq.
EXAMPL 41
Labeling of Strecker Stents with Au-199
[0197] A Strecker stent (about 350 mg) is in an electrolysis cell
(FIG. 1), and a solution that consists of 2.5% aqueous hydrochloric
acid, in which 100 mg of tetramethylammonium chloride/ml is
dissolved, is added. Then, an Au-199 solution (starting activity:
55.6 MBq) is added, and a voltage of 1.2 V is applied. Electrolysis
is done for 4 minutes at room temperature. The radioactive solution
is removed, and the stent is washed four times with physiological
common salt solution. The stent showed a radioactivity of 1.81
MBq.
EXAMPLE 42
Labeling of a Z-Stent (304 Stainless Steel) with Au-199
[0198] A Z-stent (about 250 mg) is in an electrolysis cell (FIG.
1), and a solution of 2.5% aqueous nitric acid, in which 100 mg of
tetramethylammonium chloride/ml is dissolved, is added. Then, an
Au-199 solution (starting activity: 38.6 MBq) is added, and a
voltage of 1.2 V is applied. Electrolysis is done for 3 minutes at
room temperature. The radioactive solution is removed, and the
stent is washed four times with physiological common salt solution.
The stent showed a radioactivity of 1.13 MBq.
EXAMPLE 43
Labeling of a Z-Stent (304 Stainless Steel) with Ag-110
[0199] A Z-stent (about 250 mg) is in an electrolysis cell (FIG.
1), and a solution of 5% aqueous nitric acid, in which 100 mg of
tetramethylammonium nitrate/ml is dissolved, is added. Then, an
Ag-110 solution (starting activity: 56.8 MBq) is added, and a
voltage of 1.5 V is applied. Electrolysis is done for 2 minutes at
room temperature. The radioactive solution is removed, and the
stent is washed four times with physiological common salt solution.
The stent showed a radioactivity of 1.54 MBq.
EXAMPLE 44
Labeling of a Nitinol Stent (304 Stainless Steel) with Ag-110
[0200] A nitinol stent (about 1500 mg) is in an electrolysis cell
(FIG. 1), and a solution that consists of 7.5% aqueous nitric acid,
in which 150 mg of tetramethylammonium nitrate/ml is dissolved, is
added. Then, an Ag-110 solution (starting activity: 39.4 MBq) is
added, and a voltage of 1.4 V is applied. Electrolysis is done for
10 minutes at room temperature. The radioactive solution is
removed, and the stent is washed four times with water and twice
with physiological common salt solution. The stent showed a
radioactivity of 1.78 MBq.
EXAMPLE 45
Labeling of a Nitinol Stent with In-111
[0201] A nitinol stent (about 1500 mg) is in an electrolysis cell
(FIG. 1), and a solution of 5% aqueous citric acid, in which 150 mg
of tetramethylammonium chloride/ml is dissolved, is added. Then, an
In-111 solution (starting activity: 51.3 MBq) is added, and a
voltage of 3.5 V is applied. Electrolysis is done for 7 minutes at
room temperature. The radioactive solution is removed, and the
stent is washed twice with water and twice with physiological
common salt solution. The stent showed a radioactivity of 1.45
MBq.
EXAMPLE 46
Labeling of a Z-Stent with In-111
[0202] A Z-stent (about 500 mg) is in an electrolysis cell (FIG.
1), and a solution that consists of 5% aqueous citric acid, in
which 150 mg of tetramethylammonium chloride/ml is dissolved, is
added. Then, an In-111 solution (starting activity: 36.9 MBq) is
added, and a voltage of 3.8 V is applied. Electrolysis is done for
12 minutes at room temperature. The radioactive solution is
removed, and the stent is washed twice with water and twice with
physiological common salt solution. The stent showed a
radioactivity of 1.77 MBq.
EXAMPLE 47
Labeling of a Strecker Stent with Au-199
[0203] In a cementation vessel (FIG. 2b), a Strecker stent (about
93 mg) is mixed with an aqueous hydrochloric acid solution (pH 3).
Au-199 chloride solution (starting activity: 32.6 MBq) is added,
and it is stirred for 10 minutes at room temperature. The stent is
washed four times with physiological common salt solution and can
be used directly for implantation. The stent showed a radioactivity
of 1.22 MBq.
EXAMPLE 48
Labeling of a Strecker Stent with Ag-110
[0204] In a cementation vessel (FIG. 2a), a Strecker stent (about
496 mg) is mixed with an aqueous nitric acid solution (pH 4).
Ag-110 nitrate solution (starting activity: 37.6 MBq) is added, and
it is stirred for 10 minutes at room temperature. The stent is
washed four times with dilute nitric acid (pH 3) and twice with
water, and it can be used directly for implantation. The stent
showed a radioactivity of 1.02 MBq.
EXAMPLE 49
Labeling of a Z-Stent with Au-199
[0205] In a cementation vessel (FIG. 2a), a Z-stent (about 987 mg)
is mixed with an aqueous hydrochloric acid solution (pH 3). Au-199
chloride solution (starting activity: 41.5 MBq) is added, and it is
stirred for 10 minutes at room temperature. The stent is washed
four times with physiological common salt solution and can be used
directly for implantation. The stent showed a radioactivity of 1.13
MBq.
EXAMPLE 50
Labeling of a Nitinol Stent with Au-199
[0206] In a cementation vessel (FIG. 2b), a nitinol stent (about
488 mg) is mixed with an aqueous hydrochloric acid solution (pH 3).
Au-199 chloride solution (starting activity: 39.7 MBq) is added,
and it is stirred for 10 minutes at room temperature. The stent is
washed four times with physiological common salt solution and can
be used directly for implantation. The stent showed a radioactivity
of 0.98 MBq.
EXAMPLE 51
Labeling of a Strecker Stent with Re-186
[0207] A Strecker stent is brought into an electrolysis cell (FIG.
1), and a solution of sulfuric acid zinc sulfate solution (50
mg/ml, pH 5) is added. After a zinc anode is introduced,
electrolysis is done at a voltage of 1.5 V for 10 minutes. The
galvanized stent is washed four times with water. In a cementation
vessel (FIG. 2a), the above-described stent is mixed with an
aqueous citric acid solution (pH 5). Re-186 solution (starting
activity: 41.6 MBq) is added, and it is stirred for 10 minutes at
room temperature. The stent is washed four times with physiological
common salt solution and can be used directly for implantation. The
stent showed a radioactivity of 1.31 MBq.
EXAMPLE 52
Labeling of a Z-Stent (304 Stainless Steel) with Re-186
[0208] A Strecker stent is brought into an electrolysis cell (FIG.
1), and a solution of hydrochloric acid tin(II) chloride solution
(50 mg/ml, pH 5) is added. After a tin anode is introduced,
electrolysis is done at a voltage of 3 V for 5 minutes. The stent
that is thus tinned is washed four times with water. In a
cementation vessel (FIG. 2a), the above-described stent is mixed
with an aqueous citric acid solution (pH 5). Re-186 solution
(starting activity: 37.7 MBq) is added, and it is stirred for 10
minutes at room temperature. The stent is washed four times with
physiological common salt solution and can be used directly for
implantation. The stent showed a radioactivity of 1.44 MBq.
EXAMPLE 53
Labeling of a Nitinol Stent with Cu-67
[0209] In a cementation vessel (FIG. 2b), a nitinol stent (about
488 mg) is mixed with an aqueous hydrochloric acid solution (pH 3).
Cu-67 sulfate solution (starting activity: 24.6 MBq) is added, and
it is stirred for 10 minutes at room temperature. The stent is
washed four times with physiological common salt solution and can
be used directly for implantation. The stent showed a radioactivity
of 1.55 MBq.
EXAMPLE 54
Labeling of a Palmaz Stent (316 Stainless Steel) with Cu-67
[0210] In a cementation vessel (FIG. 2a), a Palmaz stent (about 977
mg) is mixed with an aqueous hydrochloric acid solution (pH 3).
Cu-67 sulfate solution (starting activity: 24.6 MBq) is added, and
it is stirred for 10 minutes at room temperature. The stent is
washed four times with physiological common salt solution and can
be used directly for implantation. The stent showed a radioactivity
of 0.88 MBq.
EXAMPLE 55
Labeling of a Palmaz Stent (316 Stainless Steel) with Re-186
[0211] A Palmaz stent is brought into an electrolysis cell (FIG.
1), and a solution of hydrochloric acid tin(II) chloride solution
(50 mg/ml, pH 5) is added. After a tin anode is introduced,
electrolysis is done at a voltage of 3 V for 5 minutes. The thus
tinned stent is washed four times with water. In a cementation
vessel (FIG. 2b), the above-described stent is mixed with an
aqueous citric acid solution (pH 5). Re-186 solution (starting
activity: 34.5 MBq) is added, and it is stirred for 10 minutes at
room temperature. The stent is washed four times with physiological
common salt solution and can be used directly for implantation. The
stent showed a radioactivity of 1.98 MBq.
EXAMPLE 56
Labeling of a Palmaz Stent (316 Stainless Steel) with Ag-110
[0212] In a cementation vessel (FIG. 2a), a Palmaz stent (about 977
mg) is mixed with an aqueous nitric acid solution (pH 4). Ag-110
sulfate solution (starting activity: 24.6 MBq) is added, and it is
stirred for 10 minutes at room temperature. The stent is washed
four times with water and can be used directly for implantation.
The stent showed a radioactivity of 1.12 MBq.
EXAMPLE 57
[0213] A Palmaz stent (15 mm, 80.3 mg, Johnson and Johnson) is
covered with a layer of 1.0 ml of labeling solution that consists
of 173 .mu.l of sodium perrhenate solution (164 MBq) and 827 .mu.l
of 1N HCl. The reaction vessel is placed in an ultrasound bath (80%
US power) for 60 minutes at 50.degree. C. Then, the stent is
removed, rinsed with distilled H.sub.2O and dried. The dried stent
carries an activity of 36.2 MBq=0.45 MBq/mg of stent. To remove
non-specifically-bonded activity, the stent is incubated for 60
minutes in 1 ml of 0.9% NaCl solution at 37.degree. C. After
drying, the stent still carries an activity of 9.7 MBq=0.12 MBq/mg
of stent.
EXAMPLE 58
[0214] A Palmatz stent (1/11 stent=26.2 mg, Johnson & Johnson)
is covered with a layer of 1.5 ml of labeling solution that
consists of 60 .mu.l of perrhenate solution (60 MBq) and 1440 .mu.l
of IN HCl. The reaction vessel is tightly sealed and heated for 30
minutes to 100.degree. C. (boiling water bath). Then, the stent is
removed, rinsed with distilled H.sub.2O and dried. The dried stent
carries an activity of 25.9 MBq (0.98 MBq/mg of stent). To remove
or fix non-specifically-bonded activity, the stent is incubated for
10 minutes in 2 ml of 0.1 M gentisic acid/0.1 M SnCl.sub.2 solution
while being shaken. After drying, the stent carries an activity of
16.1 MBq (0.61 MBq/mg of stent).
EXAMPLE 59
[0215] A Palmatz stent (31.4 mg, Johnson & Johnson) is covered
with a layer of 1.5 ml of labeling solution that consists of 60
.mu.l of sodium perrhenate solution (81 MBq) and 1440 .mu.l of 0.75
N HCl. The reaction vessel is tightly sealed and heated for 30
minutes to 100.degree. C. (boiling water bath). Then, the stent is
removed, rinsed with distilled H.sub.2O and dried. 27.1 MBq (0.86
MBq/mg of stent) is fixed on the dried stent. To remove
non-specifically-bonded activity, the stent is then incubated in 2
ml of 0.1 M alcoholic tetrabutylammonium bromide solution for 10
minutes while being shaken. After drying, 17.0 MBq (0.54 MBq/mg of
stent) is fixed on the stent.
EXAMPLE 60
[0216] After drying at room temperature several times, the stent of
Example 59 is immersed in a solution that consists of 16% vinyl
acetate-acrylate polymer in ethyl acetate. After drying, the stent
is ready for use. TABLE-US-00014 Legend 1 Cover 2 Septum 3 Septum 4
Cell (Teflon or glass) 5 Stent 6 Solution 7 (+) Pt-anode, ring
anode 8 Magnetic stirring rod 9 (-) Pt-cathode 10 Shutoff valve 11
2-way Valve 12 Magnetic stirrer 13 Rinsing liquid 14 Active
solution
Addition of solutions: Hypodermic syringes or metering pumps When
addition is done with hypodermic syringes: Put septa in the
cover.
[0217] If electrolysis is carried out at an elevated temperature,
the solution is preheated.
* * * * *