EP1218570A1 - Dispositif a revetement radioactif et procede de fabrication de ce dernier destine a empecher la restenose - Google Patents

Dispositif a revetement radioactif et procede de fabrication de ce dernier destine a empecher la restenose

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Publication number
EP1218570A1
EP1218570A1 EP00955988A EP00955988A EP1218570A1 EP 1218570 A1 EP1218570 A1 EP 1218570A1 EP 00955988 A EP00955988 A EP 00955988A EP 00955988 A EP00955988 A EP 00955988A EP 1218570 A1 EP1218570 A1 EP 1218570A1
Authority
EP
European Patent Office
Prior art keywords
radioactive
angioplastic device
angioplastic
oligonucleotide
molecule
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00955988A
Other languages
German (de)
English (en)
Inventor
Guy Leclerc
Jeannette Fareh
Philippe Leblanc
Luc Levesque
Rémi Martel
Svetlana Kudrevich
Marcus F. Lawrence
Bernard Bourguignon
Jean Lessard
Sonia Blais
Jean-Marc Chapuzet
Michel Meunier
Têko Napporn
Suzie Poulin
Edward Sacher
Oumarou Savadogo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Angiogene Inc
Original Assignee
Angiogene Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Angiogene Inc filed Critical Angiogene Inc
Publication of EP1218570A1 publication Critical patent/EP1218570A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/44—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes for electrophoretic applications
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D13/00—Electrophoretic coating characterised by the process
    • C25D13/04—Electrophoretic coating characterised by the process with organic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0095—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof radioactive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M25/0045—Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/104—Balloon catheters used for angioplasty
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
    • A61N5/1002—Intraluminal radiation therapy

Definitions

  • the invention relates to a radioactively coated device and to a method of making same by deposition of a radioisotope-containing molecule on the device,
  • beta-emitter source i.e., 32 P, 90 Y, 90 Sr/Y
  • gamma-emitter isotopes 192 Ir
  • Radioactive stent in interventional cardiology is the complex clinical prescription of the metallic prosthesis (diameter, length, type, etc.) associated with the choice of the radioisotope and the activity in function of the physical half-life. Regarding those specifications, the production of an active inventory of such device in a daily practice can be difficult and problematic. A major difficulty to overcome is the need to load any pre-manufactured stents with defined amounts of radioactivity at the time of use. Using stents that are preloaded by the manufacturer is not ideal because the stent specifications (specific radioactivity, length diameter, etc.) may differ from the need.
  • Hafeli et al . (Biomaterials 19:925-933, 1998) suggested a method for electrodepositing Rhenium ( 186 Re or 188 Re) on a stent.
  • Hafeli et al . teach that rhenium alone do not electroporate well by itself, and that they had to co-deposit the rhenium with cobalt. Again co-deposition with cobalt caused cracking and flaking of the deposited layer.
  • Hafeli et al . deposited over the layer of cobalt rhenium previously deposited a second layer of gold to overlay cobalt and thus prevent cracking.
  • Hafeli et al . also teach that gold, being a noble metal compete with rhenium during the deposition such that gold is deposited preferentially over rhenium.
  • radioactivity emitting source such as 32 P- oligonucleotide based
  • a strong and rapid deposition process of radioactivity emitting source such as 32 P- oligonucleotide based
  • 32 P- labeled oligonucleotide was already demonstrated in an in vi tro model (Fareh et al . , Circulation, 99:1477-1484, 1999).
  • One aim of the present invention is to provide a strong and rapid deposition process of radioactive molecule on the surface of an angioplastic device for preventing restenosis post-angioplasty .
  • a method for depositing a charged molecule on an angioplastic device comprises the step of contacting the angioplastic device with a solution containing the charged molecule under suitable conditions for deposition of the charged molecule on the angioplastic device.
  • the charged molecule is preferably a radioactive charged molecule.
  • the deposition can be passive or active. By active deposition, it is meant to comprise electrodeposition .
  • the angioplastic device has preferably stainless steel or gold on its surface.
  • the charged molecule preferably comprises a thiol -containing group for attaching to the gold on the angioplastic device.
  • the surface is preferably coated with silicon oxyde (Si0 2 > or silicon (Si) to be modified with chemical or electrochemical treatments for its functionnalization.
  • Stainless steel surface can be also directly used for electrochemical functionnalization. Also in accordance with the present invention, there is provided a method for immobilizing a charged molecule on an angioplastic device using passive deposition or electrodeposition.
  • the method comprises the step of applying an electric potential difference between the angioplastic device and a solution containing the charged molecule, said charged molecule having a charge opposite to the electric potential difference and being thereby electrodeposited on the angioplastic device.
  • the electric potential difference can be made positive or negative, depending on the charge of the molecule to be coated on the device.
  • the radioactive molecule comprises a ⁇ - emitter.
  • Preferred ⁇ -emitters are selected from the group consisting of Antimony-124, Cesium-134, Cesium- 137, Calcium-45, Calcium-47, Cerium 141, Chlorine-36, Cobalt-60, Europium-152, Gold-198, Hafnium-181, Holmiun-166, Iodine-131, Iridium-192, Iron-59, Lutetium-177, Mercury-203 , Neodymium-147 , Nickel-63, Phosphorus-32 , Phosphorus-33 , Rhenium- 186, Rhodium- 106, Rubidium-86, Ruthenium- 106 , Samarium-153 , Scandium-46, Silver-llOm, Strontium-89 , Strontium-90 , Sulfur-35, Technetium-99, Terbium-160, Thulium-170, Tungsten- 188, Yttrium- 90 and X
  • the radioactive molecule is preferably selected from the group consisting of a radioactive DNA or an analog thereof, a radioactive RNA, a radioactive nucleotide, a radioactive oligonucleotide, radioactive H 2 P0 4 , radioactive diethylenetriaminepenta- acetic acid, and a radioactive polyanionic complex. More preferably the radioactive molecule is a radioactive oligonucleotide.
  • the oligonucleotide is preferably a 8- to 35-mer oligonucleotide, more preferably a 8- to 20-mer oligonucleotide, and most preferably a 15-mer oligonucleotide.
  • molecules are preferably selected from the group consisting of conjugated cationic polypeptides, cationic peptides, dextran, polyamines and chitosan. These molecules are preferably radioactive molecules. These molecules form positive ions in solutions and are therefore attracted onto the angioplastic device.
  • the angioplastic device may be for example a stent.
  • the angioplastic device has a metallic surface, such as stainless steel, gold, tantalum, nickel and titanium or any alloy thereof.
  • the method of the present invention may further comprise before the step of applying an electric potential difference, a step of surface cleaning of the angioplastic device with a solvent, electrochemical or argon-ion sputtering treatments for removing impurities at the surface of said angioplastic device, or, after the step of applying an electric potential difference, a further step of rinsing the angioplastic device for removing free molecule at the surface of said angioplastic device.
  • the surface of the angioplastic device is functionnalized for molecule coating.
  • the angioplastic device may be functionnalized for example with a diazonium treatment . Still in accordance with the present invention, there is provided an angioplastic device for preventing restenosis in a coronary and/or peripheral artery, said device comprising a radioactive charged molecule deposited on its surface.
  • a method for preventing restenosis in a coronary and/or peripheral artery comprising implanting an angioplastic device as defined above at a site of potential restenosis such as coronary and/or peripheral artery in a patient in need of such a treatment.
  • the method of the present invention is rapid and allows obtaining a radioactively coated device, on which a radioisotope-containing molecule is effectively and uniformly deposited. No adverse effects of deposition treatment are observed in coated stent in vi tro (mechanical and colorless properties) and in vivo (clotting, thrombogenicity) . Strong and effective binding of 32 P-oligonucleotides on metallic surface was obtained. Since the method of the present invention is rapid, it also allows to use simultaneously a stent with radiotherapy for preventing restenosis. It is now possible with the method of the present invention to attach a radioisotope-carrying molecule on a device such as a stent, according to a simple method. The simplicity of the method allows for that method to prepare a radioactively coated stent to be used for implantation just moments after its preparation.
  • radioactively coated device it is intended to mean any device used in the art for treating restenosis. Such device can be without limitation a stent or a radioactive filament for radiotherapy at the site of restenosis or at the site of angioplasty for preventing restenosis in coronary or peripheral vessels .
  • angioplastic device it is intended to mean any device used for angioplasty for which radiotherapy would be beneficial. Such device may be without limitation a stent or a wire or any other device to which a person of the art may think of for the prevention of an uncontrolled proliferative lesion.
  • angioplastic device is also meant to include any prosthesis to be implanted within a vessel or within other body conduit such as, but not restricted to, the bile duct or urethra for the purpose of endovascular treatment .
  • analog of DNA it is intended to mean nucleic acid sequences such as double-strand DNA sequences, single-strand DNA sequences, RNA or any combination thereof.
  • radioactive polyanionic complex it is intended to means a molecule carrying at least one radioactive element and bearing at least one negative charge .
  • Fig. 1 illustrates a schematic electrodeposition set-up in accordance with a preferred embodiment of the present invention
  • Fig. 2 is a schematic reaction chamber for glicidoxy-propyltriethoxy silane (GPTS) modification for passive deposition;
  • GPTS glicidoxy-propyltriethoxy silane
  • Fig. 3 illustrates a schematic electrodeposition set-up used for diazonium functionnalization of silicon and stainless steel surfaces for passive deposition
  • Fig. 4 shows the effect of duration of passive deposition of 32 P-oligonucleotide on bromobenzenediazonium coated stainless steel surface
  • Fig. 5 is a line graph of electrodeposition of 15-mer oligonucleotide on gold electrode as a function of potential
  • Fig. 6 illustrates the adsorption isotherm of 15-mer oligonucleotide on gold electrode at different pH of the electrolyte solutions ,-
  • Fig. 7 illustrates the adsorption isotherm of 8-mer oligonucleotide at different concentrations on gold electrode
  • Fig. 8 illustrates the effect of duration of polarization on the level of coating of radioactive 15-mer oligonucleotide onto gold plated stent
  • Fig. 9 illustrates the effect of increasing activity of radioactive 15-mer oligonucleotide on coating onto gold plated stent
  • Fig. 10 illustrates the effect of duration of polarization on the level of coating of radioactive 15-mer oligonucleotide onto stainless steel stent
  • Fig. 11 illustrates the effect of increasing activity of radioactive 15-mer oligonucleotide on coating onto stainless steel stent
  • Fig. 12 is a scan graph of gold plated stents coated with the electrochemical method of the present invention illustrating the distribution of the radioactive molecules onto the metallic surface along the length of the stent;
  • Fig. 13 is a scan graph of stainless steel stents coated with the electrochemical method of the present invention illustrating the distribution of the radioactive molecules onto the metallic surface along the length of the stent;
  • Fig. 14 is a line graph of the in vi tro retention profile of 32 P-oligonucleotide coated onto the surface of a gold plated stent
  • Fig. 15 is a line graph of the in vi tro retention profile of 32 P-oligonucleotide coated onto the surface of a stainless steel stent
  • Fig. 16 is a line graph of the retention profile of 32 P-oligonucleotide-coated gold stent (16 mm) when implanted in porcine coronary;
  • Fig. 17 is a line graph of the retention profile of 32 P-oligonucleotide-stainless steel stent (18 mm) when implanted in porcine coronary artery.
  • the deposition is an electrodeposition as illustrated in Fig. 1 with the potentiostat/Galvanostat (EG&G model 273A) 20, hereinafter referred to as the potentiostat.
  • Fig. 1 illustrates the Schematic drawing of the electrochemical cell and angioplastic device used for radioactive molecule coating onto gold and stainless steel surfaces.
  • electrodeposition is effected under a nitrogen atmosphere (N 2 ) , in a glass cell 22.
  • the stent 24, which acts as the working electrode, is submerged in the electrolyte 26 with a reference electrode 28 (preferably a PdH 2 electrode) and a counter electrode 30 (Pt plate) .
  • the three electrodes are connected to the potentiostat 20, which is itself connected to a computer 32 for recording the working conditions.
  • the cell 22 is provided with a cover 34 provided with holes for allowing the wires of the electrodes to pass through.
  • the cover 34 is also provided with a gas inlet 36 and a gas outlet 38 for allowing nitrogen to be circulated.
  • the deposition is a passive deposition in which case the set up is similar to the one illustrated in Fig. 1, with the exception that no potentiostat 20 is needed.
  • the alternate method of depositing a radioactive polyanionic complex comprises the step of modifying the oligonucleotide by adding a thiol -containing group.
  • the thiol -containing group may be for example a C 6 chain carrying a thiol function at its extremity and which is added at the 5' end of the oligonucleotide.
  • the so-modified oligonucleotide may be labeled with 3 P or other radioactive elements.
  • a gold or gold-coated stent is incubated in either 0.1M potassium phosphate buffer (KH 2 P0 4 pH 7.0) or pure tetrahydrofuran containing the radiolabeled oligonucleotide. After a 60 minute incubation period at room temperature, the stent is rinsed with distilled water. The radioactive oligonucleotide attaches to gold by the thiol group, producing a radioactively coated stent.
  • This preferred embodiment is only an example (refer to example I) of passive deposition caused by the high affinity of gold for thiol group.
  • Another example of passive deposition is based on the surface coating with silicon (Si) or silicon oxyde (Si0 2 > followed by surface functionnalization with substrates.
  • the Si0 2 -treated surface is then modified with glicidoxy-propyltriethoxy silane (GPTS) , whereas the Si-treated surface is functionnalized with 4-bromobenzenediazonium tetrafluoroborate (diazonium).
  • GPTS glicidoxy-propyltriethoxy silane
  • Stainless steel surface can be directly activated with 4-bromobenzenediazonium tetrafluoroborate without Si/Si02 pre-treatment .
  • the GPTS modification is passive (Fig. 2), whereas the diazonium deposition is an electrochemical functionalization, in which case the set up is similar to the one illustrated in Fig. 3.
  • Fig. 2 illustrates a Schematic drawing of the reaction chamber for glicidoxy-propyltriethoxy silane (GPTS) modification of silicon oxyde treated surfaces.
  • GPTS glicidoxy-propyltriethoxy silane
  • the substrates are taken out of the oven they are placed in the various slots of the 2 glass holders 50. Each holder is hooked to the reaction chamber 52 were the silanization will take place. The whole lot is then placed inside a glove box which is under dry N 2 atmosphere. Once inside the glove box the GPTS reaction compounds were then added, in sequence, to the reaction chamber. A magnetic stirring bar 54 is added to the reaction mixture, the reaction chamber is then closed and removed from the glove box. The reaction chamber is connected to a water circulator 56 with temperature control. Stirring is initiated and the reaction is allowed to proceed for 4 hours at 70°C, under continuous N 2 flow 58 originating from a gas tank.
  • Fig. 3 illustrates Schematic drawing of the electrochemical cell used for bromobenzenediazonium functionnalization of silicon and stainless steel surfaces .
  • the electrochemical cell 22 was a standard three-electrode setup.
  • the reference electrode 28 used was a saturated Calomel electrode (SCE) and the counter electrode 30 was platinum foil (1 cm 2 ) .
  • the bromo-aryldiazonium solution was used as the electrolyte for cyclic voltammetry in order to attach the bromo-aryldiazonium to the surface (0.5 cm 2 area) of the Si or 316L substrates acting as working electrode 24.
  • a scanning potentiostat was used to apply dc potentials to the working electrodes.
  • the current-voltage response was recorded on an XY recorder.
  • the alternate method of depositing a radioactive polyanionic complex comprises the step of modifying the oligonucleotide by adding an amine-containing group.
  • the amine-containing group may be for example a C e chain carrying an amine function at its extremity and which is added at the 5' end of the oligonucleotide.
  • the so-modified oligonucleotide may be labeled with 32 P or other radioactive elements.
  • This preferred embodiment is only an example of passive deposition caused by the high affinity of GPTS and diazonium substrates for amine group.
  • the radioisotope can be attached to other radioisotope- carrying molecule.
  • a negatively charged molecule can be used for an effective electrodeposition onto the stent surface.
  • Preferred negatively charged molecules can be for example without limitation labeled DNA or RNA, or labeled analogs thereof, labeled nucleotides, radioactive H 3 P0 4 , labeled diethylene triamine pentaacetic acid (DTPA) or labeled polyanionic complexes .
  • a positively charged molecule can be used for an effective electrodeposition onto the stent surface.
  • Such positively charged molecule can be for example without limitation labeled conjugated polypeptides, labeled cationic peptides, labeled dextran, labeled chitosan or labeled polyamines.
  • the vehicle carrying the radioisotopic source such as a beta-source ( 32 P) is preferably a short DNA sequence (15 mer oligonucleotides linked together by 11 phosphorothioate bounds) , rendering the molecule stable over a long time. Strong binding of DNA- oligonucleotides was reported on gold (Sellergren et al., Anal . Chem . , 68 (2) : 402-407 , 1996).
  • a first non-radiolabeled strand of this double-stranded nucleic acid can be coated on the stent in accordance with one embodiment of the invention.
  • the second complementary strand of the double-stranded nucleic acid can be labeled and annealed to the first strand.
  • a radioactively coated device While a ⁇ -emitter source of radioisotope is preferred, other sources of radioisotope can also be used in accordance with the present invention.
  • the radioisotopic source is determined according to the treatment determined. Depending on the cases, the radiotherapy might vary from one patient to another. Accordingly, the radioisotopic source will be determined based on the half-life of the radioisotopic source, its energy and the specific activity of the radioisotopic source desired. The determination of the radioisotopic source is within the skill of a person of the art.
  • the radioactive molecule comprises a ⁇ - emitter.
  • Preferred ⁇ -emitters are selected from the group consisting of Antimony-124, Cesium-134, Cesium- 137, Calcium-45, Calcium-47, Cerium 141, Chlorine-36, Cobalt-60, Europium-152 , Gold-198, Hafnium-181, Holmiun-166, Iodine-131, Iridium-192, Iron-59, Lutetium-177, Mercury-203, Neodymium-147 , Nickel-63, Phosphorus-32 , Phosphorus-33 , Rhenium- 186, Rhodium- 106, Rubidium- 86, Ruthenium- 106 , Samarium- 153 , Scandium-46, Silver-llOm, Strontium-89 , Strontium-90 , Sulfur-35, Technetium-99, Terbium-160, Thulium-170, Tungsten-188, Yttrium-90 and
  • ACS multi-link RX DUETTM stents (Guidant Vascular Intervention, Santa Clara, CA) of 13 to 23 mm of length were used in accordance with the present invention.
  • Commercial 316L stainless steel samples in the form of 1 cm diameter discs, 0.2 mm thick (Goodfellow Cambridge Ltd., Huntingdon, England) were also used.
  • Deposition or electrodeposition is more effective when the surface to be coated is cleaned to remove contaminants.
  • stents to be coated were first washed with organic solvents (acetone or methanol) for removing contaminants and then air- dried.
  • organic solvents acetone or methanol
  • Another example of surface cleaning is argon- ion sputtering. The sputtering of stents or discs was carried out under the following conditions :
  • An electrochemical method can also be used for cleaning stainless steel surface (stents or discs) .
  • Electropolishing was carried out in the glove box using a voltage generator.
  • the cleaning solution was composed of 1 M oxalic acid 15% hydrogen peroxide. Only two electrodes were used : the sample was one and the other, a Pt disk. A potential of 10 V was applied for 10 minutes between these electrodes, followed by extensive rinsing and transferred to the electrochemical deposition cell of Fig. 1.
  • NIROYALTM 24 ct gold plated stents (Boston Scientific Ireland Ltd. Ballybrit Business Park, Galway, Ireland) of 13 to 23 mm of length were used in accordance with the present invention.
  • Gold-coated 316L discs in the form of 1 cm diameter discs (Goodfellow) were also used.
  • Gold surface can be directly used for electrodeposition or cleaned with argon- ion sputtering in conditions as previously described for stainless steel metal .
  • the vehicle chosen for carrying the beta-source ( 32 P) is a short DNA sequence (15 mer oligonucleotides linked together by 11 phosphorothioate bounds, patent No. 5,821,354). This short DNA sequence was reported to be highly stable and effective in the prevention of cell proliferation with no side effects (Fareh et al . , Circulation, 99:1477-1484, 1999).
  • the radioactive molecule has at its 5 ' end either an amine-containing group as for example a C 6 chain carrying an amine function or a C 6 chain carrying a thiol function.
  • the amine- and thiol-modified oligonucleotides may be labeled with 32 P or other radioactive elements.
  • Electrodeposition is effected in an electrochemical cell containing the 32 P- oligonucleotides (75 ⁇ Ci/50 ⁇ L of water) diluted in 250 ⁇ L of acetate sodium buffer, (CH 3 CH 2 C0 2 Na .3H 2 0 at 0.2 M) at pH 8.5.
  • a metallic stent was fixed to the anode and the cathode was composed of a platinum wire of 2 mm diameter and 5 cm length or a Pt plate.
  • Electrodeposition is performed by applying a voltage of 1 Volt (50-60 mA) for 15 minutes using a standard potentiostat 20 at room temperature.
  • Electrodeposition succeeds in binding 2.5% of initial 32 P-oligonucleotides on the stent surface, when any post-treatments were applied.
  • electrolytes for effective electrodeposition is aqueous phosphate solutions.
  • the scan rate is 100 mV/s.
  • An arrow indicates the beginning of the scan.
  • Kel-F was chosen as the support material because it is inert in acidic and basic aqueous media.
  • the electrode was polished with a 0.5 ⁇ m alumina suspension.
  • Aqueous phosphate solutions were prepared from a Na 2 HP0 4 ' 7H0 (17.8897 g/L) and a KH 2 P0 4 (9.0725 g/L) solutions.
  • SCE calomel reference electrode
  • the adsorption isotherm of non- radioactive 15-mer oligonucleotide on gold at 1.1 V vs. SCE is presented for the three buffered solutions studied.
  • electrosorption of 8-mer oligonucleotides is effective onto gold electrode surface, when applying a voltage of 1.2 V during 15 minutes at room temperature. Higher electrosorption was obtained when polarization was performed at 60°C. Similar adsorption isotherm of a 35-mer oligonucleotide was reported.
  • 32 P-oligonucleotide depositions were carried out in 0,1 M HC10 4 under nitrogen (bubbler), at a potential of 1,45 V vs . SCE (saturated calomel electrode) and at a temperature of 60 ⁇ 10 °C . For that preferred embodiment, higher coating was obtained at 60°C. However, coating of 32 P-oligonucleotide onto stainless steel or gold surfaces is also feasible and effective at room temperature .
  • the electrochemical cell (Fig. 1) was composed of three electrodes : i) the working electrode (our sample) ; ii) the counter electrode (Pt disk) ; and the reference electrode (Pd/PdH 2 ) , calibrated before each measurement .
  • the reference electrode is made by flowing hydrogen on a Pd disk in 0,1 M HC10 4 for 30 minutes.
  • Fig. 8 illustrates the effect of coating duration on electrodeposition level (16 mm-gold plated stents) .
  • the maximal coating was reached at 5 to 15 min on gold surface, underlying the rapid and effective electrodeposition of 3 P-oligonucleotide onto the gold stent (average of 1.6%) .
  • Fig. 9 reports the activity-dependent coating onto gold surface when increasing activity of 3 P- oligonucleotide (0.25, 0.5, 1 and 2 mCi) were tested during 5 minutes. However, higher effective coating was obtained at low initial activity (1.9%, 1.2%, 0.8% and 0.5% for 0.250, 0.500, 1.0 and 2.0 mCi respectively) .
  • Fig. 10 illustrates the effect of coating duration on electrodeposition level (18 mm-stainless steel stents) .
  • a similar coating of 0.5% was obtained at 5 to 15-20 min to reach a maximal coating (1.0%) at 60 min on stainless steel surface, underlying the rapid and effective electrodeposition of 32 P-oligonucleotide onto the stainless steel stent.
  • 3 P- oligonucleotide (0.25, 0.5, 1 and 2 mCi) were tested, similar coating with activity of 0.25 to 1.0 mCi (average of 2.5-3.0 ⁇ Ci) were obtained, whereas higher activity (2.0 mCi) led to significant amount of 32 P- oligonucleotide onto the stainless steel stent surface
  • Fig. 11 illustrates the effect of increasing activity of 32 P- oligonucleotide on coating efficiency (18 mm-stainless steel stents) . Similar levels were obtained when the stainless steel surface was cleaned with argon-ion sputtering .
  • the electrodeposition was highly uniform on the metallic surface of gold plated (Fig. 9) and stainless steel stents (Figs. 12 and 13) .
  • Figs 12 and 13 illustrate scan graphs of a gold plated stent or of a stainless steel stent, respectively, coated with 3 P- oligonucleotide . Similar uniform distribution of radioactivity was also obtained when acetate sodium buffer as electrolytes was used to perform electrodeposition in the set-up of Fig. 1.
  • radioactive stents were rinsed in distilled water for 24 hours at room temperature and air-dried or sonicated for 30 minutes.
  • Biological treatments were investigated by incubating radioactive stents with DMEM supplemented with an enzyme solution consisting of 5 ⁇ l of Nuclease Si (332 U/ ⁇ l) , 1 ⁇ l of Exonuclease III (E. coli; 100 U/ ⁇ l), and 1 ⁇ l of phosphodiesterase (0.5 U/ ⁇ l) in presence of 10% Fetal Bovine Serum (FBS, Gibco) overnight at 37°C.
  • Nuclease Si 332 U/ ⁇ l
  • E. coli Exonuclease III
  • phosphodiesterase 0.5 U/ ⁇ l
  • Fig. 14 illustrates the retention profile of coated 32 P- oligonucleotide onto 16 mm-gold plated stent surface in in vi tro conditions (blood mimicking conditions) . As illustrated in Fig.
  • Fig. 15 illustrates the retention profile of coated 32 P-oligonucleotide onto 18 mm-stainless steel stent surface in in vi tro conditions (blood mimicking conditions) . As illustrated in Fig.
  • the metallic surface can be embedded in a simple manner.
  • a series of biostable coatings and agar solution of 1 to 2% were tested and shown to improve the molecule retention by reducing the elimination of the 32 P-oligonucleotide from the metallic surface.
  • Polymer coating (such as parylene) already used for medical application is proposed to embed the angioplastic device.
  • the well-defined elution from the coated stents can serve as a local drug delivery device to prevent restenosis, based on data obtained on intra-arterial sustained- release of beta particles. In that case no device embedding is performed.
  • Mechanical properties of the radioactive coated stents can serve as a local drug delivery device to prevent restenosis, based on data obtained on intra-arterial sustained- release of beta particles. In that case no device embedding is performed.
  • the angiography was then performed in at least two near orthogonal views that visualize the target site of right coronary artery (RCA) or left circumflex artery (LCX) of the pig.
  • a quantitative coronary angiography (QCA) measure was done to assess the vessel size for adequate stent implantation.
  • Stent was advanced to the target site and balloon inflation at 10 to 12 atm for 30 seconds was performed to adequately deploy the stent (2 stents per pig) .
  • the balloon was deflated and the catheter withdrawn.
  • Control angiography was then performed to document any residual luminal stenosis or vessel wall dissection. If spasm was documented, 1 ml of nitroglycerin solution at a concentration of 0.3 mg/mL was injected intra- coronary. Macroscopical observations
  • stent implantation After stent implantation, treated pigs were maintained for 6 hours under observation. Following pig euthanasia with a lethal dose of KCl , myocardium was dissected to remove stented arteries. A macroscopical observation of the heart and stented artery was performed to explore the potential side effects of coating stent implantation (thrombogenicity, clotting, etc.) . Stents were then removed from the artery to be counted to assess the in vivo retention of 32 P-oligonucleotides onto the stent surface. For that example, coated-stents generated with acetate sodium buffer as electrolytes and Fig. 1 as electrochemical set-up were used for coronary implantation
  • the catheter-based radiation detection via the endovascular detector permits the fine and continuous determination of the elution profile of the radioactive molecule from the stent.
  • gold-plated (16 mm) and stainless steel (18 mm) stents were used.
  • 32 P-coated stents, generated with HCL0 4 as electrolytes, were implanted in porcine coronary arteries (LCX and RCA) for 3 hours as previously described.
  • LCX and RCA porcine coronary arteries
  • measurements of radioactivity levels were done every 30 seconds to follow local 32 P-oligonucleotide elution from the stent.
  • the pig was sacrificed with a lethal dose of KCl, myocardium was dissected to remove stented arteries. Blood was collected during the experiment .
  • Figs. 16 and 17 illustrate the retention profile of coated 32 P-oligonucleotide gold-plated stent (16 mm) and coated 32 P-oligonucleotide stainless steel stent (18 mm) , respectively, when implanted in porcine coronary artery.
  • the elution profile of gold-plated and stainless steel stents, electrocoated with 32 P-oligonucleotide is characterized by two components: a rapid elution during the first 30 min. and a significant sustained radioactivity, which is maintained up to 3 hours. Few radioactivity was detected in blood samples, stented coronary and the adjacent myocardium.
  • the present invention will be more readily understood by referring to the following examples, which are given to illustrate the invention rather than to limit its scope. EXAMPLE I
  • NIROYAL gold-stents (6 mm) were placed in a piranha solution (3:7 v/v, 30% H 2 0 2 : 98% H 2 S0 4 ) at 70°C for 20 min. Stents were then washed with H 2 0, acetone, ethanol and H 2 0 and dried under a stream of N 2 gas. The pre-cleaned stents were then placed either in potassium phosphate buffer (K 2 HP0 4 - KH 2 P0 4 ; pH 7.0) or in tetrahydrofuran (THF) containing 100 ⁇ Ci of 32 P- oligonucleotide containing a 5' -end thiol moiety to be incubated 60 min. at room temperature. Radioactive stents were then rinsed 3 times with 50 ml of H 2 0.
  • K 2 HP0 4 - KH 2 P0 4 pH 7.0
  • THF tetrahydrofuran
  • Radioactivity levels of NIROYAL gold stents following passive deposition was 1.15 ⁇ Ci when incubated in pure tetrahydrofuran and 0.02 ⁇ Ci when incubated in potassium phosphate buffer, corresponding to an efficiency of passive deposition of 1.15% and 0.02% respectively.
  • stents were incubated 2 days in pig blood at 37°C with constant agitation. Stents were then removed from biological conditions to be rinsed with water and remaining radioactivity was assessed by scintillation counting.
  • NIROYAL gold stents incubated in the tetrahydrofuran solution supplemented with 32 P- oligonucleotide lost 33% (0.80 ⁇ Ci residual activity) and 66% (0.34 ⁇ Ci residual activity) of its initial activity after 1 and 2 days of incubation, respectively.
  • Stents incubated in potassium phosphate buffer lost 100% of their initial activity after 1 day of incubation.
  • the Si/Si02 substrates were 1 cm x 1 cm plates taken from diced 4 inch wafers (Tronics Microsystems, Grenoble) .
  • the Si (100) is n-type, phosphorous doped to a density of 10 15 cm "3 , and has a thickness of 0.3 ⁇ m.
  • the Si is covered with a thermally grown Si0 2 layer which is 150 A thick.
  • the back of the Si plates was covered with a Cr/Au ohmic contact .
  • the substrates were placed in boiling acetone (Spreetrograde, Aldrich) for 5 minutes, followed by another 5 minutes in boiling methanol (Spreetrograde, Aldrich) .
  • the substrates were then dipped in sulfochromic acid (prepared by adding 95 mL of concentrated sulfuric acid (H 2 S0 4 ) to 5 mL of a saturated aqueous solution of potassium dichromate (K 2 Cr0 7 ) ) for 4 minutes at room temperature.
  • the substrates were rinsed for 15 seconds with distilled-deionized (d-d) water, and then placed in boiling d-d water for 10 minutes. Following this, the substrates were dried with N 2 flow and placed in a clean oven (ambiant atmosphere) at 140°C for 1 hour.
  • the substrates with the reaction chamber illustrated in Fig. 2, are placed inside a glove box which is under dry N 2 atmosphere. Once inside the glove box, the substrates were placed in the reaction chamber and the GPTS reaction compounds were then added, in sequence, to the reaction chamber.
  • the reaction mixture consisted of 111 mL of o-xylene (98% sealed under nitrogen, Aldrich), followed by 12.5 mL of GPTS (98% purity, Fluka) , and then 1.5 mL of diisopropyl-ethyl amine (99.5% purity sealed under nitrogen, Aldrich) (for a batch of 8 substrates) .
  • a magnetic stirring bar is added to the reaction mixture, the reaction chamber is then closed and removed from the glove box.
  • the reaction chamber is connected to a water circulator with temperature control. Stirring is initiated and the reaction is allowed to proceed for 4 hours at 70°C, under continuous N 2 flow.
  • the substrates are removed from the reaction chamber, dipped in ethanol (Spectrograde, Aldrich) for 5 minutes (at room temperature) , and allowed to dry under ambiant atmosphere.
  • the substrates are finally stored individually in glass vials containing 5 mL of ethyl ether (99.9% purity HPLC grade, Aldrich) .
  • 32 P-oligonucleotide (40 ⁇ Ci , with or without a C 6 amino linker at the 5' end) is directly deposited onto the surface of a GPTS modified substrate.
  • the 32 P-oligonucleotide solution was left to react for 2 hours on the GPTS surface in 0.01M in KOH, under humid atmosphere. The substrate surface was then rinsed with d-d water.
  • the silicon (Si, 100) substrates were lxl cm 2 , taken from a diced wafer purchased from Tronics Microsystems (Grenoble, France) .
  • the Si was phosphorous doped (n-type) to a density of 10 15 crrf 3 .
  • a gold/chromium film was deposited under vacuum at the backside of the Si substrate providing an ohmic contact.
  • the stainless steel substrates were 316L type (Fe/Crl8/Nil0/Mo3) , 10 mm in diameter and 0.2 mm thick, from Goodfellow Cambridge Ltd. (Huntingdon, England) .
  • ACS multi-link RX DUETTM stents (Guidant Vascular Intervention, Santa Clara, CA) of 18 mm of length were used in accordance with the present invention. Stents were cut to have a 9 mm of length for experiments.
  • both types of substrates were submitted to a cleaning/etching procedure.
  • the Si substrates were cleaned by immersing in trichloroethylene, acetone, and methanol for 1 minute each, respectively. They were rinsed in distilled-deionized (d-d) water and dried with N 2 flow. The Si substrates were then chemically etched for one minute in hydrofluoric acid and six minutes in buffered ammonium fluoride, rinsed once again and dried using N 2 .
  • the 316L substrates were immersed in 50 mL of aqua regia (concentrated HC1:HN0 3 , 4:1 (v/v)) for 1 minute, rinsed with d-d water and dried with N 2 flow.
  • aqua regia concentrated HC1:HN0 3 , 4:1 (v/v)
  • a 20mM aqueous solution of 4- bromobenzenediazonium tetrafluoroborate in 0.1M H 2 S0 4 and 2% HF was prepared by dissolving 0.54g of 4- bromobenzenediazonium tetrafluoroborate, 0.56 mL of concentrated H 2 S0 4 and 4mL of concentrated HF in 100 mL of d-d water. The solution was deaerated by bubbling N 2 for approximately 20 minutes.
  • Electrochemical functionalization The electrochemical cell was a standard three- electrode setup.
  • the reference electrode used was a saturated Calomel electrode (SCE) purchased from Fisher Scientific and the counter electrode was platinum foil (1 cm 2 ) .
  • the electrochemical cell is illustrated in Fig. 3.
  • the bromo-aryldiazonium solution was used as the electrolyte for cyclic voltammetry in order to attach the bromo-aryldiazonium to the surface of the Si or 316L substrates acting as working electrode.
  • a scanning potentiostat (EG&G Princeton Applied Research Model 362) was used to apply dc potentials to the working electrodes.
  • the current-voltage response was recorded on an XY recorder (Phillips, Model PM 8143) .
  • a single-cycle voltammogram was run on each substrate.
  • the current range was set at 1mA.
  • the reductive scan was run from an initial potential of - 0.3 V to a final potential of - 1.9 V vs. SCE, and back.
  • the scan rate was set at 100 mV/s.
  • a typical reductive wave (at ⁇ -1.5 V) was observed for modification of a Si substrate.
  • the current density is greater for the 316L substrate because of its greater conductivity and the reduction wave is observed at ⁇ - 0.95 vs. SCE.
  • Coating was better at a reaction temperature of 52°C, when compared to 22 and 70°C.
  • a 2 to 3 fold-increase of coating was reported when deposition was performed at 52°C (8 to 18 ⁇ Ci/cm 2 ) , when compared to room temperature conditions.
  • the level of coating increased with the reaction time (5, 15, 30, 60 and 120 minutes) .
  • the radioactivity undergoes a gradual increase with reaction time, going from approximately 6 ⁇ Ci/cm 2 at 5 minutes to 17.5 ⁇ Ci/cm 2 at 120 minutes.
  • immobilization efficiency was increased by 1.4 fold on stainless steel stent surface.
  • Fig. 4 illustrates the effect of duration of passive deposition on 32 P-oligonucleotide coating onto bromobenzenediazonium-treated stainless steel surface.

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Abstract

La présente invention concerne un procédé électrochimique rapide et reproductible permettant de produire un dispositif d'angioplastie radioactif tel qu'un stent, qui fait appel au dépôt ou à l'électrodéposition rapide et efficace d'une molécule de revêtement à charge radioactive sur des surfaces de charges opposées (inoxydables ou en or).
EP00955988A 1999-08-23 2000-08-22 Dispositif a revetement radioactif et procede de fabrication de ce dernier destine a empecher la restenose Withdrawn EP1218570A1 (fr)

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US6471671B1 (en) 2000-08-23 2002-10-29 Scimed Life Systems, Inc. Preloaded gas inflation device for balloon catheter
US6416492B1 (en) 2000-09-28 2002-07-09 Scimed Life Systems, Inc. Radiation delivery system utilizing intravascular ultrasound
US20020119178A1 (en) * 2001-02-23 2002-08-29 Luc Levesque Drug eluting device for treating vascular diseases
US7776379B2 (en) 2001-09-19 2010-08-17 Medlogics Device Corporation Metallic structures incorporating bioactive materials and methods for creating the same
US7208172B2 (en) 2003-11-03 2007-04-24 Medlogics Device Corporation Metallic composite coating for delivery of therapeutic agents from the surface of implantable devices
KR101023164B1 (ko) * 2007-06-19 2011-03-18 (주)바이오니아 화학물질로 코팅된 금도금 스텐트, 올리고뉴클레오타이드를 바인딩시킨 금도금 스텐트 및 이들의제조방법
US8058612B2 (en) 2009-01-30 2011-11-15 Georgia Tech Research Corporation Microirradiators and methods of making and using same
EP2435103B1 (fr) 2009-05-29 2014-01-08 Medovent GmbH Procédé de fabrication d'un produit médical creux comprenant une paroi interieure revêtue de polymère
CN110438536A (zh) * 2019-07-30 2019-11-12 华东师范大学 一种电沉积-自沉积制备α放射源实验装置及其实验方法

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EP0643706A1 (fr) * 1991-11-27 1995-03-22 Zynaxis Inc. Composes, compositions et procedes permettant de lier des substances bio-actives aux membranes de surface de bio-particules
WO1998017331A1 (fr) * 1995-06-07 1998-04-30 Cook Incorporated Dispositif medical implantable et contenant de l'argent
US5871436A (en) * 1996-07-19 1999-02-16 Advanced Cardiovascular Systems, Inc. Radiation therapy method and device
US5776183A (en) * 1996-08-23 1998-07-07 Kanesaka; Nozomu Expandable stent
US5821354A (en) * 1996-11-26 1998-10-13 Angiogene Inc. Radiolabeled DNA oligonucleotide and method of preparation
IT1291001B1 (it) * 1997-01-09 1998-12-14 Sorin Biomedica Cardio Spa Stent per angioplastica e suo procedimento di produzione
DE19724229C1 (de) * 1997-04-30 1999-04-01 Schering Ag Verfahren zur Herstellung radioaktiver Stents und ihre Verwendung zur Restenoseprophylaxe
US5919126A (en) * 1997-07-07 1999-07-06 Implant Sciences Corporation Coronary stent with a radioactive, radiopaque coating
US6077413A (en) * 1998-02-06 2000-06-20 The Cleveland Clinic Foundation Method of making a radioactive stent
US5980566A (en) * 1998-04-11 1999-11-09 Alt; Eckhard Vascular and endoluminal stents with iridium oxide coating
DE19819426A1 (de) * 1998-04-30 1999-11-11 Christoph Hehrlein Katheter und Gefäßstütze, insbesondere zur kombinierten, radioaktiven Strahlen- und Medikamententherapie sowie Verfahren zu ihrer Herstellung
DE19838183A1 (de) * 1998-08-21 2000-03-09 Alexei Kalatchev Verfahren zur Herstellung von Gegenständen mit einer gekapselten Radioaktivität, insbesondere bei medizinischen Implantaten
EP1157076A1 (fr) * 1998-11-18 2001-11-28 Radiovascular Systems, L.L.C. Solutions de revetement radioactives, procedes et substrats associes

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* Cited by examiner, † Cited by third party
Title
See references of WO0114617A1 *

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