WO1997048452A1

WO1997048452A1 - Rhenium radioactive catheter

Info

Publication number: WO1997048452A1
Application number: PCT/IL1997/000181
Authority: WO
Inventors: Efraim Lavie
Original assignee: The State Of Israel, Atomic Energy Commission Soreq Nuclear Research Center
Priority date: 1996-06-17
Filing date: 1997-06-09
Publication date: 1997-12-24
Also published as: CA2258631A1; IL118669A0; IL118669A; EP0921843A1

Abstract

A device and method for local irradiation of walls of a tubular organ, comprising a radioactive metallic member insertable within the tubular organ comprising a member selected from the group consisting of Rhenium 186 and Rhenium 188.

Description

RHENIUM RADIOACTIVE CATHETER

FIELD OF THE INVENTION

The present invention relates to a device for local irradiation treatment within a tubular organ. In accordance with a specific embodiment, the present invention relates to a local irradiation treatment within arteries for the purpose of prophylaxis of restenosis, e.g. such which may occur following balloon angioplasty.

BACKGROUND OF THE INVENTION

Non-surgical angioplasty procedures developed to unblock vascular lumens in early sixties, and specifically balloon angioplasty developed in 1974, have become a standard therapeutic method for the treatment of a variety of peripheral and coronary vascular diseases. In balloon angioplasty, a catheter equipped at its distal end with a dilatable balloon is inserted intravascularly to a site of an atherosclerotic occlusion. Inflation of the balloon presses the surrounding walls of the blood vessels while stretching them and thus widening the atherosclerotic site. However, although such a treatment is usually effective in initial stretching of the walls of the blood vessel, restenosis resulting from the growth of smooth muscle cells at this site often occurs. Following restenosis, reapplying balloon angioplasty in order to widen the blood vessel is usually ineffective and surgery is then usually the only available treatment.

Stents have in recent years gained popularity as an angioplasty aid. Stents, which are helical devices, can be inserted at an atherosclerotic site following angioplasty, and they then form a physical barrier against restenosis. However, even the use of stents only partially inhibits restenosis and often, notwithstanding the existence of the stent, there is growth of smooth muscle cells into the lumen, which eventually blocks the blood vessel. Another method of inhibiting the occurrence of restenosis known in the art is radioactive irradiation of the atherosclerotic site. U.S. Patent 5,059,166, discloses a tubular intra-arterial stent which is made of a radioactive material. The stent in addition to supporting the wall of the blood vessel, also serves to locally irradiate the tissue thus reducing the proliferative capacity of the smooth muscle cells.

U.S. Patent 5,199,939, discloses a device comprising a flexible carrier which can be inserted into a blood vessel, having a radioactive source located at a distal section of the carrier. The radioactive source disclosed in this U.S. patent is a γ emitter, Iridium 192. The use of Iridium 192 in the operation or catherization theater is complicated in view of the protective equipment required for dealing with the radioactive source. In addition there is today a reluctance of medical personnel to deal with γ emitters.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel device for local irradiation of walls of a tubular organ.

It is a further object of the invention to provide a method and device for prophylaxis of restenosis.

Further objects of the invention will be clarified from the description below.

The present invention provides, by a first of its aspects, a device for local irradiation of walls of a tubular organ, comprising a metallic O 97/48452 PCML97/00181

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member insertable within the tubular organ comprising a member selected from the group consisting of Rhenium 186 and Rhenium 188.

The device of the invention can be implemented for local irradiation in a variety of tubular organs. Local irradiation within a blood vessel to inhibit restenosis is a preferred, albeit not exclusive, embodiment of the invention. As will be appreciated, the device may also be adopted for local irradiation of other tubular organs.

It should be understood that whenever a reference is made herein to a radioactive member or device comprising Rhenium 186, the latter may be replaced by Rhenium 188.

Rhenium 186 and Rhenium 188 are radioactive materials which are primarily a /3-emitter. The advantage of a /3-emitter over a γ-emitter used in prior art devices such as that of U.S. Patent 5,199,939, is, that β- radiation has a limited depth of penetration into biological tissues, in the order of millimeters.

The amount of Rhenium 186 or Rhenium 188 will be chosen based on the desired irradiation intensity. For example, for irradiating walls of a blood vessel in order to inhibit the occurrence of restenosis, the radiation will be in the range of 1,000-2,500 cGy. According to a preferred embodiment of the invention, the insertable member radiates at 1,400-2,000 cGy measured at a distance of 2 mm from the longitudinal axis of the device.

Another aspect of the invention concerns the use of the device within the framework of prophylaxis of restenosis. In accordance with this method, the device is inserted into a blood vessel at a site of occlusion following its widening, e.g. by balloon angioplasty, and is then maintained at that site for a time required for the surrounding tissue to absorb a quantity of irradiation sufficient to inhibit subsequent growth of smooth muscle cells at that site. In accordance with one embodiment of the invention the device is a wire, e.g. made of nitinol (nickel-titanium alloy) having a portion at a distal end, e.g. of a length of about 2-3 cm, comprising Rhenium 186. This portion may be a Rhenium piece welded to the wire or may be a distal portion of the wire coated by Rhenium 186 or Rhenium 188.

In accordance with another embodiment of the invention the device is a wire, e.g. nitinol wire, having a distal portion carrying several short cylindrical portions made of or comprising Rhenium 186. The distal portion may for example be about 2-4 cm long and carry several, e.g. 6-8 small cylindrical pieces, each one of a length of about 2-3 mm.

In accordance with yet another embodiment of the invention, the device is a wire according to one of the above two embodiments, enclosed within a catheter, e.g. a balloon catheter, with the radioactive portions being within the distal portion of the catheter. In the case of a balloon catheter, the radioactive portion is typically contained beneath the inflatable (balloon) portion.

In accordance with a further embodiment, the device is a stent, e.g. carried on a balloon catheter, having Rhenium 186 or Rhenium 188 comprising portions or being at least partially coated by Rhenium 186 or Rhenium 188.

In accordance with a still further embodiment, the device comprises a catheter holding Rhenium 186 or Rhenium 188 at a distal portion thereof, e.g. in a capsule or an enclosure within a distal portion of the catheter. The Rhenium 186 or Rhenium 188 according to this embodi¬ ment may be in the form of powder, in the form of small spheres, rods, etc. In addition, the Rhenium 186 or Rhenium 188 may also be in the form of a small particulate solids, e.g. in suspension, a solution, e.g. an aqueous solution of perrehenate (such as ¹⁸⁶ReO₄ ^"), or may be linked to a complexing or chelating agent, etc.

It will be appreciated that the above embodiments are but an example and many other embodiments wherein a Rhenium 186 or Rhenium 188 comprising member is at a distal portion of a device insertable within a tubular organ, are all encompassed within the framework of the invention. In accordance with another aspect of the invention there is provided a method of preventing restenosis in a portion of a blood vessel, comprising:

(a) introducing said device into a blood vessel such that said radioactive member or segment lies within said portion;

(b) maintaining the device in place for a time sufficient to irradiate the walls of the blood vessel at the site with a quantity of radiation sufficient to seriously affect the smooth muscle cells so as to inhibit their subsequent proliferation. The present invention also provides a method of preparing such a device. In accordance with one embodiment, the method comprises:

(a) preparing a device as defined above, using a non-radioactive Rhenium;

(b) irradiating the Rhenium-comprising portion of said device so as to convert part of the Rhenium into Rhenium 186 or Rhenium 188.

It is also possible to reverse steps (a) and (b), i.e. first irradiating a non-radioactive Rhenium to convert at least part of the Rhenium to Rhenium 186 and then incorporating the obtained Rhenium 186 within the device. The irradiation may be carried out, for example, by using a flux of neutrons of about 10¹³ to 5xl0¹³ N/cm²/sec for 0.5-10 hrs.

Rhenium 186 or Rhenium 188 are advantageous in that they have a relatively short half life of 3.78 days and 17 hours respectively, and accordingly there is only a limited internal exposure to radioactive irradiation. However, after the Rhenium is irradiated to render it radioac- tive, it should be shielded so as to avoid radioactive radiation to the surrounding. Such a shield constitutes an aspect of the invention. The shield typically comprises a casting made of radioactive impermeable material, e.g. lead, and a receiver within the container adapted to hold said device or at least the radioactive portion thereof. The present invention will now be illustrated further by the following non-limiting specific embodiments with occasional reference to the annexed drawings. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. l(A-E) show several embodiments of devices in accordance with the invention; and

Fig. 2 shows a longitudinal cross section through a shield in accor- dance with the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Reference is first being made to Fig. 1, in which Fig. IA shows a device in accordance with the invention comprising a wire 10 e.g. made of nitinol, having a portion 12 at a distal end thereof, comprising Rhenium 186 or Rhenium 188. This portion may be a Rhenium 186 or Rhenium 188 piece welded to said wire 10, a portion coated by Rhenium 186 or Rhenium 188, etc. A specific example of portion 12 is shown in Fig. IB. Portion 12 comprises a wire 10', being an extension of wire 10 (Fig. IA) and carries a plurality of short cylindrical pieces 13 made of or comprising Rhenium 186 or Rhenium 188. Portion 12 may for example be about 3 cm long and the plurality of pieces 13 (seven in this specific embodiment) may be each about 2 cm long. Such an arrangement may be helpful in overcoming the problem of rigidity of one long Rhenium member. Of course these segments are not limited to cylinders but may be of any other shape, e.g. spheres.

The device shown in Fig. 1C comprises a wire 14, which may be similar to that of Fig. IA, having a radioactive portion 16 at its front end which is comprised of a member selected from the group consisting of

Rhenium 186 and Rhenium 188. Wire 14 is held within a catheter 18, having a distal portion e.g. which is inflatable (represented by dotted line).

In Fig. ID, the device is a stent 20 mounted on a balloon catheter

22. The stent is made primarily from nitinol but is coated with a metallic coating comprising a member selected from the group consisting of Rhenium 186 and Rhenium 188. Turning now to Fig. IE, it shows a catheter 24 having a balloon portion 26, containing in its lumen an enclosure 28. This enclosure may hold powder of Rhenium 186 or Rhenium 188, small spheres of Rhenium

186 or Rhenium 188 or a solution comprising a Rhenium 186 or Rhenium 188 compound or complex, e.g. a solution comprising ^18fiReO₄'.

The device shown in Figs. 1A-1E, are particularly the devices of Figs. 1C and ID, are intended primarily for insertion into a blood vessel. It is however understood that the illustrated embodiments are but an example, and the invention is applicable mutatis mutandis, also to local irradiation within other tubular organs, e.g. digestion tracts, respiratory tracts, etc.

The device shown in Fig. IA, may be inserted into an artery so that portion 12 will be placed at a previously occluded site where restenosis may be expected. It is then retained within the artery for a time sufficient to administer the required irradiation dose to the surrounding tissue. A device such as that shown in Fig. IA, is inserted into the site typically after but at times also before balloon angioplasty.

Regarding a device such as that shown in Fig. 1C, the fact that it is incorporated within a balloon catheter, enables irradiation at the time of balloon angioplasty which saves time and procedure complexity. During catheterization, the balloon portion of the catheter is inflated, the constricted tissue widens and at the same time, as well as after deflation of the balloon and as long as the catheter is maintained in place, radioactive portion 16 irradiates the previously occluded site.

In the case of the device of Fig. ID, which has the form of stent 20, it is typically coated with a coating comprising Rhenium 186 or Rhenium 188. The coating may be applied on the entire stent or only on a portion thereof. The stent may be placed at the site for a prolonged period of time but in the first few days, the required irradiation dose will be administered to the surrounding tissues to help in inhibiting restenosis. The irradiation effect will occur until a substantially complete decay of the radioactive Rhenium 186 or Rhenium 188 is obtained. Reference is now being made to Fig. 2 showing a shield 30 for shielding the radioactive portion of the device. The shield comprises a lead casing 32 and an internal medium 34 made from a plastic material such as PVC. Medium 34 has a central longitudinal bore 36 which accommodates and holds the end of a wire 38 which contains the hot Rhenium wire portion 40. The container is sealed by a lead lid 42 which defines a duct or a lumen accommodating portion of the wire.

The following is an example of the manner of preparation of a hot (radioactive) Rhenium wire for use in the device of the invention.

EXAMPLE

A 3 cm long Rhenium wire having 0.5 mm diameter and weighing about 120 mg was irradiated for 30 minutes at a thermal neutron flux of about 4.5X10¹³ N/cπr/sec. Typical gamma spectrum lines were: E_(γ) 137 KeV with a frequency of 8.65%;

E_(γ) 631 KeV with a frequency of 0.0238%; and E_(v) 768 KeV with a frequency of 0.0268%.

The following results were obtained: γ radiation measurements:

E_(v) 137 KeV - 2.3 mCi;

E_(γ) 631 KeV - 5.21 mCi; and

E_(γ) 768 KeV - 5.4 mCi.

The following /3-radiation measurements were conducted 14 days after irradiating the Re wire, by using pure Germanium detector positioned at a distance of 101 cm from said wire. These measurements were carried by using a variety of radiation detectors and TLD crystals. The results of these measurements are summarized in the following table: O 97/48452 PC17IL97/00181

During the Ram ion measurement a distance of 3 cm was set as the geometrical zero point, whereas during the Ran gene measurement, this point was set at a 1 cm distance.

The meaning of these results is that the radiation of said wire interpolated for 89 hours from its irradiation (a period which is roughly the period between turning the device radioactive and its actual application), which would have reached a blood vessel wall, assuming 50% absorption in the blood, would be 1500 cGy for 10 minutes.

Further isotopes obtained during irradiation of the nitinol wire alone under similar conditions were CO-58 (0.5 μCϊ) and CO-60 (15 nCi).

Claims

CLAIMS:

1. A device for local irradiation of walls of a tubular organ, comprising a radioactive metallic member insertable within the tubular organ comprising a member selected from the group consisting of Rhenium 186 and Rhenium 188.

2. A device according to Claim 1, wherein the amount of the member selected from the group consisting of Rhenium 186 and Rhenium 188 is such to provide radioactive irradiation of about 1,000-2,500 cGy measured at a distance of 2 mm from the longitudinal axis of the device.

3. A device according to Claim 2, wherein the radioactive radiation is about 1,400-2,000 cGy.

4. A device according to any one of Claims 1-3, having the form of a wire having a radioactive, Rhenium 186 or Rhenium 188 comprising segment at its front end.

5. A device according to Claim 4, being contained within a catheter.

6. A device according to Claim 5, wherein the catheter is a balloon catheter, and the radioactive segment is located within the balloon segment of the catheter.

7. A device according to any one of Claims 1-3, having the form of a stent comprising a member selected from the group consisting of Rhenium 186 and Rhenium 188.

8. A device according to Claims 1-3, having a plurality of Rhenium 186 or Rhenium 188 comprising segments which are mounted on a catheter or a wire.

9. A device according to Claims 1-3, wherein the member selected from the group consisting of Rhenium 186 and Rhenium 188 is in a form of powder.

10. A device according to Claims 1-3, wherein the member selected from the group consisting of Rhenium 186 and Rhenium 188 is in a form of solution.

11. A method of preventing restenosis in a portion of a blood vessel, comprising:

(a) introducing a device according to any of Claims 1-10, into a blood vessel such that the radioactive member or segment lies within said portion; and

(b) maintaining the device in place for a time sufficient to irradiate the walls of the blood vessel at the site with a quantity of radiation sufficient to seriously affect the smooth muscle cells so as to inhibit their subsequent proliferation.

12. A method of preparing a device of Claims 1 to 10, comprising:

(a) preparing said device using a non-radioactive Rhenium;

(b) irradiating Rhenium-comprising portion of the device so as to convert part of the Rhenium into Rhenium 186 or Rhenium 188.

13. A method of preparing a device of Claims 1 to 10, comprising: (a) irradiating a non-radioactive Rhenium piece or composition so as to convert part of the Rhenium into Rhenium 186 or Rhenium 188; (b) combining said piece or composition to obtain said device.