WO2000059550A2

WO2000059550A2 - Indium-114m and related compositions applicable in brachytherapie

Info

Publication number: WO2000059550A2
Application number: PCT/US2000/007855
Authority: WO
Inventors: Saed Mirzadeh; W. Scott Aaron; Lee Zevenbergen
Original assignee: Ut-Battelle Llc
Priority date: 1999-04-02
Filing date: 2000-03-24
Publication date: 2000-10-12
Also published as: AU4176300A; WO2000059550A3

Abstract

The preparation of a very fine wire of a homogenous alloy of indium and aluminum of up to ∩17 weight percent of indium-113 or -114m (∩0.3 mm in thickness) for use as a brachytherapy source is disclosed. Also disclosed are methods and compositions of 114mIn for brachytherapy. The 114mIn isotope has a half-life of 49.5 days, an average β-particle energy of 773 keV, and a dose rate of 1.66 rad.g.νCi?-1.h-1. 114m¿In emits a gamma-ray at 190 keV with 16 % intensity useful in diagnostics.

Description

INDIUM -114M AS A SOURCE FOR BRACHYTHERAPY AND RELATED COMPOSITIONS AND METHODS

1.0 BACKGROUND OF THE INVENTION

1.1 Field of the Invention

The present invention relates to a new source for providing radiation to localized region or tissue of a patient. More specifically, this invention relates to compositions suitable for use in radiation therapy containing ^U4mIn and compounds and alloys of ^1I4mIn and methods for their use in brachytherapeutic applications, including endovascular radiation therapy to prevent restenosis after angioplasty and the treatment of localized cancers.

2.1 General B ackground

Discrete brachytherapy sources have been known to provide an effective method in the medical treatment of diseased tissue (Lawton et al. 1998). Brachytherapy designates the use of radioactive sources within or in contact with the body as opposed to treatment with an external radiation beam (teletherapy). In brachytherapy the radioactive materials are placed in relatively close proximity (mm) to selected tissues or areas within a subject. Interstitial brachytherapy involves insertion of implants that emit radiation into a tumor or tissue containing a tumor, such as the prostate (Lawton et al. 1998). The purpose of the implant is to shrink and destroy the tumor by exposing the cancerous cells in the immediate vicinity of the implant to radioactivity. For this procedure, the radioactive implant, as a sealed source, is typically inserted through a plastic catheter, or similar means, which has been inserted into the tumor from a point external to the body of the patient. Examples of such applications include implants employed to treat prostate cancer (Lawton et al. 1998) and brain tumors (Bernstein et al. 1995). As another example, radioactive sources placed in the uterus and upper vagina can deliver high doses of radiation to gynecological malignancies with relative sparing of the rectum and bladder (Michael Stutz et al. 1998).

The brachytherapy sources of radiation may be used to expose the selected tissue to doses of radiation for short- or long-term. Where long-term exposure is desired, the source is implanted into a patient at the site of the diseased tissue. To effectively treat a patient with either short- or long-term exposure to radiation, it is desirable to employ a radioactive source which will irradiate the diseased tissue while minimizing damage to nearby healthy tissue. It is also desirable to employ a source that uniformly irradiates the treated area with a controlled dosage of radiation.

Brachytherapy may be classified as either high dose rate (HDR) or low dose rate (LDR) brachytherapy. HDR brachytherapy simply means that the radiation dose is delivered more quickly than with traditional or low dose rate (LDR) brachytherapy. With HDR the dose may be delivered over a matter of minutes as opposed to traditional LDR techniques, which may involve the same dose being delivered over several days or months (Michael Stutz et al. 1998). Thus, HDR is often employed in instances where short-term exposure is desired while LDR is more often employed where long-term exposure is desired.

In some circumstances, HDR presents certain advantages as explained by Stutz et al. By avoiding prolonged bed rest, the risk of adverse thromboembolic, cardiac, and pulmonary events may be reduced (Michael Stutz et al. 1998). HDR also offers the convenience and reduced health care costs of outpatient care. HDR brachytherapy offers other advantages over LDR. With reduced treatment times, applicator movement during treatment is minimal, making planning calculations more representative of the actual treatment delivered (Michael Stutz et al. 1998). Also, the hardware used in the HDR procedure is smaller, more easily manipulated, and more comfortable for the patient (Michael Stutz et al. 1998). Because the radioactive sources are remotely afterloaded, exposure risk to hospital personnel is decreased (Michael Stutz et al. 1998). The computer driven radioactive source can also better customize treatment for the individual patient, optimizing dose to the selected tissue, region or tumor and minimizing dose to normal tissues.

When comparing HDR to LDR, one must realize that there is currently less clinical experience with HDR. However, evidence over the past several decades indicates roughly equivalent results in terms of tumor control and treatment related complications. A possible disadvantage to HDR is that more applications, usually three to five, are required as opposed to the usual one to two insertions for LDR. Exemplary art includes: U.S. Patent Nos. 2,429438 and 2,322,902 which relate to tubular bodies of radium seeds and an apparatus for making these bodies; U.S. Patent No. 3,438,365 which relates to radioactive seeds containing xenon gas; U.S. Patent No. 5,322,499 which relates to methods of forming and employing implantable solid radioactive segments of desired lengths for brachytherapy; and U.S. Patent Nos. 4,994,013 and 5,163,896 which relate to radioactive pellets and seeds for brachytherapy. All of these references are hereby incorporated by reference.

High dose rate brachytherapy for prevention of restenosis after percutaneous transluminal coronary angioplasty is a short-term exposure application for which there is a pronounced need for the development of new sources of radioactivity. Balloon dilatation of coronary artery stenosis is a standard treatment of atherosclerotic heart disease. Unfortunately, restenosis due to excessive intimal cell proliferation occurs in approximately 20-50% of patients, representing a major clinical problem with this treatment.

High energy β-particle emitters have recently been recognized as suitable sources for brachytherapy. Potential sources include only a few radioisotopes: ⁹⁰Y (half life (t,_/2) of 64 hrs), ¹⁸⁶Re (t,_Λ of 90 hrs), ³²P (t,_/2 of 14 days), and ¹⁸⁸W (t,_/2 of 60 days), β-particle emitters are preferable to γ-emitters in terms of safety for medical personnel and the patient. Evidence from clinical trials shows that, in general, exposure to the patient and operator with gamma emitters is much higher than for beta emitters. However, none of the β-emitting radioisotopes identified for medical use are ideal for most therapeutic applications. ⁹⁰Y and

¹⁸⁶Re suffer from a lack of shelf-life as evidenced by their relatively short half lives. ¹⁸⁸W has a low specific activity requiring long irradiation time for most therapeutic applications; manufacturing difficulties associated with the high melting point of tungsten; and relatively scarce availability as only a few nuclear reactors in the world are capable of producing ¹⁸⁸W having a useful specific activity. Manufacturing of ³²P sources is time consuming and expensive because of the nonmetallic characteristics of phosphorous.

^nιIn has been used for radio labeling in various applications including studies described by Khalifa et al. (1997); however, other radioisotopes, such as ^114mIn and ^114gIn, have not been previously employed in biomedical applications. These isotopes have probably not been employed because of their masked nuclear properties. ^U4mIn decays with a half-life of 49.5 days with 95% isomeric transition to ^114sIn (ground state) which has a half- life of only 72 sec, which in turn decays with 100% β-emission with an end-point energy of 2 MeV to stable ^U4Sn. In other words, the high energy β-particle is actually emitted from the very short-lived daughter of ^114mIn which is in secular equilibrium with its parent at all times.

Therefore, there is a need to discover and develop new radiation sources for brachytherapeutic applications. Such sources should be relatively available and/or able to be produced and manufactured in the appropriate form; capable of safe handling by medical workers; and have an appropriate specific activity and type of radiative emission for the particular application. A useful radiation source should also be sufficiently stable to be stored on site; having a shelf-life of a few weeks to a few months.

2.0 SUMMARY OF THE INVENTION

The present invention addresses many of the problems inherent in the field by providing a new radiation source for brachytherapy and methods and compositions for employing this source. This new source ^114mIn is readily produced in a moderate-sized nuclear reactor within a relatively short period of time; easily manipulated into the proper physical form; and has a sufficiently long shelf life so that it can be stored on site. ^U4mIn also has a high specific activity, emitting primarily β-particles with some emission of γ rays. From the point of view of energy deposition (dosing), activation level, manufacturing, and shelf-life, ^U4mIn source is superior to most other brachytherapy sources. Its nuclear properties make it particularly well-suited for endovascular radiation therapy and treatment of very localized conditions or cancers requiring short-term, localized high doses of radiation.

Further, because this source emits primarily β-particles and relatively few γ rays, it is also safer and easier to handle by medical care workers than many other sources currently employed.

An embodiment of the present invention encompasses a method of delivering radiation to a selected tissue of a patient in need thereof by obtaining a ^114mIn source; and exposing the tissue to the source. Potential biomedical applications include the following: intravascular radiation therapy to prevent restenosis (see Waksman 1998, incorporated herein by reference); treatment of diseased or cancerous tissues (see Lawton et al. and Stutz et αl, incorporated herein by reference); radioimmunotherapy applications (see Colcher et αl. and Blumenthal et αl., incorporated herein by reference); radiation therapy to control or palliate skeletal metastases (Louw et αl., incorporated herein by reference); and applications in radiation synorectomy (see Wang et αl., incorporated herein by reference). As used herein, the term "^,14mln source" refers to all physical forms of the metastable radioisotope of indium- 114, which is the "source" of radiation for the methods disclosed herein.

The tissue is exposed to the source by insertion into the body of the patient. The source may be inserted physically at the site of the tissue by insertion; for example, via a catheter or other means, placed into the particular tissue from a point external to the body of the patient with the aid of a pusher rod or wire or in an angioplasty balloon.

The amount, size and shape of the ^114mIn source and the source employed will depend on the particular application and desired dose. For example, one may vary the amount or concentration of indium in the source as well as vary the coating or encapsulate layer.

Standard detection and dosimetry may be employed to monitor the extent of irradiation of the tissue for short- and long-term exposure applications.

For these applications, the ^114mIn source may be either a solid or liquid. Any shape solid may be employed. However, it is envisioned that tubular structures or bodies may be preferable for many applications, particularly those that insert the source through a catheter or similar structure into the tissue that is to be exposed. Thus, the indium source may be in the form of a solid wire or pellet. Although the size of the source will vary depending on the application, typically, the source will have a diameter of from about 0.05 to about 4.0 mm and a length of from about 1 mm to about 15 mm. For angioplasty applications, the source may preferably be a pellet —wire segment— having a diameter of from 0.15 to 0.3 mm and about 2 cm in length, which is the length of the angioplasty balloons. Spherical structures may also be desirable to help attain a uniform dose of radioactivity to the tissue. The source may also be encased, partially or substantially, in an external capsule to form a radioactive seed. "Radioactive seeds" denotes compositions that comprise an ^U4mIn pellet substantially or partially encased in an external capsule made of a suitable material and intended for medical purposes to be placed onto a body surface or into a body cavity or tissue as a source of nuclear radiation for therapy. The capsule may be any shape and sized depending upon the application and is usually roughly the same shape and of slightly larger size than the indium pellet, wire or other solid or liquid it is encasing. For example, where a wire or tubular pellet is employed, the capsule may have a cylindrical or tubular shape and one sealed end. The source is then inserted into the capsule and the capsule may be employed either with one end open or after substantially sealing the other end. The level of sealing required depends on the application. For example, long-term implantation requires more stringent sealing than may be required for short-term irradiation of tissue and removal.

As used in these embodiments, the definition of "substantially" encased means that is enclosed on all sides sufficient for the particular application while a partially encased pellet would typically not be enclosed on at least one side.

Capsules may also be employed with liquid sources. In these instances the capsule will be loaded with desired amount of radioactivity and sealed at both ends or injected into a sealed capsule.

Often the capsule will be sealed at both ends and then manipulated physically with a pusher rod or wire, which allows the worker to position the radioactive pellet or seed into the tissue to be irradiated. For example, the pellet may be pushed into the catheter and into the tissue using the pusher rod or wire. Typically there will be some means for attaching the pusher rod or wire to the pellet or seed so that the pellet or seed may be removed from tissue after short-term irradiation or if improperly placed for longer-term implantation.

The external capsule should be made of a material that does not substantially inhibit irradiation from the source. Although depending upon the application and dose involved, some shielding by the external capsule may be desirable. The material should also be resistant to corrosion by body fluids as required by the nature of the application, short-term exposure and removal of source versus implantation. The external capsule may comprise titanium, stainless steel, platinum, gold, nickel alloys, nylon, silicon, rubber, polyester resin, chlorinated hydrocarbon resins, aluminum, aluminum alloys or organic plastic materials. As used herein "organic plastic materials" include organic polymers such as nylon, silicon, rubber, polyester resin, and fluorinated hydrocarbons. For many applications, it may also be desired to use a protective over or inner coating on these materials to decrease any reactions between the capsule and either bodily fluids or the source. One may also employ an outer coating on the source.

Typically, the external capsule has a wall thickness of from about 0.05 mm to about 1.0 mm, a length of from about 1.5 mm to about 15 mm and a diameter of from about 0.3 mm to about 4.0 mm.

The source may comprise ^114mIn as well as mixtures and alloys of ^114mIn. Mixtures and alloys may prove useful to vary radiative dosing or to vary the melting point of the source. For example, for some applications where one wishes to employ a solid source, it may be desirable to fabricate the indium into the proper shape and size before it is converted in a nuclear reactor to ^n4mIn. In these cases, given indium's low melting point, it may be necessary under certain conditions to either cool the indium source or form an alloy or mixture that has a higher melting point so that the heat in the nuclear reactor does not affect the shape and size of the indium by melting it to any substantial degree.

The present invention encompasses the use of indium alloys. Preferable alloys include alloys of aluminum, copper, gold, and platinum. The composition of the alloy depends on the melting temperature desired and the phase diagrams of the various alloys employed. For example, concentrations of indium in indium aluminum alloys may typically be less than about 18 % indium by weight with a range from about 1 % to about 15 % percent indium by weight being preferred and 17.3% being particularly preferred. It is understood that such percentages are not limiting and that concentrations may be inclusive of 18, 17, 16, 15, 14 and so forth down to below 1% so that the term "about" is understood to indicate any whole or fractional percentage within the indicated ranges as well as up to 2-3% above the high end indicated. Indium complexes in liquid form may also be useful where one desires a uniform dosing of radioactivity but there is concern about potential leakage of liquid indium. For example, one may desire to employ an angioplasty balloon. The use of a liquid, as opposed to solid source, may allow for more uniform distribution in the balloon and thus a more uniform dose of radioactivity to the tissue involved. Although one could employ liquid indium radioisotope, if there is leakage into the body of the patient, the indium may go directly to untargeted tissues, for example, the bone marrow or other major organs. It may be desirable to employ a complex that facilitates the excretion or other removal of any leaked source.

Exemplary molecules that may be complexed with ^114mIn include: ethylenediamine tetraacetic acid ("EDTA"), diethylenetriamine-N,N,N^,,N",N"-pentaacetic acid ("DTP A"), 1,4,7, 10-tetraazacyclododecane-l,4,7,10-tetraacetic acid ("DOTA"), and others.

Another embodiment encompasses a radioactive seed for use in radiation therapy including a pellet containing a ^114mIn source; and an external capsule. The seed may employed for long- or short-term exposure.

The source may also be a complex of ^114mIn and a carrier biomolecule. It is envisioned that such complexes may be particularly preferable for radioimmunotherapy applications. In those instances the carrier biomolecule is selected based on the tissue or region or cells of the body's patient that is targeted. The radioactive complex may then be injected into the patient. The biomolecule then directs the indium source to a particular site in the patient's body and the radioactive source, and thus the exposed tissue, may be imaged or detected by methods well known in the art, such as conventional gamma cameras.

As with the methods described above, the source may be pure ^114mIn; mixtures, alloys or complexes of ^114mIn; or "^4mIn labelled immunoproteins and biomolecules depending on the particular application. 3.0 BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1. Irradiation scheme for production of ^U4mIn in a nuclear reactor.

FIG. 2. Production of ^114rnIn in the hydraulic tube irrradiation facility of High Flux

4.0 DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

4.1 Nuclear Properties of ^U4lTn

The present invention discloses the use of ^114mIn as a suitable source for brachytherapy. A comparison between the nuclear properties of ^114mIn with other radioisotopes as given in Table 1 illustrates some advantages of the present invention. ^114mIn may also be produced with a high specific activity (10-100 mCi/mg) in a moderate size nuclear reactor within a short period of time. Alternative production routes via charge particles (proton, deutron, He-3, He-4, and others) induced reactions (accelerators) and photon induced reactions (electron accelerator) are also feasible; thus, energy deposition, activation level, manufacturing, and shelf-life indicate that ^U4mIn source is superior to other brachytherapy sources.

Table 1. High Energy β-Particles Emitters Used in Brachytherapy

E_β ^av E Or) Dose

Radionuclide tl 2 (keV) (keV)(%) (rad»g/μCi»h)

^114mIn/^1,4gIn 49.5 d/72 s 773 190 (16) 2.10 ¹⁸⁶Re 90.64 h 350 many low 0.776 ¹⁸⁸W/^,88Re 69.4 d/16 h 78 155 (15) 1.99

^114mIn has not been previously identified as a potential source for brachytherapy, likely because of its concealed nuclear properties. ^U4mIn decays with a half-life of 49.5 days with 95%> isomeric transition to ^u4gIn (ground state) which has a half-life of only 72 sec, which in turn decays with 100% β-emission with an end-point energy of 2 MeV to stable ¹¹⁴Sn. In other words, the high energy β-particle is actually emitted from the very short-lived daughter of ^114mIn which is in secular equilibrium with its parent at all times. The isomeric transition of ^U4raIn to ^π4gIn takes place with emission of a 190-keV gamma-ray intensity of only 16%; thus, greater than 80% of this photon has been converted in the K-shell of the In atom, resulting in emission of very short-range secondary electrons and X-rays (on the order of 20 keV energy). 4.3% of the decay of ^114mIn take place by the electron capture to stable ^U4Cd. Although the secondary electrons do not contribute to the total dose in sealed sources used in brachytherapy, they will contribute to the total dose in other potential applications of this radioisotope.

4.2 Physical Forms of ^U4mIn

^114mIn may be employed as a relatively pure liquid or solid or it may be employed as part of a liquid or solid mixture or alloy. Where one desires to work with a solid indium source, alloys may be employed to increase the melting temperature. Exemplary alloys include alloys of aluminum, copper, gold, or platinum. The use of alloys allows one to fabricate the desired shape of the source before irradiation by increasing the melting temperature of the indium above the temperature source in the nuclear reactor. For example, In/Al alloy wire may be manufactured relatively simply employing stable enriched ⁿ³In isotope, the wire may be activated to contain the desired level of radioactivity in a moderate size nuclear reactor within a rather short irradiation time. The indium may also be complexed to a ligand such as a multi-dentate ligand, including EDTA, DTP A, DOT A, and others. The form of the indium may be determined based on the particular application employed.

4.3 Applications

The present invention may be useful in most, if not all, applications of HDR and LDR brachytherapy, including the prevention of restenosis after angioplasty and the treatment of cancerous and other diseased tissues (see, e.g., Stutz et al, 1998).

4.3.1 In the Prevention of Restenosis after Angioplasty

The present invention is expected to be particularly useful in preventing restenosis after trauma, such as trauma caused by surgery or the inflation of an angioplasty balloon. For example, it has been found that modest doses (between 6 and 20 Gy) of radiation administered shortly after surgery have resulted in modifying wound healing and scar formation and preventing heterotopic bone formation after arthroplasty (Blount et al. 1990); recurrence after excision of a keloid in a previous surgical scar (Borok et al. 1988; Kovalic and Perez 1989); pterygia of the eye, and intimal cell proliferation after angioplasty (Waksman 1998). It has also been shown that modest doses of radiation are effective in preventing certain types of abnormal cellular proliferation resulting from surgical trauma or trauma caused by balloon inflation.

Intravascular radiation therapy prevents restenosis after vascular intervention by reducing smooth muscle cell proliferation and matrix formation and by minimizing late constriction of the vessel wall. Several animal studies and Phase I clinical feasibility trials have demonstrated the effects of ionizing radiation on cell proliferation and vascular remodeling (Waksman 1998). Popowski et al. (1995) describe dosimetry studies employing yttrium-90 wires in an angioplasty balloon. Condado et al. (1997) describe human trials employing an Ir-192 source wire in conjunction with angioplasty. These results indicate that intracoronary radiation therapy is feasible for the prevention of restenosis and free of any acute complications. Amols et al. (1996) describe analytical calculations of dose distributions for the use of Ir-192, 1-125, Pd-103, P-32 and Sr-90 sources in intracoronary irradiation and many drawbacks associated with these sources. Wilensky et al. (1995) present studies of the regional and arterial localization of radioactive microparticles after local delivery by unsupported or supported porous balloon catheters with a cerium- 141 source. These studies indicate many factors that should be considered in selecting a source for intravascular radiation therapy.

A radioactive source for prophylactic radiation following percutaneous transluminal coronary angioplasty ideally should (i) selectively irradiate the artery wall without undue irradiation of the surrounding tissues; (ii) provide a sufficient dose in a short application time, despite the presence of contrast media; (iii) be accurately dosed; be adaptable to the radiation protection conditions of a cardiac catheterization laboratory with minimal irradiation of the medical staff and low risk of radioactive contamination; and (iv) have a sufficiently long half-life to allow source transformation and availability for multiple applications, or preferably storage on site. Waksman (1998) describes many problems associated with the choice of an appropriate radioisotope for brachytherapy applications.

Endo vascular radiation therapy currently has two forms: catheter-based systems and radioactive stenting. Studies and considerations to be considered in the design of these systems are discussed in Waksman (1996), Amols et al. (1996), Condado et al. (1997), and Waksman (1998).

For angioplasty applications, selective irradiation of coronary arteries should be compatible with conditions imposed by a cardiac catheterization laboratory. A feasible irradiation technique should be able to deliver a dose of the order of 10 Gy to the intima of the coronary artery in a conveniently short time, without significant irradiation of adjacent organs and without exposing the personnel in the catheterization laboratory to unnecessary irradiation. Endoluminal brachytherapy with ^114mIn solves this problem by providing a source — wire, pellet, liquid (complex in solution) which the ballooon can be filled with ~ that has a small enough diameter to be inserted into a coronary vessel in conjunction with a standard angioplasty balloon. Because the normal coronary artery wall thickness varies between 0.3 and 0.8 mm, the indium β-emitting sources disclosed in this application are particularly useful. These sources are also optimal for radioprotection as they do not penetrate to as great - 13 -

a depth as other radioactive sources, such as gamma-emitters. Dosing may be determined for this as well as other applications by studies similar to those described in Popowski et al. (1995) or by extrapolation from dosimetry studies with known β-emitters.

When strongly complexed with multidentates ligands, ^114mIn may be useful for the liquid-filled angioplasty balloon approach for prevention of restenosis or closure of arteries following high pressure angioplasty. ^I14mIn may also be used as therapeutic radionuclide when it is attached via bifunctional chelators to a carrier molecules such as antibodies, peptides, etc.

4.3.2 In the Treatment of Cancer

The disclosed compositions and methods may be useful in other brachytherapeutic applications, such as the treatment of cancer. Although it is contemplated that the indium- 114m compositions and methods may be useful in LDR brachytherapy, it is envisioned that these compositions and methods will be preferred for HDR applications. HDR applications encompassed by the present invention included any and all HDR brachtherapy applications, including the treatment of cancers, such as prostate, brain, and gynecological cancers to name a few. Further, it is contemplated that the methods and compositions disclosed herein may be particulalry useful for HDR applications involving treatment of cancers in infants and young children. For example, it has been shown that fractionated HDR brachytherapy may be used to deliver adequate rumoricidal radiation while preserving bone and organ growth in children having rhabdomyosarcoma and soft tissue sarcoma and avoiding the need for continuous sedation and observation in LDR brachytherapy (Nag et al, 1995).

5.0 EXAMPLES

The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

5.1 EXAMPLE 1 -MANUFACTURE OF IN/AL WIRE

Two batches of In/Al alloy were prepared for initial irradiation testing and testing of ^{11 m}In uniformity using indium of natural isotopic abundance (Al is monoisotopic in nature). Batch A contained 2 weight percent indium and Batch B contained 15 weight percent indium with the remainder consisting of aluminum. Several other batches were prepared with intermediate indium contents for metalworking tests. The In/Al system is a eutectic system at the Al-rich end of the equilibrium phase diagram, with the eutectic at 17.3 weight percent (4.7 atom per cent) indium. Alloys were prepared by arcmelting indium and aluminum. The alloys in the 0-17.3 weight percent indium range consist of a eutectic at the high end and an increasing aluminum phase with the eutectic distributed in the matrix as the indium content is decreased. The test alloys were remelted several times to ensure mixing of the 2 components. Crucible melting of the alloy may also employed as long as the 2 components are thoroughly melted and permitted to homogenize.

The resulting metal buttons were then wire rolled to form rods (having a diameter of approximately 3.0 mm). The rods were further metal-worked by swaging to final size or were swaged and the wire drawn to final size. Depending on the composition, lamination of the wire as it approached final size was often encountered. At low indium concentrations, wires having a final diameter of ~0.3 mm were successfully produced by coldworking and no annealing. At higher indium concentrations, wire breakage and lamination were often encountered. Annealing the wires at temperatures of 550-600°C for about 30 minutes under a hydrogen atmosphere improved the workability of the wire. Annealing was performed when difficulty was encountered at the start of the next step of diameter reduction. Wires less than 0.3 mm diameter were successfully produced by coldworking and annealing. Further composition-dependent melting and metal working sequences are being investigated at different compositions to optimize cold working/annealing sequences for various compositions.

5.2 EXAMPLE 2--IRRADIATION SCHEME AND YIELD DETERMINATION

The irradiation scheme for production of ^114mIn in a nuclear reactor is shown in

FIG. 1. As seen, the thermal neutron cross-section and epithermal resonance integrals for ¹¹³In[n,γ] ^n4mIn reaction are 12.0 b and 220 b (b≡barns, lxlO^"24 cm), respectively.

Small pieces (1-3 mg) of In/Al wire (0.3 mm OD), randomly cut from ends and center sections, were encapsulated into standard quartz ampoules. The ampoules, sealed in aluminum rabbit canisters, were irradiated at position 1 of the hydraulic tube irradiation facility of Oak Ridge National Laboratory HFIR. Thermal neutron flux at this position is 9.0 x 10¹⁴ n.s^_1.cm^"2, with thermal to epithermal ratio of -40. In parallel, a target containing 2 mg of highly enriched ¹¹³In (as In₂O₃) was also irradiated for yield determination and comparison. The results are summarized in Table 2, and shown in FIG. 2. The theoretical calculations using published cross-sections for this reaction is also shown (solid line). As the burn-up cross-section of ^U4mIn is not known, a value of 2 b was used in the calculation. As seen, the theoretical model is within a factor of 2 of the experimental results. Based on these data, the expected yield of ^114mIn for one week of irradiation at a neutron flux of 1 x 10¹⁵ n»s^" 'cm^"2 would be in order of -100 mCi/mg of ¹¹³In. A typical seed wire, 2 cm in length, 0.03 cm in diameter, containing -0.12 mg of ^U3In (2% In), would contain -10 mCi of ^{U m}In. As pointed out earlier, wires of up to 15% In have been made without appreciable separation of In from Al. Post irradiation examination of the integrity of the wire has shown no visible deformation of the wire. FIG. 3 shows a photograph of wire R6-176 [In(2%)/Al] under a 200 fold magnification. Table 2. Summary of HFIR Production of ^{n n,}In

Target *

Target Yield at EO >B (mCLmg ¹)

Mass Enrich. Chem. HT

(mg) (at.%) Form Level T ^■* ιrr Exp. Exp./Theo

R6-154 1.6 96.26 In₂O₃ (1) 24 h 1.05 x 10' 0.43

R6-176 a) 1.34 0.043 In(2%)/Al (1) 68 h 7.96 x 10' 1.2 b) 1.77 0.043 In(2%)/Al (1) 68 h 9.91 x 10¹ 1.4

R6-177 a) 1.19 0.043 In(15%)/Al (1) 24 h 2.09 x 10' 0.85 b) 2.55 0.043 In(15%)/Al (1) 24 h 3.72 x 10' 1.52 c) 2.01 0.043 In(15%)/Al (1) 24 h 2.10 x 10' 0.86

"Reactor power level = 85 MWt

All of the brachytherapy compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the brachytherapy compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. 6.0 REFERENCES

The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

U.S. Patent No. 4,994013

U.S. Patent No. 5,163,896 U.S. Patent No. 5,322,499

Amols et al. "Dosimetric Considerations For Catheter-Based Beta And Gamma Emitters In The Therapy Of Neointimal Hyperplasia In Human Coronary Arteries," Int. J. Radiation Oncology Biol. Phys., 36(4):913-921: 1996.

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Claims

WHAT IS CLAIMED IS:

1. A radioactive seed, comprising an alloy of "^4mIn and an element selected from the group consisting of aluminum, gold, platinum, and copper wherein said alloy is encased in an external capsule comprising at least one material selected from the group consisting of titanium, stainless steel, platinum, gold, nickel alloy, nylon, silicon, rubber, polyester resin, chlorinated hydrocarbon resin, aluminum and aluminum alloy.

2. The radioactive seed of claim 1 wherein the alloy comprises "^4mIn and aluminum.

3. The radioactive seed of any of claims 1-2 wherein the alloy comprises about 2% to about 17% indium.

4. The radioactive seed of any of claims 1-3 wherein the alloy comprises about 17% indium.

5. The radioactive seed of any of claims 1 -4 comprised within a source.

6. The radioactive seed of any of claims 1-5 further comprising an external capsule.

7. Use of a radiation source comprising an alloy of "^4mIn or an "^4mIn complex , to provide radiation to a selected tissue of a subject comprising exposing the tissue to said source wherein said alloy comprises an element selected from the group consisting of aluminum, gold, platinum and copper.

8. The use of claim 7, wherein the source is encased in an external capsule comprised of at least one material selected from the group consisting of titanium, stainless steel, platinum, gold, nickel alloy, nylon, silicon, rugger, polyester resin, chlorinated hydrocarbon resin, aluminum and aluminum alloy. WO 00/59550 PCT/TJSOO/ 07855

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9. The use of any of claims 7-8 wherein the alloy is an indium aluminum alloy having 2%-l 8% indium.

10. The use of any of claims 7-9 wherein the alloy is 17% indium.

11. The use of claim 7 wherein the complex is ' ^14mIn EDTA, ' ^14mInDTPA or ' ^14mInDOTA.

12. The use of claim 7, further comprising detecting the tissue exposed to the radiation source.

13. The use of claim 7 wherein the tissue is exposed to the source by injection or topical application of a liquid comprising said source.

14. The use of claim 7 wherein the subject is a human.

15. The use of claim 7 wherein the tissue is selected from the group consisting of prostate, uterine, brain, cervix, soft tissue sarcoma and rhabdomyosarcoma tissue.

16. Use of brachytherapy in the treatment of a condition in a human, comprising:

a) obtaining an indium aluminum alloy comprising "^4mIn encased in an external capsule; and

b) exposing a selected cancerous tissue of the human to the encased alloy.

17. Use of claim 16 wherein the cancerous tissue is identified as prostate, uterine, brain, _^ cervix, soft tissue sarcoma or rhabdomyosarcoma.

18. Use of the radioactive seed of any of claims 1-6 for high dose rate (HDR) brachytherapy in the treatment of a condition in a human, comprising: a) obtaining an indium aluminum alloy comprising "^4mIn encased in external capsule made from at least one material selected from the group consisting of titanium, stainless steel, platinum, gold, nickel alloy, nylon, silicon, rubber, polyester resin, chlorinated hydrocarbon resin, aluminum or aluminum alloy, and;

b) exposing a selected tissue of the human to the encased alloy, wherein the tissue comprises a vascular or a tissue affected by cancer.