MXPA99008952A - Targeted therapy to a biomedical device - Google Patents

Abstract

A biomedical device assembly, such as a stent, for the targeted treatment of a tissue, such as the inhibition of restentosis. The stent is coated with an antigen, which is an example of a lock. The antigen can be bound by a labelled antibody, which is an example of a key and an effector. The antibody is preferably labelled with a radioactive source. According to one method of preparing the biomedical device assembly, after the stent has been placed in the blood vessel of the subject, the antibody is injected. The antibody then binds to the antigen on the stent, thereby localizing the radioactive source to the area to be treated, for example for restenosis. Other biomedical devices, such as a coil, an artificial valve or a vascular graft, could also be used in the place of the stent. The biomedical device could be placed in a solid tissue such as a solid tumor, or another biological passageway, such as the gastrointestinal tract, an airway or the genitourinary tract.

Description

THERAPY DIRECTED TO A BIOMEDICAL DEVICE FIELD AND BACKGROUND OF THE INVENTION The present invention relates to the targeting of a therapeutic effector for a biomedical device and, in particular, to the use of radioimmunotherapy for the localization of radioactivity to stents for the reduction or elimination of restenosis. .

Restenosis of blood vessels occurs after thinned or clogged arteries are strongly dilated by balloon catheters, drills, lasers, and the like, in a procedure known as angioplasty. Such forced dilation is required to reopen arteries that have been narrowed or obstructed by atherosclerosis. However, up to 45% of all arteries that have been treated with angioplasty return to their narrow state through a process of restenosis. Restenosis is caused by a number of mechanisms, such as the return of the vessel wall to its original dimensions, hyperplasia induced by trauma to the vessel wall, accumulation of an extruded matrix, tissue remodeling and other biological processes. Restenosis can significantly reduce the efficacy of angioplasty and as such is an important barrier to effective treatment of thinned arteries.

Efforts to reduce or eliminate restenosis have generally focused on the insertion of biomedical devices, such as stents, into the treated artery. Stents can reduce restenosis by preventing the springing of the treated blood vessel to its original dimensions. Several stents are known in the art, including springs and sleeves, which are expandable by balloon-expandable catheters, and self-expanding stents. Unfortunately, stents alone can not prevent restenosis caused by neointimal hyperplasia of the tissues of the vessel wall. In fact, the stent material itself can accelerate such hyperplasia, since it is foreign to body tissues.

Recently, as noted above, radionuclear irradiation of blood vessels has been proposed as a method to prevent restenosis caused by neointimal hyperplasia. The application of radionuclear irradiation of a subject's body is a well-accepted mode of therapy in medicine. The main use of said irradiation is for the treatment of tumors whether benign or malignant. Radionuclear irradiation can also be used to inhibit unwanted proliferation of cells in other rapidly growing tissues, such as keloids and blood vessels suffering from restenosis.

One study has shown that such irradiation completely prevented restenosis of the treated arteries [H.D. Bottcher et al., Int. J. Radiation Onology Biol. Phys., 29: 183-186, 1994]. A number of studies in animal models also support the effectiveness of radionuclear irradiation of blood vessels for the prevention or reduction of restenosis after angioplasty [J.G. Wiedermann et al., JACC, 23: 491-8, 1994; R. Waksman et al., Circulation, 92, 3025-3031, 1995; R. Waksman et al., Circulation, 91: 1533-1539, 1995]. Thus, the clear exposure of blood vessel walls to radioactivity is a valuable method to prevent and treat restenosis caused by neointimal hyperplasia.

Currently, radionuclear irradiation of blood vessels is carried out by inserting temporary or permanent radionuclear sources into the vessels. For example, yttrium-90 radioactive wires were inserted into the central opening of a balloon catheter to irradiate the walls of the blood vessel [Y. Popowski et al., Int. J. Radiation Oncology Biol. Phys., 43: 211-215, 1995]. Other radioactive sources have included iridium-92, administered by catheter to arteries that had been treated by angioplasty [P.S. Teirstein et al., Circulation, 94: 1-190, 1996; . Teirstein et al., New Eng. J. Med. 336; 1697-1703, 1997]. U.S. Patent No. 5,213,561 discloses a device for inserting a radionuclear source into a blood vessel, in which the source of radioactivity is mounted on a stent, for example.

Unfortunately, the insertion of radionuclear sources directly coupled to a catheter or stent, in which the catheter or the stent is radioactive prior to insertion into the blood vessel, has a number of disadvantages. First, such procedures require a highly specialized clinical setting, which is appropriate at the same time for catheterization procedures and for the management of radioactivity. Second, these procedures are highly invasive. Third, these sources of radioactivity require repeated treatments. However, these radioactive sources also have the disadvantage of decaying according to their specific half-lives. Thus, current methods for irradiating blood vessels have significant disadvantages.

The concept of targeting tumor cells specifically is a goal of modern radiation oncology. The development field of radiolabeled immunoglobulin therapy (BIT) uses monoclonal antibodies labeled with Radionuclides that recognize tumor-related antigens, thereby targeting tumor cells. Beta particles, alpha particles and gamma rays emitted from a radiolabeled antibody bound to a tumor cell also killed immediate cells because these particles can penetrate several cell diameters. In B cell lymphoma refractory to chemotherapy, RIT has been associated with a high proportion of durable remissions [Kaminki et al., JCO, 14: 1974-1981, 1996].

RIT can be effective for the treatment of cancer because tumor cells have special antigens on their surface, against which antibodies can be raised. Unfortunately, the situation is much more complicated for the prevention and treatment of restenosis. Restenotic tissue is not known to express special antigens, to which antibodies against that tissue would also bind to walls of normal blood vessels and would not be specific enough for the tissue to be treated. Thus, directing the antibodies directly to the tissue itself is not possible.

However, the specific targeting of effector moieties to the restenotic tissue would have many benefits for the treatment and retention of restenosis. For example, a targeted drug or an isotope could be injected into a patient at a distant site of the catheterized blood vessel. The targeted drug or isotope would remain in the area of catheterization, specifically treating the restenotic tissue without serious or problematic side effects. In addition, the directed effector could be injected substantially after catheterization, which would allow the effector to be injected in a different position. For example, if the effector is an isotope, the injection could be carried out in a special facility for treatment with radioactivity. In addition, the effector could potentially be chosen according to the degree of severity of the restenosis, which could be monitored after insertion of the catheter or stent. Thus, the separation of the procedures for catheterization and for the treatment with an effector would clearly increase the flexibility of the restenosis treatment.

Of course, restenosis is not the only pathological condition that would benefit from treatment with a directed effector. Other types of biomedical devices could cause the overgrowth or internal growth of tissue that surrounded the insertion point of the device. Such growth of pathological tissue in the area of an inserted biomedical device can be difficult to treat, since these devices are not always immediately accessible through surgery, for example. The treatment with a directed effector, which would be specifically placed to the tissue surrounding the biomedical device without the requirement of additional surgery, would clearly be more beneficial. Moreover, such a device would be implanted for that purpose within a tumor to prevent highly localized treatment of malignancies, particularly that of solid tumors.

There is then a widely recognized need for, and it would be highly advantageous to have, a method for directing an effector, such as a radioactive isotope, to specific areas near an inserted biomedical device, such as a solid tissue or a blood vessel, to carry localized therapy for the treatment or prevention of a pathological condition, such as restenosis of a catheterized blood vessel.

SUMMARY OF THE INVENTION An object of the present invention is to provide localized therapy to a tissue or a biological passage.

Another objective of the present invention is to provide said localized therapy by directing an effector to a biomedical device, so that the area surrounding the biomedical device is treated.

Still another objective of the present invention is to direct the effects to the biomedical device with a safe and key system, in which the key is attached to the effector and the safety device is attached to the biomedical device.

Still another object of the present invention is to provide a method for manufacturing such a biomedical device.

These and other objects of the present invention will become apparent from the following description, claims and figures.

In accordance with the teachings of the present invention, a biomedical device assembly comprising a biomedical device is provided, wherein the biomedical device has an antigen and an antibody having a tag coupled, wherein the antigen and the antibody are linked. Preferably, the biomedical device is inserted into a solid tissue or a biological passage selected from the group consisting of blood vessels, air passages, gastrointestinal tract, bile duct and genitourinary tract. More preferably, the biological passage is a blood vessel.

Preferably, the antigen is a drug molecule. Also preferred, the biomedical device is chosen from the group consisting of spring, artificial valve, vascular graft and stent. More preferably, the biomedical device is a stent.

Preferably, the label is chosen from the group consisting of radioactive source and pharmaceutical moiety. More preferably, the label is a radioactive source.

According to another example of the present invention, there is provided a method for substantially inhibiting restenosis in a blood vessel of a subject, comprising the steps of: a) inserting a stent into a patient's blood vessel, the stent has a coupled antigen; and b) administering an antibody to the subject, the antibody is capable of binding to the antigen and the antibody has a tag attached where the tag is capable of inhibiting restenosis.

Preferably, the label is chosen from the group consisting of radioactive source and pharmaceutical moiety. More preferably, the label is a radioactive source. Preferably, the antigen includes a plurality of different types of antigens, so that the step of administering the antibody is repeated for a plurality of different types of antibodies.

According to another example of the present invention, a biomedical device assembly for targeted treatment is provided, comprising: a) a biomedical device; b) an insurance, the insurance is coupled to the biomedical device; c) a key to interact specifically with the insurance; and d) an effector to carry out the directed treatment, the effector is coupled to the key.

Preferably, the key and the lock are each independently selected from the group consisting of an antibody, an antigen, a non-regular antibody, a combination of mixed proteins and not proteins, and a non-protein molecule, and combinations of them. More preferably, the antibody is selected from the group consisting of a polyclonal immunoglobin, a monoclonal immunoglobin, a SFv (single chain antigen binding protein), Fab1 fragment, a Fab2 fragment and a humanized monoclonal immunoglobin.

Also more preferably, the antigen is selected from the group consisting of a protein, a peptide and fragments thereof, a carbohydrate macromolecule, an oligonucleotide and a pharmaceutical molecule and combinations thereof. More preferably, the protein is selected from the group consisting of avidin and biotin.

According to preferred specimens of the present invention, the non-regular antibody is selected from the group consisting of an IgG macromolecule, a bifunctional antibody, avidin and biotin. Preferably, the non-protein molecule is selected from the group consisting of a carbohydrate macromolecule, an oligonucleotide and a bifunctional chelator. Also preferred, the mixed protein and non-protein combination is a protein with an attached oligonucleotide.

According to other preferred specimens of the present invention, the effector is selected from the group consisting of a radioactive isotope, a drug, a hormone, a growth factor, a cytokine, a T cell, a toxin, an endothelial cell, a chelator of a radioactive isotope and a two-component effector. Preferably, the chelate of the radioactive isotope includes a chelator related to the group consisting of DOTA, DTP A, nitro-benzyl DOTA and a bifunctional chelator. More preferably, the radioactive isotope is selected from the group consisting of yttrium 90 (90Y), lutetium 177 (177Lu), rhenium 186 (186Re), rhenium 188 (188Re), phosphorus 32 (32P), bismuth 212 (212Bi), astatin 211 (211At), iodine 131 (131I), iodine 125 (125I), iridium 192 (192Ir), palladium 103 (103Pd) and copper 67 (67Cu). Preferably, the bifunctional effector is an enzyme and a prodrug, in which the enzyme chemically alters the prodrug to activate the prodrug. Also preferably, the toxin is selected from the group consisting of a plant toxin, a bacterial toxin, a füngal toxin and a synthetic toxin.

According to yet other preferred specimens of the present invention, the latch is coupled to a material that covers at least a portion of a surface of the biomedical device. Preferably, the material is selected from the group consisting of a derivatizable polymer and a metal. More preferably, the material is the derivatizable polymer and the safe is coupled to the polymer derivatizable by a covalent bond. More preferably, the covalent bond is formed by a chemical reaction between the safe and the derivatizable polymer. Also more preferably, the chemical reaction is activated by exposure of the safe and the derivatizable polymer to ultraviolet light.

Preferably the latch is coupled to the derivatizable polymer by a non-covalent bond.

According to yet another example of the present invention, a method for manufacturing a biomedical device assembly is provided, the method comprises the steps of: a) providing a biomedical device, b) attaching a latch to the biomedical device, c) coupling an effector to a key to form a coupled effector, and d) to incubate the lock and the key, so that the lock and the key interact to form the assembly of the biomedical device.

Preferably, the step of attaching the latch to the biomedical device is carried out ex vivo, and the step of incubating the latch and the key to form the biomedical device assembly is carried out first by placing the biomedical device with the latch in place. a subject, and then administer the key with the effector coupled to the subject, so that the assembly of the biomedical device is formed by an interaction of the lock and the key in the subject. As an alternative, and preferably, the step of coupling the secure 1 biomedical device is carried out ex vivo, and the step of incubating the safe and the key to form the biomedical device assembly is carried out ex vivo.

From here, the terms "radionuclide" and "radioactive isotope" include, but are not limited to, yttrium 90 (90Y), lutetium 177 (177Lu), rhenium 186 (186Re), rhenium 188 (188Re), phosphorus 32 ( 32P), bismuth 212 (212Bi), astatine 211 (211At), iodine 131 (13II), iodine 125 (125?), Iridium 192 (192Ir), palladium 103 (103Pd) and copper 67 (67Cu).

From here, the term "DTPA" includes 1,4,7-triazaheptane-N, N'-N "-pentaacetic acid and derivatives thereof The term" DOTA "includes acid 1,4,7,10 -tetraazacyclododecane - N, N ', N ", N'" - tetraacetic and derivatives thereof.

From here, the terms "sFv" and "single chain antigen binding protein" refer to a type of a fragment of an immunoglobin, an example of which is sFv CC49 (Larson, SM, et al., Cancer , 80: 2458-68, 1997).

BRIEF DESCRIPTION OF THE DRAWINGS The invention is described herein, by way of example only, with reference to the accompanying drawings, in which: Figure 1 is a schematic illustration of an exemplary biomedical device in accordance with the present invention; Figure 2 is a schematic illustration of a portion of the biomedical device of Figure 1; Figure 3 is a schematic illustration of a portion of an antibody according to the present invention; Figure 4 is a schematic representation of the biomedical device of Figure 1 with the antibody of Figure 3; Figure 5 is a schematic representation of an exemplary biomedical device system in accordance with the present invention with avidin and biotin as the safe and the key; Figure 6 is a schematic representation of an exemplary biomedical device system in accordance with the present invention with a macromolecule of IgG and an antigen such as the lock and key; Figure 7 is a schematic illustration of an exemplary biomedical device system in accordance with the present invention with a bifunctional antibody and an antigen such as the lock and the key; Figure 8 is a schematic illustration of an exemplary biomedical device system in accordance with the present invention with a carbohydrate macromolecule and an antigen such as the lock and key; Figure 9 is a schematic illustration of a biomedical device system according to the present invention with a bifunctional chelator and an antigen such as the lock and the key; Figure 10 is a schematic illustration of a biomedical device system according to the present invention with a safe and mixed key system.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a method and a device for the targeted treatment of a tissue with an effector. The effector is directed to the tissue to be treated by a "safe and key" system. The "lock and key" system includes a "lock" attached to a biomedical device, which is inserted into a subject as part of a normal insertion procedure. The "key" is attached to the effector. In some circumstances, the "key" and the effector may be the same molecule or complex. The effector / spanner combination is then injected into the subject, or otherwise introduced into the subject, at a site that may be at any appropriate distance from the insertion point of the biomedical device. The key allows the effector / key combination to locate the biomedical device, through interaction of the key and the insurance in the biomedical device. For example, the key could be attached to the insurance, or the insurance could be attached to the key, or the key and the insurance could be linked together. Thus, the effector specifically targets the tissue surrounding the biomedical device.

Examples of appropriate combinations of insurance systems and braces include, but are not limited to, a combination of antibody and antigen, non-immunological proteins such as avidin and biotin, and non-protein macromolecules such as complex carbohydrate ligands and receptors. These systems could be adapted from insurance systems and padlocks known as combinations of antibodies and antigens. As an alternative non-protein macromolecules, such as carbohydrates or oligonucleotides, they could be designed and synthesized specifically to interact as ligands and receptors. Such non-protein macromolecules would have a number of advantages, including reduced degradation by the body and reduced likelihood of undesirable cross-reactions with other tissues in the body. Thus, many insurance and key systems could be used to direct effectors to biomedical devices.

The designation of a component of the system as a "safe" and another component as a "key" is also flexible. For example, an antibody could be an example of a key, while the corresponding antigen could be the safe one. In such a situation, the antigen would be coupled to the biomedical device and the effector would be coupled to the antibody. The antibody / antigen combination would then be injected into the patient, for example. As an alternative, the antigen could be the key and the antibody could be the insurance. The antibody would be coupled to the biomedical device and the effector would be coupled to the antigen. Thus, the term "safe" refers to the half coupled to the biomedical device, while the term "key" refers to the half that is either coupled to the effector or that is itself the effector, with the understanding that the The same molecule could be either an insurance or a key.

The term "effector" includes any molecule, combination of molecules or even a whole cell, which has a therapeutic effect. For example, the effector could be a radioactive isotope, a drug, a hormone, a growth factor, a cytokine, a T cell or a toxin. The effector could be chosen to inhibit tissue growth, for example to treat or prevent restenosis. Another example of an effector could be an endothelial cell, particularly for coating the inner surface of a stent to prevent the formation of thrombi and to allow the treatment of the surrounding tissue with the products of the endothelial cell such as nitric oxide. In some circumstances, the effector and the key could radioactive isotope were combined shortly before the stent was inserted into the patient. Thus, the stent and the isotope would be manufactured and sent preferably separately, and then be combined at, or just before, the moment of insertion.

As an alternative, even following the current manufacturing processes, the manufacturer could combine the stent and the isotope at the point of stent manufacturing. Such a method would still have an advantage over the methods of the prior art, which require a cyclotron to bombard the stent to make the radioactive stent material. Thus, the present invention provides greater flexibility in the manufacture of biomedical devices such as radioactive stents.

The lock and key system described above also allows the stent and the radioactive isotope to be combined just prior to insertion. The insurance would still be coupled to the stent, for example, as part of the regular manufacturing process for the stent. The key would still have the radioactive isotope effector coupled as part of a key / effector combination. However, the combination of the key and the effector could be in contact with the insurance now ex vivo. Once the radioactive material is attached to the stent through the lock and key system, the stent would then be inserted into the patient during a regular surgical procedure. Thus, the stent would only become radioactive shortly before insertion into the patient.

The insurance system and key of the present invention clearly allows the addressing of an effector to the tissue to be treated, regardless of whether the safety and the key are combined in vivo, for example by injection of an antiquake with a radioactive isotope coupled within the patient , or ex vivo, for example by coupling a radioactive isotope to the stent just prior to insertion of the patient's blood vessel. Thus, the method and device of the present invention clearly allow targeting of a therapeutic effector to a biomedical device.

DESCRIPTION OF THE PREDILECT EXAMPLES The present invention is directed towards a method and a device for the targeted treatment of a tissue with an effector. The effector is directed to tissue to be treated by means of an insurance system and key, in which the safety is coupled to a biomedical device and the key is coupled to the effector. For example, the present invention could be used to locate radioactive isotopes to a stent.

The principles and operation of said therapy directed according to the present invention can be better understood with reference to the accompanying drawings and description. The following description is directed specifically toward targeted therapy for a stent solely as an example, with the understanding that many other biomedical devices could also be used. For example, artificial valves, springs or vascular grafts or other implantable foreign bodies could also be used with the present invention.

Example 1 Radioimmunotherapy for a Stent With reference now to the drawings, Figure 1 shows an intraluminal stent 10 after being deployed within a blood vessel (not shown). The stent 10 can be self-expanding, or inflated with a balloon catheter, for example. The stent 10 can be used to support collapse vessel walls or to expand partially obstructed segments of a dilated blood vessel, communication created by catheter between portal and hepatic veins, narrow esophagus, intestine, ureters, urethra, intercerebrally, bile ducts or any other pipeline or passage in the human body, whether born, created or artificially made.

The stent 10 preferably and optionally is coated with a biocompatible material 12, so that the biocompatible material 112 is cod to at least a portion of the surface of the stent 10. From here, the term "co" includes connecting to, or be formed in an integral way with. The biocompatible material 12 can be any material, such as Teflon or Dacron, which are suitable for insertion into the body of a subject. Such materials are well known in the art and could be chosen by anyone with ordinary skill in the art. As an alternative and preferably, the stent 10 could be formed directly from an appropriate material if the addition of the biocompatible material 12. From here, the term "subject" refers to a human or other mammal upon which the method of the present invention is practiced.

Figure 2 shows a schematic enlargement of a portion of the biocompatible material of Figure 1. The biocompatible material 12 has at least one antigen 14 cod. As noted above, antigen 14 can be any molecule that can be cod by a second molecule, which can be an antibody, for example (not illustrated). Antigen 14 is an example of a safe of the present invention. Antigen 14 should not be a compound that is present at high levels within the body and that is accessible to the antibody, since that would reduce the location of the antibody to the stent 10 (see below). Accessibility could be restricted by the use of a compound or molecule that is not present in an extracellular surface, for example. The antigen 14 could be a pharmaceutical molecule such as an antibiotic, digoxin, colchicine and tricyclic antidepressants, for example. The advantage of using a known and clinically proven pharmaceutical molecule is that the safety of said molecule has already been extensively tested. Thus, the presence of said molecule within the body of a subject would not be toxic in and of itself.

The antigen 14 could be either protein, such as a peptide, a protein or a fragment thereof or non-protein, such as a pharmaceutical molecule, an oligonucleotide or a carbohydrate macromolecule. The advantage of non-protein molecules is that they are less likely to be degraded by the body of the subject, and they are also less likely to suffer undesirable transreaction with other tissues or molecules of the subject's body, such as the components of the immune system. Preferably, these molecules would not have any harmful effect on the blood vessel wall itself, although they could act to inhibit restenosis. More preferably, these molecules would not have been administered to the subject during the implantation of the stent 10, or for an appropriate period of time before and after the implantation of the stent 10. Such an appropriate period of time could be five half lives of the drug. , or any other period of time sufficient for the drug to be substantially cleansed from the body.

Preferably, the antigen 14 is coupled to the biocompatible material 14 by a chemical reaction. For example, antigen 14 could be coupled to biocompatible material 12 by co-incubation with a cross-linking reagent. More preferably, such a chemical reaction would cause the antigen 14 to present itself to the d vessel for maximum recognition and binding by means of an antibody (not shown). As an alternative and preferably, antigen 14 could be coupled directly to the stent 10.

Figure 3 is an illustration of a labeled antibody. An antibody 16 is illustrated, with a tag 18 coupled, and is designed as a "labeled antibody". The term "antibody" hereinafter includes any monoclonal or polyclonal immunoglobin such as an IgG, or a fragment of an immunoglobin such as sFv (single chain antigen binding protein), Fab1 or Fab2. Antibody 16 could also be a "humanized" monoclonal antibody, in which the murine variable regions are fused to human constant regions, or in which regions that determine the complementarity of murine are grafted onto a human antibody structure (Wilder , RB, et al., J. Clin. Oncol., 14: 1383-1400, 1996). Unlike mouse monoclonal antibodies, the "humanized" monoclonal antibodies often do not undergo an undesirable reaction with the subject's immune system. The antibody 16 is an example of a key while the label 18 is an example of an effect of the present invention.

The label 18 is preferably a radioactive source which can be any element suitable for medicinal or therapeutic use that emits radioactivity, such as yttrium-90, iodine-131 or iridium-192, for example, and could be chosen by someone with experience ordinary in the art. The label 18 could also, as an alternative and preferably, be a pharmaceutical moiety, which is a composition used for medicinal or therapeutic purposes, such as an antibiotic, a chemotherapeutic agent, an enzyme, a growth factor, an inhibitor of a enzyme or an inhibitor of a growth factor, for example. Said pharmaceutical moiety could take the form of a slow release formulation, for example. Said pharmaceutical moieties could easily be prepared by those of ordinary skill in the art. The label 18 is an example of an effector according to the present invention, and could also be chosen from those described in any of the examples or in the "Brief Description of the Invention", for example.

The advantage of using a drug molecule for antigen 14 is that antibodies to many of these drugs are commercially available. Of course, new antibodies could be developed according to procedures well known in the art, if required.

Figure 4 is an illustration of the stent after administration of the labeled anti-cough. The stent 10 has been placed in the d vessel of a subject, as described for Figure 1. Antibody 16 has been administered to the subject and is now bound to antigen 14 in the biocompatible material 12. The combination of the stent, anti-convulsant 16 and antigen 14 and label 18 is an example of a "biomedical device assembly" according to the present invention.

Antiquake 16 is preferably administered parenterally, by intravenous injection for example, which is particularly preferable for administration to the genitourinary tract and d vessels, for example. Other examples of methods of administration include inhalation within an air passage of the subject and oral administration to the gastrointestinal tract, for example. Since the antiquase 16 is labeled with the label 18, the tissue of the d vessel is now irradiated in a specific manner. However, since the antigen 14 is present substantially uniquely in the stent 10, substantially only the tissue of that portion of the wall of the d vessel to be treated is irradiated, in the case of a radioactive source for the label 18. Thus, restenosis of the blood vessel is specifically inhibited, without exposing large areas of a subject's body to radioactivity. Said specific inhibition could be used either for prevention or treatment, or both, of restenosis.

In addition, since the stent itself is not directly labeled, the stent 10 can be implanted into the blood vessel of a subject according to any appropriate catheterization procedure, which are well known in the art. The labeled anti-tag 16 can then be administered to the subject, at a later time and in a different location, if desired. Thus, the stent could be implemented in a standard catheterization laboratory, while anti-knock 16 could be administered in a standard radionuclear medicine laboratory, if the label 18 is a radioactive isotope, for example. Also, the time of catheterization should not be prolonged to expose the blood vessels to the radioactive source, and the stents themselves would not require special handling.

Preferably, the biocompatible material 12 has more than one type of antigen 14 coupled, so that the treatment could be repeated more than once with different anti-tips 16. As an alternative and preferably, the different labels 18 could also be used in this specimen, particularly for radioactive sources. The advantage of the different treatments for these sources is that smaller and therefore less toxic amounts of radioactivity could be administered with each treatment. Another advantage of the repetition of the treatment with different radioactive isotopes is that the cells are more vulnerable in certain points of the cell cycle, as it is during mitosis. Multiple treatments are more likely to affect more cells that may be at different points in the cell cycle. In addition, radioactive sources with different penetration forces could be used, which would allow the sources to be customized to the biological characteristics of the tissue to be treated. Preferably, antiquake 16 could have one or more coupled antigens (not illustrated) to which a second antiquase could be coupled, either at substantially the same time or at a later time of administration. Such an arrangement would also facilitate multiple radioactive sources, or even a combination of one or more radioactive sources with another pharmaceutical moiety.

Thus, an example of using this example of the biomedical device assembly would be to first insert the stent 0 into a blood vessel of a subject, the stent 10 would have an antigen 14 coupled. Then, the antiquake 16 the label 18 could be administered to the subject. Such a method could be used to inhibit restenosis in a subject. The term "inhibition" may at the same time include prevention, substantially before restenosis has occurred, or treatment, substantially after restenosis has occurred, or both.

EXAMPLE 2 Non-Regular Protein Antigen / Antigen Combinations The term "non-regular protein antigen / antigen combination" is used herein to describe a combination of a protein that has properties similar to those of the antiquase with an antigen, either protein or different. The protein with properties similar to those of the antibody is specifically non-immunoglobin such as an IgG, or a fragment of an immunoglobin such as sFv (single chain antigen binding protein), FAB1 or Fab2. Examples of proteins with properties similar to those of the antiquase include avidin or biotin, a macromolecule of an IgG and a bifunctional antibody, although of course many other examples of such proteins are possible. An appropriate effector could be chosen from those described in any of the examples or from the "Brief description of the invention", for example.

Figure 5 is an illustration of a biomedical device after administration of a safe / effector combination to a subject, in which the key and the insurance are avidin and biotin. A biomedical device 20, here a stent for the purposes of illustration, has been placed on the subject. Since the biomedical device 20 is illustrated here as a stent, the biomedical device 20 is placed within the blood vessel of the subject. The biomedical device 20 presents a biocompatible material 22 to which a latch 24 engages. As an alternative and reference, the latch 24 is directly coupled to the biomedical device 20. In this example, the latch 24 is either avidin or biotin. Preferably, the insurance 24 is avidin.

A key 26 with an attached effector 28 has been administered to the subject. The key 26 is time bound to the latch 24 on the biocompatible material 22. For this example, the key 26 is either avidin or biotin. Preferably the key is biotin and the safe 24 is avidin. Avidin and biotin are two proteins that are well known in the art to have a high affinity for each. Therefore, if the lock 24 is avidin, the biocompatible material 22, or also the biomedical device 20, would have avidin proteins coupled. If the key 26 is biotin, the effector 28 would be coupled to the biotin protein and then injected into the subject, similar to the injection of the antibody in Example 1 above. The biotin protein would then bind specifically to the avidin protein, so that the lock 24 and key 26 would be joined as illustrated in Figure 5. The combination of the biomedical device 20, the lock 24, the key 26 and the Effector 28 is another example of a biomedical device assembly 30.

Since the key 26 is either biotin or avidin, both are proteins, the combination of the key 26 and the effector 28 is preferably administered parenterally, by intravenous injection for example, which is particularly preferred for administration to the genitourinary tract and for blood vessels. Other examples of methods of administration include inhalation for air passages of the subject and oral administration to the gastrointestinal tract, for example.

Once the key 26 has been attached to the latch 24, the surrounding tissue of the biomedical device 20 is being treated specifically with the effector 28. For example, if the biomedical device 20 is a stent, the tissue of the vessel wall Blood is now being treated specifically. However, since the safety 24 is present substantially only in the biomedical device 20, substantially only the tissue of that portion of the wall of the blood vessel to be treated is irradiated, in the case of a radioactive source for the effector. 28. Thus, if the biomedical device 20 is a stent, restenosis of the blood vessel is specifically inhibited, without exposing large areas of a subject's body to radioactivity. Said specific inhibition could be used either for the prevention or treatment, or both, of restenosis.

In addition, if the effector 28 is a therapeutic substance that could be toxic to that medical person who handles the substance, such as a radioactive isotope, the biomedical device assembly 30 has another advantage. Since the biomedical device 20 itself is not directly labeled, the biomedical device 20 can be applied within the subject according to any appropriate procedure. For example, as a stent, the biomedical device 20 could be implanted in the blood vessel of a subject according to any appropriate catheterization procedure, which is well known in the art. 1 technique The key 26 with the effector 28 can then be administered to the subject, at a later time and in a different location, if desired. Thus, as a stent, the biomedical device 20 could be implemented in a standard catheterization laboratory, while the key 26 could be administered in a standard radionuclear medicine laboratory, if the effector 28 is a radioactive source, for example. Also, the time of catheterization would not have to be prolonged to expose the blood vessels to the radioactive source, and the stents themselves would not require special handling.

Preferably, the biocompatible material 22 has more than one type of latch 24 coupled, so that the treatment could be repeated more than once with different keys 26. For example, a first type of latch 24 could be avidin, while a second type of insurance 24 could be an antigen as described in Example 1. Alternatively and preferably, different effectors 28 could also be used in this example, in particular for radioactive nuclides. The advantage of multiple treatments for such sources is that smaller and therefore less toxic amounts of radioactivity could be administered with each treatment. Another advantage is that cells are more vulnerable at certain points in the cell cycle, such as during mitosis. Multiple treatments are more likely to affect more cells that may be at different points in the cell cycle. In addition, radioactive sources with different penetration forces could be used, which would allow the sources to be customized to the biological characteristics of the tissue to be treated.

Figure 6 is an illustration of a second type of biomedical device after administration of the key / effector combination to the subject, wherein the key 26 is a macromolecule of an IgG, and the lock 24 is any appropriate antigen as described in Example 1 or in Figure 5, for example. As illustrated in Figure 6, the IgG 32 macromolecule contains a plurality of antigen binding sites 34 and is a synthetic molecule. Typically, all of the binding sites with antigen 34 bind to the same antigen, which is safe 24. The advantage of the macromolecule of IgG 32 over a regular immunoglobin is that a single macromolecule of IgG 32 can bind to many antigens, that would provide a narrow and specific particular link. In addition, the situation could be reversed, and the insurance 24 could be a macromolecule of IgG 32. Under these circumstances, the macromolecule of IgG 32 could be attached to many keys 26, or antigens, which would be injected into the subject, for example. Thus, like insurance 24, the macromolecule of IgG 32 could act to concentrate many keys 26 in the biomedical device 20.

Figure 7 shows still another example of a biomedical device 20, in which the key 26 is a bifunctional antiquase 36 and the safe is any appropriate antigen, as described in Example 1 and Figure 5, for example. The bifunctional antiquake 36 has two link sites. A first linkage site 38 recognizes and binds to the lock 24 as an antigen. A second linkage site 40 recognizes and binds to effector 28, which could be an yttrium chelate, for example. As previously noted, the chelate could include DOTA or DPTA and Yt90, which is a radioactive isotope. The advantage of the bifunctional antiquake 36 as the key 26 is that the effector 28 could be administered to the subject at a later time even. In other words, the bifunctional antiquake 36 could be administered to the subject first. The bifunctional antibody 36 would then be coupled to the antigen as the safe 24. Any bifunctional anti-cotylation without free binding 36 would then be removed in 24 hours. Finally, effector 28, which would be an yttrium chelate, could be administered to the subject. The situation could be reversed, with the bifimcional anticúfo 36 as the insurance 24.

Thus, the bifunctional antiquase 36 allows greater flexibility for the administration of the effector 28.

EXAMPLE 3 Combinations of Non-Protein Antibody / Antigen The term "combination of anti-protein non-protein / antigen" is used herein to describe a combination of a non-protein molecule with properties similar to an antiquase and an antigen, protein or different. Examples of the non-protein molecule include, but are not limited to, a carbohydrate macromolecule, a bifunctional chelator, and an oligonucleotide. The carbohydrate macromolecule could be synthesized specifically to be able to bind to the antigen, which could be another carbohydrate. An appropriate effector could be chosen from those described in any of the examples or from the "Brief Description of the Invention", for example.

Figure 8 is an illustration of an exemplary biomedical device after administration of a key / effector combination to a subject, in which the key and the 'sure are both non-protein carbohydrate molecules. Similar to Examples 1 and 2 above, a biomedical device 42 would have a latch 33 engaged. Insurance 44 could be any type of carbohydrate macromolecule. The lock 44 would specifically bind to a key 46, which would be a complementary carbohydrate macromolecule. The key 46 would have an effector 44 coupled, as described in Examples 1 and 2 above.

As another example, illustrated in Figure 9, a bifunctional chelator might be safe 44. Bifunctional chelators are known in the art (Meares et al., Br. J.

Cancer, 62: 21-26, 1990). The bifunctional chelator could have a functional group that would bind directly to a group 43 in the biomedical device 42. For example, if the biomedical device 42 exhibits a metal portion, a functional group of the bifunctional chelator would bind to the metal portion of the biomedical device 42. The other functional group of the bifunctional chelator would be a metal chelator, which could then bind to a radioactive nuclide. The radioactive nuclide would form the key 46 and the effector 48, since an additional half would not be needed. The radioactive nuclide could be administered to the subject, for example by injection, and would be present in the bloodstream. The radioactive nuclide would be bound by the chelator functional group and would be concentrated in the position of the biomedical device 42.

The advantage of using a non-protein molecule, such as a carbohydrate molecule, n oligonucleotide or a bifunctional chelator, is that said molecules are less subject to degradation by the subject's body. Non-protein molecules can be administered non-parenterally under some circumstances, and could even be administered orally. These molecules could also be specifically designed to be the 44 or the 46 key, without the chemical, synthetic or structural restrictions of the amino acids or proteins. Thus, non-protein molecules could potentially offer more flexibility to the lock and key system of the present invention.

Example 4 Mixed Insurance System and Key A mixed insurance and key system in accordance with the present invention combines several characteristics of the insurances and keys of the previous Examples to exploit their desirable properties. Such combinations could include both protein and non-protein molecules, or various combinations of each type of molecule. In particular, the mixed lock and key system of the present invention could include an oligonucleotide as at least one key component, and an antisense oligonucleotide as at least one key component, and an antisense oligonucleotide as at least one component of the key. safe, or vice versa (Bos, ES et al., Cancer Res., 54: 3479-86, 1994).

The key oligonucleotide would be complementary to the safe oligonucleotide and would therefore bind specifically to the safe oligonucleotide. Preferably, any type of macromolecule that could present the oligonucleotide could be coupled to the oligonucleotide of the key or of the insurance. As part of the insurance, such a large macromolecule would allow the oligonucleotide to be coupled to the biomedical device material while still maintaining the spatial separation of the material, for example. As part of the key, such a large macromolecule would provide a site or binding sites for one or more effectors, for example. Thus, in spite of the fact that the oligonucleotide could form the safe or the key alone, preferably a macromolecule would be coupled to the oligonucleotide as part of the lock or key.

For example, the macromolecule could be a protein to which the oligonucleotide is coupled, forming a mixed oligonucleotide / protein complex. The protein could be an immunoglobin or a fragment thereof, avidin or biotin, for example if the binding properties of said protein are desired. As an alternative, another type of protein without such properties could be used, as is albumin for example.

As an alternative, a non-protein molecule could be used as the macromolecule. For example, a carbohydrate macromolecule could be used. A bifunctional chelator could also be used to present the oligonucleotide and to bind a radionuclide. These two macromolecules would form part of a mixed key and insurance system according to the present invention.

Figure 10 shows an exemplary mixed padlock and insurance system 50 in accordance with the present invention after administration of the secure / key combination to the subject. The insurance system / mixed key 50 includes a biomedical device 52, illustrated here as a stent for the purpose of illustration, with a latch 54 attached to a key 56. In this example, the latch 54 includes a secure sense oligonucleotide 58 coupled to an appropriate separator 60. The separator 60 could be an organic polymer, a carbohydrate macromolecule or a peptide, for example. The key 56 includes an antisense key oligonucleotide 62. Although not illustrated, the key oligonucleotide 62 could be coupled to any appropriate macromolecule as described above, either directly or through an appropriate separator such as an organic polymer, a carbohydrate macromolecule or a peptide, for example. In addition, the key 56 could also be coupled to an appropriate effector (not illustrated) substantially as described in any of the Examples or in the "Brief Description of the Invention".

Example 5 Production Methods The biomedical device systems of the present invention can be manufactured in a number of different ways. First, a biomedical device would be manufactured according to methods well known in the art. Next, an insurance would be attached to the biomedical device. The next step would depend on whether the system would be manufactured in vivo or ex vivo. For ex vivo production, the key would then be added and you would be allowed to attach to the insurance. The complete biomedical device system would then be placed inside the subject. For in vivo production, the biomedical device with the attached latch would be placed inside the patient. The key would be administered to the patient and he would be allowed to join the insurance, thus completing the biomedical device system.

Several examples are given herein for the manufacture of stents as exemplary biomedical devices, it being understood that this is for the purpose of illustration only and is not intended to be limiting in any way. Two examples are given for the ex vivo manufacturing of the biomedical device system. and an example is given for the in vivo manufacture of the biomedical device system.

Method 1: Ex vivo Manufacturing of a Radioactive Stent First, a stent is manufactured in accordance with standard manufacturing practices for a biomedical device. At least a portion of the stent, such as the inner surface, is preferably made of a derivatizable polymer. As an alternative and preferably, the surface could be made of metal, and then covered with a derivatizable polymer. The derivatisable polymer preferably has functional groups that can form covalent crosslinks with a safe moiety, such as a protein, after exposure to a catalyst such as a source of ultraviolet light. As an alternative and preferably, a non-covalent bond could be formed between the lock and the stent material. Also as an alternative and preferably, half of the insurance could form covalent bonds with a metallic portion of the stent.

Next, the derivatisable polymer is derivatized by coupling the lock, as is an antigen, to the polymer. Coupling occurs by incubating the antigen or other half with the stent polymer under appropriate conditions, and then exposing the stent to an activator if necessary. For example, to form a covalent bond between the safe and the derivatizable polymer, the activator could be ultraviolet light.

In the next step, the combination of the key and the effector is incubated with the stent under appropriate conditions, so that the key and the safety catch join. For example, if the insurance were an antigen, the key would be an antiquake with a radioactive isotope like the effector. The antiquase would bind with the antigen, so that the radioactive isotope was connected to the stent. The stent would then become radioactive, and would be ready for implantation within the subject.

In a variation of this method, the insurance, the key and the effector could be a unit that would be directly attached to the stent. For example, the antibody with the radioactive isotope could be attached directly to the stent polymer, to form a radioactive stent.

In another variation, the antigen again would bind as the safe to the stent. Next, a bifunctional antiquake would be allowed to join as the insurance to the stent. Afterwards, a bifunctional antibody would be allowed to join the insurance as the key. One binding site of the bifunctional anti-coterver would bind to the antigen, while the other binding site would bind to the effector. The effector could be a chelated isotope, as is the combination of DOTA or DPTA and yttrium or cobalt described above. Once the radioactive isotope was attached, the stent would again become radioactive and would be ready for implantation within the subject.

Method 2: Ex vivo Manufacturing of a Coated Stent As noted above, coating the inner surface of a stent with endothelial cells has been proposed as a way to inhibit thrombi or atherosclerosis around the stent. The endothelial cells normally line up in the blood vessel, so a stent that also has cells growing inside would also be able to better copy the natural state of the blood vessel. Unfortunately, no method has yet been proposed for the manufacture of such stents covered with endothelial cells outside research laboratories. The present invention is only capable of providing such stents, in which the endothelial cells is either a key according to the present invention, or if it is not coupled directly to the surface of the stent.

A stent is manufactured and prepared as described in method 1 above. The insurance could be a specific anti-cues for some portion of endothelial cells so that the anti-cues specifically bind to these cells. Next, the endothelial cells are incubated with the stent under appropriate conditions, so that the anti-cotermin binds to the endothelial cells. The inner surface of the stent is coated with endothelial cells. The stent is now ready to be implanted into the subject's body.

As an alternative and preferably, an antigen could be coupled to the stent as previously described. An antibody with a coupled endothelial cell could then be incubated with the stent, such that the antibody binds to the antigen. The stent is now coated with endothelial cells. The antiquase could be a bifunctional anticuefo, so that the coupling of the antiquase to the endothelial cells is not covalent. As an alternative and preferably, the antiquase could be covalently coupled to a protein or other half on the surface of the endothelial cell.

Of course, fragments of immunoglobulins or carbohydrate macromolecules could be used instead of the antibody for coupling the endothelial cell to the stent. In addition, the biomedical device system could optionally be completed in vivo, by administering an endothelial cell, alone or in combination with an antiquase or other appropriate macromolecule, to the subject. For example, the endothelial / anti-coterie cell combination could be injected into the subject after implantation of the stent to which an antigen has been coupled. Preferably, the antibody / cell combination could be injected into a stented artery during temporary occlusion of the artery distant from the stent with a balloon catheter. However, in the preferred specimen of this biomedical device system, the endothelial cell would attach to the stent ex vivo, since the injection of these nonlocal cells within the subject could potentially cause unwanted medical complications.

Method 3: In Vivo Production of a Radioactive or Covered Stent As described in Method 1 above, a safe is attached to a stent. Next, the stent is inserted into a blood vessel of a subject. Then, a key and an effector, such as an antibody with a radioactive coupled isotope, or an antiquase coupled to an endothelial cell, could be administered to the subject. The key would then be attached to the safety device, thereby specifically delivering the effector to the area immediately surrounding the biomedical device. For example, the radioactive isotope coupled to the anti-cue would locate the stent, thus specifically treating the surrounding tissue of the stent with radioactivity. As an alternative, the endothelial cells would cover the stent to form an in vivo coated stent as described above, which would specifically treat the surrounding tissue with endothelial cell products such as nitric oxide or other naturally formed products, or even products formed by endothelial cells with genetic engineering.

EXAMPLE 6 Exemplary Effectors The term "effector" includes any molecule, combination of molecules or even a whole cell, which has a therapeutic effect. For example, the effector could be a radioactive isotope, a drug, a hormone, a growth factor, a cytokine, a T cell or a toxin. The effector could be chosen to inhibit the growth factor, for example to treat or prevent restenosis. Another example of an effector could be an endothelial cell, particularly for coating the interior surface of a stent to prevent the formation of thrombi or neointimal hyperplasia. In some circumstances, the effector and the key could be the same half. For example, a chelate of a metal could be specifically linked to a safe, such as an antiquake, in a biomedical device. The chelate could include DOTA or DPTA and yttrium, for example. Yttrium is an example of a potentially radioactive isotope that is used for the inhibition of growth factor.

Another type of effector would be a two-component effector with an enzyme coupled to the anti-cough. The enzyme would activate a prodrug by chemically altering the prodrug. Preferably, the prodrug would have little or substantially no effect on the subject. However, the activated drug would have a desirable effect or effects for the treatment. For example, the activated drug would be a cytotoxic drug for the inhibition of restenosis.

Thus, many different types of effectors are possible and one would be chosen by someone with ordinary skill in the art.

Radionuclides as Effectors Localized radioimmunotherapy has been studied particularly extensively for the treatment of cancer. For example, anticyclols with radionuclides such as yttrium 90 (90Y), iodine 131 (131I), and copper 67 (67Cu) have been used to successfully treat non-B cell Hodgkin lymphoma (Wilder, RB, et al. ., J. Clin. Oncol., 14: 1383-1400, 1996). However, the relatively low levels of localization of anti-tags radioactively labeled for solid tumors have been shown to be effective for treatment. For example, 0.1% to 10% specific binding of said anti-convolutions to solid tumors has still resulted in effective therapy. Thus, the low levels of antiquake localization for the biomedical devices of the present invention would presumably be sufficient for effective treatment.

The selection of a particular radionuclide depends on the therapy that is intended. For example, the dose ratios for maximal tumors are higher for antichodes with yttrium 90 and copper 67 coupled (about 0.40 Gy / h) than for anti-cues with coupled iodine 131 (about 0.10 Gy / h) (Wilder, RS. , et al., J. Clin. Oncol., 14: 1383-1400, 1996). However, dose ratios as low as 0.02 and 0.03 Gy / h have been calculated as the minimum dose of high malignant cell proliferation in vivo (Wilder, RS., Et al., J. Clin. Oncol., 14: 1383-1400, 1996). Since certain specimens of the biomedical device system of the present invention are intended to inhibit or prevent tissue growth in the surrounding area, presumably this therapeutically effective dose could also be applied to these specimens of the system of the present invention. Certainly the teachings of the prior art with respect to the treatment of cancer with radiolabelled anti-plates could be applied to these specimens of the biomedical device system of the present invention.

Thus, the use of anti-convolutions labeled with radionuclides for the treatment of cancer is well known in the art.

Chelates as Effectors Radionuclides are often used as part of a chelated complex. For example, yttrium, cobalt and iodine can be chelated with a quelator such as DTPA 1,4,7-triazaheptane - N, N '- N "- pentaacetic), DOTA 1,4,7,10 - tetraazacyclododecane - N, N ', N ", N'" - tetraacetic or derivatives thereof, such as nitrobenzyl-DOTA (2-p-nitrobenzyl-1,4,7,10-tetraazacyclododecane - N, N ', N ", N'" - - tetraacetic) These chelated radionucleotides can then be specifically bound by antiquake against the chelator to form the key / effector complex of the present invention.Clockes with high specific binding to said chelators are known in the art (Kraneborg, MHGC , et al., Can. Res. Supp., 55: 5864-5867, 1995; Meares, CF, et al., Br. J. Cancer, 62: 21-26, 1990.) Thus, a complex of a chelator with a radionuclide could be used as an effector for the biomedical device system of the present invention.

Toxins as Effectors Many different types of toxins have been used for localized therapy, particularly for cancer. From here, the term "toxin" means any cytotoxic moiety. Examples of toxins include, but are not limited to, plant toxins such as ricin, modecina, viscumin, herb antiviral protein, saporin, gelonin, momoridin, trichosanthin, barly toxin and abrin, bacterial toxins such as diphtheria toxin and Pseudomonas endotoxin, fungal toxins such as alpha-sarcin and restrictocin and synthetic toxins. Plant, bacterial and fungal toxins often have their effect through the inhibition of cell synthesis. For example, the diphtheria toxin and the endotoxin Pseudomonas inactivate both the elongation factor 2, whereas ricin and abrin inactivate the 28S ribosomal subunit UThrush, G.R., et al., Ann.

Rev. Immunol., 14:49 - 71, 1996). Other toxins can inhibit other activities of the cell, such as DNA synthesis or the activities of the mitochondria. When coupled to an objective half as an antiquase, these toxins have been tested in vitro to remove tumor cells from autolugose bone marrow transplants and for the in vivo treatment of patients with cancer, autoimmune disease and infection with VLH.

(Thrush, G.R., et al., An. Rev. Immunol., 14: 49-71, 1996).

It will be appreciated that the foregoing descriptions are intended only as examples, and that many other examples are possible within the spirit and scope of the present invention.

Claims (56)

1. CLAIMS: 1. A biomedical device assembly comprising a biomedical device, wherein said biomedical device has an antigen and an antiquague that has a tag attached, wherein said antigen and said anti-cell are linked.
2. 2. The biomedical device assembly of Claim 1, wherein said biomedical device is placed in a position chosen from the group constituting a solid tissue and a biological passage.
3. 3. The biomedical device assembly of Claim 2, wherein said biological passage is selected from the group consisting of blood vessels, air passages, gastrointestinal tract, intercerebral, biliary duct and genitourinary tract.
4. 4. The biomedical device assembly of Claim 1, wherein said antigen is a drug molecule.
5. 5. The biomedical device assembly of Claim 1, wherein said biomedical device is selected from the group consisting of a spring, an artificial valve, a vascular graft and a stent.
6. 6. The biomedical device assembly of Claim 5, wherein said biomedical device is a stent.
7. 7. The biomedical device assembly of Claim 1, wherein said label is selected from the group consisting of a radioactive source and pharmaceutical moiety.
8. 8. The biomedical device assembly of Claim 7, wherein said label is a radioactive source.
9. 9. A method of substantially inhibiting restenosis in a blood vessel of a subject, comprising the steps of: a) inserting a stent into a patient's blood vessel, the stent has a coupled antigen; and b) administering an antibody to the subject, the anti-cotuefo is capable of binding antigen and the anti-cotuefo has a tag attached where the tag is capable of inhibiting restenosis.
10. 10. The method of Claim 9, wherein said label is selected from the group consisting of radioactive source and pharmaceutical moiety.
11. 11. The method of Claim 10, wherein said label is a radioactive source.
12. 12. The method of Claim 9, wherein said antigen includes a plurality of different types of antigens, so that the step of administering said anti-cue is repeated for a plurality of different types of anti-buds.
13. 13. A biomedical device assembly for targeted treatment, comprising: a) a biomedical device; b) an insurance, the insurance is coupled to the biomedical device; c) a key to interact specifically with the insurance; and d) an effector to carry out the directed treatment, the effector is coupled to the key.
14. 14. The biomedical device assembly of Claim 13, wherein said key and said latch are independently chosen from the group consisting of an antiquase, an antigen, a non-regular antibody, a mixed protein and non-protein combination and a non-protein molecule and combinations thereof.
15. 15. The biomedical device assembly of Claim 14, wherein said antiquase is selected from the group consisting of a polyclonal immunoglobin, a monoclonal immunoglobin, a SFv (single chain antigen binding protein), Fab1 fragment, a Fab2 fragment and an immunoglobin humanized monoclonal
16. 16. The biomedical device assembly of Claim 14, wherein said antigen is selected from the group consisting of a protein, a peptide and fragments thereof, a carbohydrate macromolecule, an oligonucleotide and a pharmaceutical molecule and combinations thereof.
17. 17. The biomedical device assembly of Claim 16, wherein said protein is selected from the group consisting of avidin and biotin.
18. 18. The biomedical device assembly of Claim 14, wherein said non-regular antishock is selected from the group consisting of an IgG macromolecule, a bifunctional antiquase, avidin and biotin.
19. 19. The biomedical device assembly of Claim 14, wherein said non-protein molecule is selected from the group consisting of a carbohydrate macromolecule, an oligonucleotide and a bifunctional chelator.
20. 20. The biomedical device assembly of Claim 14, wherein said mixed protein and non-protein combination is a protein with a coupled oligonucleotide.
21. 21. The biomedical device assembly of Claim 14, wherein said effector is selected from the group consisting of a radioactive isotope, a drug, a hormone, a growth factor, a cytokine, a T cell, a toxin, an endothelial cell, a chelate of a radioactive isotope and a two-component effector.
22. 22. The biomedical device assembly of Claim 21, wherein said chelate of said radioactive isotope includes a chelator selected from the group consisting of DOTA, DPTA, nitrobenzil DOTA and a bifunctional chelator.
23. 23. The biomedical device assembly of Claim 21, wherein said radioactive isotope is selected from the group consisting of yttrium 90 (90Y), lutetium 177 (177Lu), rhenium 186 (186Re), rhenium 188 (188Re), phosphorus 32 (32P) ), bismuth 212 (212Bi), astatin 211 (211At), iodine 131 (131I), iodine 125 (125I), iridium 192 (192Ir), palladium 103 (103Pd) and copper 67 (^ Cu).
24. 24. The biomedical device assembly of Claim 21, wherein said two-component effector is an enzyme and a prodrug, wherein said enzyme alters the chemically prodrug to activate said prodrug.
25. 25. . The biomedical device assembly of Claim 21, wherein said toxin is selected from the group consisting of plant toxins, a bacterial toxin, a fungal toxin and a synthetic toxin.
26. 26. The biomedical device assembly of Claim 21, wherein said biomedical device is inserted into a solid tissue or a biological passage selected from the group consisting of blood vessel, air passage, intercerebral, gastrointestinal tract, bile duct and genitourinary tract.
27. 27. The biomedical device assembly of Claim 26, wherein said biological passage is a blood vessel.
28. 28. The biomedical device assembly of Claim 26, wherein said biomedical device is a stent.
29. 29. The biomedical device assembly of Claim 13, wherein said latch engages a material covers at least a portion of a surface of the biomedical device.
30. 30. The biomedical device assembly of Claim 29, wherein said material is selected from the group consisting of a derivatizable polymer and a metal.
31. 31. The biomedical device assembly of Claim 30, wherein said material is said metal, and said latch is coupled to said metal by a covalent bond.
32. 32. The biomedical device assembly of Claim 30, wherein said material is said derivatizable polymer and said latch is coupled to said derivatizable polymer by a covalent bond.
33. 33. The biomedical device assembly of Claim 32, wherein said covalent is formed by a chemical reaction between said safeguard and said derivatizable polymer.
34. 34. The biomedical device assembly of Claim 33, wherein said chemical reaction is activated by exposing said safe and said derivatizable polymer to ultraviolet light.
35. 35. The biomedical device assembly of Claim 31, wherein said latch is coupled to said derivatizable polymer by a non-covalent bond.
36. 36. A method for manufacturing a biomedical device assembly, the method comprises the steps of: a) providing a biomedical device, b) attaching a latch to the biomedical device, c) coupling an effector to a key to form an attached effector, and d) incubating the insurance and the key, so that the insurance and the key interact to form the assembly of the biomedical device.
37. 37. The method of Claim 36, wherein said latch engages a material that covers at least a portion of a surface of the biomedical device.
38. 38. The method of Claim 37, wherein said material is selected from the group consisting of a derivatizable polymer and a metal.
39. 39. The method of Claim 37, wherein said material is said derivatizable polymer and said latch is coupled to said derivatizable polymer by a covalent bond.
40. 40. The method of Claim 39, wherein said covalent bond is formed by a chemical reaction between said safeguard and said derivatizable polymer.
41. 41. The method of Claim 40, wherein said chemical reaction is activated by exposing said safe and said derivatizable polymer to ultraviolet light.
42. 42. The method of Claim 38, wherein said latch is coupled to said derivatizable polymer by a non-covalent bond.
43. 43. The method of Claim 36, wherein said key and said safe are each independently chosen from the group consisting of an antiquase, an antigen, a non-regular antiquake, a mixed protein and non-protein combination and a non-protein molecule and combinations thereof.
44. 44. The method of Claim 43, wherein said antiquase is selected from the group consisting of a polyclonal immunoglobin, a monoclonal immunoglobin, a SFv (single chain antigen binding protein), Fab1 fragment, Fab2 fragment and a humanized monoclonal immunoglobin.
45. 45. The method of Claim 43, wherein said antigen is selected from the group consisting of a protein, a peptide, fragments thereof, a carbohydrate macromolecule, an oligonucleotide and a pharmaceutical molecule and combinations thereof.
46. 46. The method of Claim 45, wherein said protein is selected from the group consisting of avidin and biotin.
47. 47. The method of Claim 43, wherein said protein is selected from the group consisting of an IgG macromolecule, a bifunctional antiquake, avidin and biotin.
48. 48. The method of Claim 43, wherein said non-protein molecule is selected from the group consisting of a carbohydrate macromolecule, an oligonucleotide and a bifunctional chelator.
49. 49. The method of Claim 43, wherein said mixed protein and non-protein combination is a protein with a coupled oligonucleotide.
50. 50. The method of Claim 43, wherein said effector is selected from the group consisting of a radioactive isotope, a drug, a hormone, a growth factor, a cytokine, a T cell, a toxin, an endothelial cell, a chelator of a radioactive isotope and a two-component effector.
51. 51. The method of Claim 50, wherein said chelate of said radioactive isotope includes a chelator selected from the group consisting of DOTA, DPTA, nitrobenzil DOTA and a bifunctional chelator.
52. 52. The method of Claim 50, wherein said radioactive isotope is selected from the group consisting of yttrium 90 (90Y), lutetium 177 (177Lu), rhenium 186 (186Re), rhenium 188 (188Re), phosphorus 32 (32P), bismuth 212 (212Bi), astatin 211 (211At), iodine 131 (131I), iodine 125 (125I), iridium 192 (192Ir), palladium 103 (103Pd) and copper 67 (67Cu).
53. 53. The method of Claim 50, wherein said two-component effector is an enzyme and a prodrug, wherein said enzyme chemically alters said prodrug to activate said prodrug.
54. 54. The method of Claim 50, wherein said toxin is selected from the group consisting of plant toxins, a bacterial toxin, a fungal toxin and a synthetic toxin.
55. 55. The method of Claim 36, wherein the step of attaching said latch to said biomedical device is carried out ex vivo, and the step of incubating said latch and said key to form the biomedical device assembly is carried out by placing first of said biomedical device with said insurance in a subject, and then administering said key with said effector coupled to said subject, so that the biomedical device assembly is formed by the interaction of said key and said safe in said subject.
56. 56. The method of Claim 36, wherein the step of attaching said latch to said biomedical device is carried out ex vivo, and the step of incubating said latch and said key to form the biomedical device assembly is carried out ex vivo. EXTRACT OF THE INVENTION A biomedical device assembly, such as a stent, for the targeted treatment of a tissue, such as the inhibition of restenosis. The stent is covered with an antigen, which is an example of a padlock. The antigen can be found by an anti-tagging label, which is an example of a key and an effector. The antiquake is preferably labeled with a radioactive source. According to a method for preparing the biomedical device assembly, after the stent has been placed in the subject's blood vessel, the antibody is injected. The antiquase is then linked with the antigen to the stent, thus locating the radioactive source to the area to be treated, for example by restenosis. Other biomedical devices, such as a spring, an artificial valve or a vascular graft, could also be used in place of the stent. The biomedical device could be placed in a solid tissue such as a solid tumor, or another biological passage, such as the gastrointestinal tract, an airway or the genitourinary tract.