MXPA01012781A - Iodine-containing radioactive sources. - Google Patents

Abstract

A radioactive source for use in brachytherapy comprising a radioactive isotope of iodine in the form of iodide ions or an iodine-containing compound adsorbed on the surface of a substantially non-radiation attenuating substrate. Preferably the source is a seed and the radioisotope is iodine-125. Preferred substrates include carbon, particularly activated carbon. The sources may be useful for the treatment of restenosis.

Description

RADIOACTIVE SOURCES CONTAINING IODINE This invention relates to radiotherapy. More particularly, it refers to radioactive sources for use in brachytherapy and methods for the preparation of such sources. Brachytherapy is a general term that covers medical treatment which includes the placement of a radioactive source close to the infected tissue and may include the implantation or temporary or permanent insertion of a radioactive source into a patient's body. The radioactive source is located in such a way in the proximity to the area of the body being treated. This has the advantage that the required dose of radiation can be delivered to the treatment site with relatively low doses of radiation in healthy intermediate or adjoining tissue. Brachytherapy has been proposed to be used in the treatment of a variety of conditions, including arthritis and cancer, for example breast, brain, liver and ovarian cancer and especially prostate cancer in men (see for example JC Blasco et al. ., The Urological Clinics of North America, 23, 663-650 (1996), and H. Radge et al., Cancer, 80, 442-453 (1997)). Prostate cancer is the most common form of malignancy in men in the US, with more than 44,000 deaths in 1995 alone. Treatment may include the temporary implantation of a radioactive source for a calculated period, followed by its elimination. Alternatively, the radioactive source can be permanently implanted in the patient and allowed to disintegrate in a state inert for a predictable time. The use of permanent or temporary implantation depends on the selected isotope and the duration and intensity of the treatment required. Permanent implants for the treatment of prostate include radioisotopes with relatively short half-lives and lower energies in relation to temporary sources. Examples of permanently implantable sources include iodine-125 or palladium-103 as the radioisotope. The radioisotope is generally encapsulated in a titanium shell to form a "seed" which is thus implanted. Temporary implants for the treatment of prostate cancer may include iridium-192 as the radioisotope. Currently, brachytherapy has also been proposed for the treatment of restenosis (for reviews see R. Waksman, Vascular Radiotherapy Monitor, 1998, 1, 10-18, and MedPro Month, January 1998, pages 26-32). Restenosis is a re-narrowing of the blood vessels after the initial treatment of coronary heart disease. Coronary heart disease is a condition resulting from the narrowing or blockage of the coronary arteries, known as stenosis, which may be due to several factors that include the formation of atherosclerotic plaques within the arteries. Such blockages or narrowing can be treated by mechanical removal of the plaque or by the insertion of stent to keep the artery open. One of the most common forms of treatment is percutaneous transluminal coronary angioplasty (PTCA) - also known as balloon angioplasty. Currently, more than half of one million PTCA procedures are performed annually in the US alone. In PTCA, a catheter that has an inflatable balloon at its distal end is inserted into the coronary and placed at the site of the blockage or narrowing. The balloon is thus inflated, which leads to flattening of the plaque against the artery wall and lengthening of the artery wall, resulting in an enlargement of the intraluminal passage path and henceforth elevated blood flow. The PTCA has a high initial success scale but 30-50% of the patients present themselves with stenotic recurrence of the disease, ie, restenosis, within 6 months. A treatment for restenosis which what has been proposed is the use of intraluminal radiation therapy. Various isotopes that include iridium-192, strontium-90, yttrium-90, phosphorus-32, rhenium-186 and rhenium-188 have been proposed for use in treatment festenosis. Conventional radioactive sources for use in brachytherapy include so-called seeds, which are sealed containers, for example made of titanium or stainless steel, that contain a radioisotope inside a sealed chamber but which allows radiation to exit through the walls of the body. container / camera (US-A-4323055 and US-A-3351049). Such seeds are only suitable for use with radioisotopes that emit radiation which can penetrate the chamber / container walls. Therefore, such seeds are generally used with radioisotopes that emit radiation? or low energy X-rays, as opposed to radioisotopes that emit ß. Brachytherapy seeds comprising a coating of radioactive silver iodide on a silver wire encapsulated within a titanium container are known in the art (US-A-4323055). Such seeds provide radiation emission which is equivalent to between 0.1 and 100 millicuries of radioactivity. Such seeds are commercially available from Medi-Physics, Inc., under Trade Name 1-125 Seed® Model No. 671 1. Other conventional brachytherapy seeds comprise titanium containers that encapsulate ion exchange resin beads in which a radioactive ion, for example 1-125, has been absorbed (US-A-3351049). The immobilization of a radioactive powder within a polymeric binder has also been proposed (WO 97/19706). GB-A-1187368, US-A 4729903, WO99 / 41755 and WO99 / 40970 describe the absorption of molecular iodine-125 in various substrates including graphite and zeolites. However, these are safety implications with working with iodine-125 in the form of molecular iodine due to its volatility. The use of volatile radioisotopes can give rise to radiation hazards during the production of radioactive sources or if a radioactive seed breaks during handling. US-A-4323055 discloses activities for iodine-125 which contains seeds of up to 100 mCi / seed, and iodine-125 containing seeds based on metallic wires have not demonstrated the ability to carry very high levels of radioactivity. With the radioactive seeds based on the metal wires there is also the disadvantage that some of the radioactivity is absorbed by the wire by itself. The amount of radioactivity absorbed by the wire increases as the atomic number of the metal used to form the wire increases.

AB-5a-tj? Í .. -t-tJAi-ta. ^ E- »t-" e * '! Fe ^ "* - The precise amount of attenuation will be a function of the dimensions of the wire. For example, with a iodide-125 silver coated 0.5 mm diameter silver wire, up to about 20% of the radioactivity is absorbed by the wire by itself. To make a radioactive seed from a given external radiation dose, the extra radioactivity must be loaded on the wire to take into account the absorption of some of the activity by the wire and also by the seed container. As the desired activity of the seed increases, so does the cost of the amount of extra percentage of radioactivity which must be loaded into the wire. Attempts to make high activity radioactive seeds comprising radioactive anions absorbed in ion exchange resin beads as in US-A-3351049 have not been completely successful, we believe that due to the opposite effect of radiation on the polymer bonds of the pearls by themselves. We have found that there is a tendency for pearls to degrade under the influence of high levels of radioactivity, leading to unreliable results. There is still a need for a high activity radioactive source which is suitable for use in brachytherapy and which does not increase the safety problems inherent in the use of radioactive molecular iodine, and for methods for making such sources. Such sources may be useful for temporary brachytherapy of cancers and proliferative diseases, and especially for the prevention of restenosis following PTCA. üfcalii. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ a radioactive source suitable for use in brachytherapy, preferably a sealed source, comprising a radioactive isotope of iodine in the form of iodide ions or a compound containing iodine absorbed on the surface of a substantially attenuating substrate is provided radiation, with the proviso that when the iodine is in the form of iodide ions, then the substrate is not an ion exchange resin. Preferably, the source has an activity in the range of about 0.1 mCi to about 1200 mCi. Preferably for use in the treatment of restenosis, the source has an activity in the range of about 200 mCi to about 1200 mCi, preferably 300 mCi at 1000 mCi, and more preferably 400 mCi at 600 mCi. Preferred sources for use in prostate brachytherapy have an activity in the range of about 0.1 mCi to about 5 mCi, more preferably about 0.2 to about 2 mCi. Suitable iodine radioisotopes are iodine-125, iodine-31 and iodine-123. The preferred one due to its long half-life is iodine-125. As used herein, where the term iodine-125 is used, this should be interpreted as being applicable also to iodine-131 or iodine-123. The iodine radioisotope can be in the form of iodide ions or in the form of a compound containing iodine. As used herein, the term "iodine-containing compound" includes any covalently bound iodine-containing compound wherein the iodine is bound to at least one other atom that is not a halogen. Thus, molecular iodine (12) or iodohalogens such as Icl are not included. Examples of suitable compounds include an organic compound containing an iodo-carbon bond, a iodoso compound such as iodosobenzene, phenyliodose diacetate, and o-iodosobenzoic acid, a diaryl iodide salt such as difenyl iodide bromide and dipheniodium iodide wherein either or both of the iodine atoms may be a radioisotope of iodine, an N-iodoamide such as N-iodosuccinimide, an iodoaryl compound such as iodoxibenzene, or a covalently bound inorganic iodine compound such as tributyltin iodide. Iodine-containing compounds are not volatile. Preferably, the sources of the invention comprise a sealed container, for example a substantially cylindrical tubular container made of metal or some other suitable material, having a cavity in which a suitable amount of iodine-125 is presented. The container material should be resistant to corrosion, compatible with body fluids and non-toxic and should not unduly absorb the X-ray radiation emitted from the radioisotope. Suitable containers include those made of atomic numbered metals such as titanium or stainless steel. Higher atomic number metals such as gold, copper or silver result in too much radiation attenuation to be useful per se. However, they can be useful for plating on certain low-atomic number metals such as beryllium that could otherwise be too toxic if used without an external coating. Titanium, mixtures of titanium or stainless steel are preferred metals for the container. Others foáfcfeáÉlti * ...... ~ mA ** ~ Ll ** m ?. . »H? R? to?**,. '.? * Hi? ^ *? * ~? Í * * ^ tj ^ Jblti¡k *** i,? * 4 & Suitable container materials include inert synthetic materials, for example Teflon ™. The container is preferably sealed completely inward so that there is no loss damage. The source must be of a global size and of adequate dimensions for its intended use. For example, the overall dimensions of each radioactive source should each preferably be such that it can be delivered to the treatment site using conventional techniques, for example it can be loaded into a conventional catheter for delivery at the site of restenosis. Seeds for use in the treatment of prostate cancer, for example, are typically substantially cylindrical in shape and approximately 4.5 mm long with a diameter of approximately 0.8 mm, such that they can be delivered to the treatment site using a needle hypodermic For use in the treatment of restenosis, a source should be of suitable dimensions to be inserted into a coronary, for example with a length of approximately 10 mm and a diameter of approximately 1 mm, preferably a length of approximately 5 mm and a diameter of about 0.8 mm, and more preferably with a length of about 3 mm and a diameter of about 0.6 mm. Sources for use in the treatment of restenosis are typically delivered at the treatment site using conventional catheter methodology. The substrate can be of any material that is capable of absorbing iodide ions or a compound containing iodine (either by physical absorption or by chemical absorption) and which is sufficiently stable 1 = ¡i-a ¿< j¡t-a &^ 8¡ ,, SA. in radiation to allow the substrate process in a source of brachytherapy once the iodine radioisotope has been absorbed. Preferably, the substrate is in the form of a substantially rigid body, for example, a bacillus, filament or sphere. Preferably, the substrate has a long surface area available for absorption. The substrate can also be in powder form. The substrate must be attenuating substantially without radiation. Preferably, the substrate comprises at least 60% by volume, more preferably at least 80% by volume and more preferably at least 90% by volume of atom atoms of low atomic number. Atoms may be present in elemental form, or in mixtures or compounds. As used herein, a low atomic number is preferably an atomic number £ 30, and more preferably <; 25. Preferred substrates contain a minimal amount (for example, only as a coating) of the high atomic number, radiation attenuating materials such as silver, gold or palladium of metals. In such substrates, the minimum amount is sufficient to allow the production of the radioiodine coating. For example, the substrate may comprise an attenuating material substantially free of radiation coated with a thin layer of a metal such as silver. Iodide ions or iodine-containing compound should be coated on the surface of the substrate only, instead of being uniformly distributed along the body of the substrate. Presenting the radioiodine as a coating on the surface of the substrate also helps to minimize attenuation of the radiation.

One of the main purposes for using substrates comprising high atomic number materials in brachytherapy sources such as seeds traditionally allows the visualization of the location of the seed in vivo post-implantation by X-rays. Preferably, the sources of the invention they comprise a biocompatible container that is sufficiently echogenic so that the source can be visualized in liquid in vivo by ultrasound instead of X-rays. The use of substrates comprising materials of high atomic number is not necessary in order to allow visualization of the seed. As a further aspect of the invention there is thus provided a radioactive source suitable for use in brachytherapy comprising a radioactive isotope of iodine in the form of iodide ions or a compound containing iodine absorbed on the surface of an attenuating substrate substantially without radiation, the radioisotope and the substrate being sealed inside a biocompatible ecogenic container. Iodide ions or iodine-containing compounds can be physically absorbed on the surface of the substrate (physical absorption) or there may be some degree of chemical bond between the substrate and the iodide ions or iodine-containing compound (chemisorption): chemo-absorption is preferred instead of the physical absorption. Suitable substrates include carbon, aluminum, titanium oxides, silica and silicon oxides, trivalent metal silicates, zeoite type, metal phosphates and hydroxyphosphates including hydroxyapatite, calcium hydroxyapatite, crystalline materials, aluminum nitride, ceramics, radiation resistant polymers and natural materials such as bone, coral, coal, limestone, cellulose, starch, agar, gelatin, chitin, and filament either alone or processed together to make substantial bacilli. A preferred substrate is carbon, and in particular activated carbon. Suitable activated carbon is in the form of activated stick carbon from American Norit Co., Inc. under the trade names Darco® and Norit®. Preferably, the substrate comprises atomic low number element atoms in such a way that the absorption of radioactivity by the substrate is minimized. Preferably, the substrate is also of low density to help minimize the absorption of radiation. For these reasons, carbon is particularly preferred. For the absorption of iodide ions, positively charged substrates are preferred. For example, ceramics at a pH below the isoelectric point (ie, their pl) will express a positive surface charge that will attract the negatively charged iodide anions. If the substrate is carbon, it may be in the form of a filament, bacillus, sphere, powder, particles, powder, compressed powder, carbonized polymers including starch, cellulose, chitin, agar or gelatin, carbon yarn available from Alpha Aesar, and carbonized polymers derived from acetylene, stick coal, soot or graphite which includes fibers and graphite bacilli, or a clathrin, fulerene or other box carbon. An organic compound that is absorbed in the chosen substrate can be iodinated with 125 μl and the radioiodonized compound is thus absorbed in the substrate. Organic compounds that are absorbed into a desired substrate can be known in the art or can be identified using routine experimentation. Any known method for the iodonization of organic compounds can potentially be adapted to use a radioactive iodine isotope instead of a "cold" isotope. For example, iodine can be reacted with an organic molecule to form a bond between the iodine atom and a carbon atom in that molecule. For example, radioactive sodium iodide can be reacted with tyrosine to achieve radiolabeled tyrosine. In addition, methods for the covalent attachment of radioisotope of iodine to organic molecules are known in the art, for example in Parker, C.W. "Radiolabelling of Proteins" in Methods of Enzymology, Vol. 182, 721 (1990); Noel, J-P. "The radioactive synthese avec le carbone 14, le tritio, le soufre 35 et l'iodi 125, L'Act. Chim. (R), 1 997), 7, 5-1 3. (Radioactive synthesis with carbon 14, tritium , sulfur 35 and iodine 125. Current, Chim (1997), (7), 5-1 3), Scherberg NH and Refetoff S. "Radioiodine Labeling of Ribopolimers for Special Applications in Biology", Methods in Cell Biology (1975) 10 , pages 343-359 (Chapter 19), and Baldwin, RW "Chemistry of Radioiodine", Appl. Radiat, Isot. Vol. 37, No. 8, pp 817-821, 1986, all of which are incorporated for reference. reagents and methods useful for the radioiodonization of organic molecules can also be found in the Pierce Catalog and Handbook, for example, 1994-1995 edition, page T-335, Technical Section, "Yodonization" (incorporated for reference). Preferred organic compounds for iodination include tyrosine phenylalanine either alone or as a dimer or polymer, tyrosine, phenylalanine containing peptides and proteins, phenols, and aromatic molecules with a reactive site for iodination; hydroxyaromatic compounds capable of enol and keto type tautomerism such as a phenolic compound containing a hydrogen in the ortho- or para- position, for example catechol or poly (3,4-dihydroxystyrene) which can be prepared by latex polymerization or by the limited coalescence of free radical polymerization of 1-vinyl-3,4-methoxystyrene followed by treatment with boron tribromide at low temperatures in methylene chloride; and aryldiazonium compounds which are known to form aryl iodides in a Sandmeyer type reaction in the presence of potassium iodide (see Lucas HJ and Kennedy ER, Org. Syn., Coil., Vol. 2, 351-1943 (incorporated for reference)), for example the diazonium salt of anthraminic acid can provide diiodobenzene according to the method of Friedman L. and Logullo F.M, Angew. Chem., 77, 217, 1965, (incorporated for reference). The substrate is preferably of an appropriate size and dimensions (o) to be fixed within a container to form a sealed source. For example, the substrate may be similar to the bacillus or substantially spherical. However, the substrate can be of any size or shape capable of irradiating the lumen of the occluded blood vessels for the prevention of restenosis, and the size and shape of the container can be chosen depending on the dimensions of the vessel. substrate A source may comprise one or more substrates, or a plurality of substrates combined together, for example by compression and / or use of a suitable binder. A plurality of substrates may be combined, optionally with the use of a binder. A binder is a material that can bind two or more activated substrates or a plurality of substrates together to form a large compound. A binder can be a cohesive agent such as a gum, for example new gum and its Dermabond ™ medical grade counterpart, available from Ethicon, and other polymerized cyanoacrylate esters, an adhesive such as a fusion adhesive either, or a polymer such such as vinyl alcohol, polyvinyl acetate, poly (ethylene-co-vinyl acetate) and polymers partially hydrolyzed poly (ethylene-co-vinyl acetate), polyvinylpyrrolidone or polyvinyl chloride. Also useful as binders are carbohydrates such as sucrose, mannitol, lactose, and the like, dextran, and cyclodextran; amino acids and proteins such as albumin, and salts such as alkali earth metal and alkali metal salts of halides, sulfates, phosphates, and nitrates. Binders comprising low molecular weight elements are preferred in order to minimize the attenuation of radioactivity by the binder. Preferably, the substrate body is in the form of a bacillus. A single container may contain only one substrate that occupies substantially all of the interior of the container cavity. Alternatively, each container may contain two or more substrates, for example optionally separated by a spacer suitable. Preferably, the adjustment of the substrate will be such that there is a uniform radiation field around the surface. The level of radioactivity of a prepared substrate using the method of the invention will depend in part on the amount of radioactive iodine used in the method. The amount of iodine-125 required to provide a given source of activity will depend in part on the amount of radiation absorbed by the substrate and the container. The amount by an expert person, for example by trial and error or by calculation. The sources of the invention can be prepared by exposing a suitable substrate to a source of iodide ions or a compound containing iodine., for example an organic compound containing all 125l. POF safety reasons it is not preferable to use compounds containing volatile radioiodine, or isotopic precursors for them. As a feature of the invention, therefore, there is provided a method for preparing a substrate suitable for use in a brachytherapy source, the method comprising exposing an attenuating substrate substantially free of radiation to a source of iodide-125 ions or a compound containing iodine-125 in such a way that the iodide ions or the iodine-containing compound 125 is absorbed on the surface of the substrate, provided that when the iodine is in the form of iodide ions, then the substrate is not an ion exchange resin. Preferably, the compound containing iodine-125 is an organic compound containing 125 l. Iodide ions can be presented as a solution of a iodide salt soluble in a suitable solvent, for example a solution of potassium or sodium iodide-125 in water. Preferably, an aqueous solution of iodide-125 ions is used. Fixed substrates, such as Eichrom's ABEC® resins (Aqueous Biphasic Extraction Chromatography), can be used to selectively absorb iodine (in the form of iodide) from concentrated solutions of certain salts. Once loaded with iodine and dried, the substrates can be encapsulated in a container to form a source of brachytherapy. The compound containing iodine-125 can be presented in solution in a suitable solvent. Alternatively, if the compound is a liquid it can be used without mixing. The substrate may alternatively be exposed to the vapor of an organic compound containing * 2St, but this method is not preferred for safety reasons when working with radioactive compounds. The substrate should be exposed to the iodide ions or the iodine-containing compound for a sufficient period of time for the desired level of radioactivity to be absorbed in each substrate. Suitable exposure times can be determined by routine experimentation, for example by monitoring the level of the remaining radioactive iodide not absorbed in the reaction medium. If the iodine is in the form of an organic compound containing iodine, the absorption can take place in the same reaction vessel as the iodination reaction. For example, the substrate can be added to the reaction mixture after the reaction of -t.S ^^ i. , Iodonization has occurred in such a way that the iodonized product is absorbed into the substrate without the need for any isolation of the iodonized product. Substrates in which iodine-125 has been absorbed can thus be isolated from the reaction mixture, for example by filtration, dried if necessary and loaded in suitable containers to form radioactive sources for use in brachytherapy. After absorption, the substrate can be further processed if required. For example, a plurality of substrates can be formed in a compound by the application of pressure and / or by the use of a binder. In one aspect of the invention, low melt binders can be fused and mixed with an activated carbon substrate containing molecules containing absorbed iodine, and then molded, emptied or formed into a desired shape such as a thin bacillus, pellet, strip , wire, ring or tube, and then cool down. The temperature should be below any temperature at which any substantial amount of compound containing iodine-125 must be re-absorbed from the activated carbon. In another aspect of the invention, the binder can be mixed with an activated carbon substrate containing molecules containing absorbed iodine, and then molded, emptied or formed into a desired shape under pressure. If the substrate comprises a coating of silver ions or ions of some other metal forming an insoluble iodide salt, the substrate can be exposed to a solution of iodine-125, for example a solution of Na125l, such that a coating of Insoluble iodide salt will form on the surface of the attenuating substrate k? JiJLi? t - * ... .stA. -aJfc, - < *, eX. ^ ilB? M? j &lUk ± lm ** liaittμlrM & *? .._? ^ substantially without radiation. Such a method comprises a further feature of the invention. Substrates comprising a coating of silver ions include substrates such as polyvinyl alcohol, agar, gelatin, silica, carbonaceous materials or carbon yarn that have previously been exposed to a source of plant ions, for example in a solution of a salt of silver. Preferably, a sufficient amount of radioactive iodine is used in the method of the invention to produce substrates with activity levels in the range of about 0.1 mCi to about 1 Curium. Such substrates can, for example, to be incorporated into radioactive sources for use in brachytherapy that have an activity of approximately 0.1 mCi to approximately 900 mCi. In order that substantially all the radioactive iodine is absorbed on the surface of the substrate, the substrate and the reaction medium are preferably stirred. Preferably, the agitation has the form of rotation of the reaction vessel in such a way that the substrates are "stirred" or wrapped in the reaction medium with each rotation. For example, if the reaction vessel comprises a single sealed bottle, the bottle can be turned vertically end to end such that the contents are turned from end to end of the bottle with each rotation. The rotation at a speed of 20 to 60 rpm is adequate. Alternatively, the reaction vessel can be rotated at an angle in the horizontal such that the substrate is wrapped over the reaction mixture in each rotation. An angle of approximately i.ú.ÁA¡. Mu 30 ° is adequate. Proper agitation of the reaction mixture also helps to ensure that the maximum iodine output occurs, and that the output is uniform over the entire surface of the substrate. The radioactive sources of the invention can be used as temporary implants for the treatment of cancers, for example head and neck cancers, melanoma, brain cancers, non-small cell lung cancer, breast and ovarian cancer, uterine and cervical cancer and other diseases including proliferative diseases, arthritis, urethral structure and fibroid uterine tumors. Due to its high levels of radioactivity, it is different that the sources will be useful for permanent implantation brachytherapy. The sources may also be useful in the prevention of restenosis following PTCA fa. As a further aspect of the invention there is provided a method for the treatment of a condition which is a response to radiation therapy, for example cancer and especially restenosis, which comprises the temporary placement of a radioactive source comprising an amount of iodine. 125 absorbed in the form of iodide ions or a compound containing iodine on the surface of an attenuating substrate substantially without radiation, provided that the substrate is not an ion exchange resin, at the site to be treated within a patient for a sufficient period of time in relation to deliver a therapeutically effective dose. Preferably, the method of treatment of the invention is used to inhibit restenosis at a site within the vascular system of a patient who has previously undergone a PTCA. The invention will be further illustrated by the following non-limiting Examples. Example 1 Precipitation of Silver Iodide in Polyvinyl Alcohol Particles (Ivalon) In a small beaker, 1 g of PVA particles (150-250 microns) was balanced with a 0.5 molar solution of silver nitrate for 1 hour. At the end of the hour, the particles were allowed to settle on the bottom of the beaker and the supernatant was decanted to be replaced with 50 ml of distilled water. The particles were rinsed 3 times in this manner to prepare them for the final stage. After decanting as much water as possible after the 3rd wash, the particles were equilibrated with a solution of potassium iodide for 1 hour. Afterwards, the particles were rinsed again with water and thus suspended in a small volume of saline for further testing. A 1 ml sample tube of HPLC was used to transport the sample to the Center for Pharmaceutical Research and Representation (CIPR) at the Massachusetts General Hospital to be represented on a Toshiba CT scanner at 80 kV. This initial sample of PVA with Agi precipitated in it was measured as 441 Hounsfield Units (HU) in saline. The conventional instruction is that every 35 HU = 1 mg of silver iodide or approximately 0.5 mg of iodide, and in this way It can be estimated that 6.6 mg of iodide / ml of closed packed particles is present in this sample or approximately 50 μg of iodide per particle. In a specific activity of 12 Curios / mg, each particle could have approximately 600 mCurios of radiation on board. Example 2 Multiple Preparations in Polyvinyl Alcohol Particles (Ivalon) A suspension of polyvinyl alcohol particles (PVA) was prepared as in Example 1 above. At the end of the water rinse after the addition of potassium iodide, the particles were again exposed to a silver nitrate solution for another hour. The suspension was then rinsed with water before a second aliquot of potassium iodide was added to precipitate a second layer of silver iodide. This was then repeated for a part of the sample by a third precipitation of silver iodide in the PVA particles. The particles were represented in the General Hospital of Massachusetts with the following results: * assuming 12 Curios / mg of specific activity of 125l. In this way, it is clear that the multiple layers of iodide Silver can be deposited in the PVA particles to obtain a wide range of iodide charges and activities. Example 3 Precipitation of Agi in a zeolite Zeolites containing silver ions were purchased from Aldrich as 1.6 mm pellets and 20 mesh spheres with a composition of Ag7.6Na0.4 [(A1O2) 8 (Si? 2) 4o] and Ag84Na2 [(A1O2) 86 (Si? 2)? O6], respectively. In the exposure of these ceramic materials in a solution of sodium iodide, they changed in appearance from a silver color to a yellow green one demonstrating the formation of Agi within the zeolite by itself. The amount of iodide taken was not confirmed, but theoretically the materials possessed 220 mg Ag / gram in the zeolite pellets and 350 mg Ag / gram in the zeolite spheres that could bind an equivalent amount of iodide in the formation of Silver iodide. Example 4 Precipitation of Agi in a source of natural carbon The agar or gelatin in a suitable concentration is prepared with water and a silver salt (silver nitrate), filled in a glass or fused silica tubes and allowed to convert a solid to room temperature. The glass tubes are cut to the desired length and soaked in a sodium iodide solution to create sodium iodide captured in the agar or gelatin phase of the tube. Example 5 Precipitation of Agi in solidified carbonaceous materials and substrates of silica The natural carbonaceous sources such as wooden sticks and rice grains, and glass tube were first coated with a silver coating by adding the articles in solution A: 7% sodium carbonate solution, and they were mixed well for a few minutes. Then an equivalent amount of the following solution mixture was added and allowed to mix at room temperature for five minutes: solution B: 0.72% silver nitrate, 0.72% ammonium nitrate, and 1.31% formaldehyde. The articles were removed and dried by air. The articles had a silver coating from colorless to glossy. After drying, the articles were immersed in a Nal solution with potassium ferricyanide and mixed well. The silver coating now had a yellow-green color that points to the formation of silver iodide. Example 6 Solution A is prepared as a 7% solution of sodium carbonate in water. Solution B is prepared as 0.72% silver nitrate, 0.72% ammonium nitrate, and 1.31% formaldehyde in water. Solution C is prepared as 1.0% Nal solution and 2. 0% solution of potassium ferricyanide in water and contains 600 mCi of 125? A piece of 5 mm carbon yarn 0.076 mm in diameter obtained from Alpha Aesar in 5 meters of length is placed in an aliquot of solution A. To this is added an aliquot of solution B at room temperature. After about 5 minutes, the silver-coated carbon yarn was isolated by filtration, dried by air, and immersed in an aliquot of solution C for not less than 30 minutes. The excess solution is removed by suction, and the yarn containing new radioiodine is dried in a stream of nitrogen. Example 7 The method of Example 1 is repeated using 125l. Example 8 The method of Example 2 is repeated using 125l. Example 9 The method of Example 3 is repeated using 125l. Example 10 The method of Example 4 is repeated using 125 l. Example 11 The method of Example 5 is repeated using 125l. Example 12 7-Iodo-8-quinolinol of 5-aminium-8-quinolinol is prepared by means of a Gattermann reaction according to the method of Gershon et al. (J. Heterocycl. Chem., 1971, 8 (1), 129-131) by the treatment of the amine with sodium nitrite to allow the covalent attachment of 125 I in the presence of copper and H125l which is formed of Na125l in the pH of the reaction. The reaction product is extracted in a small volume of methylene chloride. A piece of carbon yarn, 0.076 mm in diameter and 5 mm long (from Alpha Aesar) is heated in a tube furnace above 400 ° C in a flow of argon, cooled in the absence of moisture and added to the methylene chloride solution. The solvent is allowed to evaporate in order to leave the reaction product absorbed in the carbon yarn. The yarn is placed in a titanium container and the container is sealed to form a seed suitable for use in brachytherapy. Example 13 The anthranilic acid is diazotized and treated with K125l according to the method of Friedman L. and Logullo F.M. (Angew. Chem., 1965, 77, 217) to provide a mixture of products comprising radioactive iodinated aromatic organic compounds. This mixture is absorbed in carbon yarn according to the method of Example 12. Example 14 Absorbency of Iodine-125 in Naturally Occurring Material A naturally occurring carbonaceous substance, rice grains, was subjected to a silver-plating process followed by the reaction with a solution of sodium iodide containing iodine-125. The grains were shown to absorb radioactivity. Experiment. 1. Selection Material. Four samples of rice were obtained, (these were detailed in Table 1 below) and a sample of each was weighed and placed in separate beakers. 10 ml of Sodium Carbonate Solution (Solution 1, Table 2) were added to each beaker. The samples were mixed using a magnetic stirrer and flea for 1 minute. The samples were dried and weighed. The results they are reported in Table 3. Agitation was repeated using the same samples and fresh solution for about 2 more minutes; it was observed that all the samples showed signs of deterioration, and that these were more marked in samples 1 and 4. The experiment was repeated with fresh rice grains and the solution and agitation was continued for 5 minutes by hand using an agitator bacillus plastic to minimize the damage. The samples were dried and weighed, and the 10 results are shown in Table 4. Rice samples 1 and 4 still show signs of damage. Non-Radioactive Procedure. Rice samples 2 and 3 were selected by this section of the experiment based on results from section 1. The aliquots of 15 each of the rice samples were weighed and placed in 25 ml beakers; 10 ml of solution 1 was added and shaken for 5 minutes by hand. 10 ml of a silver nitrate, ammonium nitrate, formaldehyde solution (solution 2) were added to 20 each beaker and the mixture was stirred for about 5 more minutes. The samples were observed to turn black, the samples were dried and weighed, and the results are reported in Table 5. The samples were returned to clean 25-year-old beakers. 25 ml and 10 ml of solution 3 were added and the mixture was He stirred for 5 minutes. The samples were dried and weighed, and the results are reported in Table 5. At the base of this experiment the rice sample 3 was selected for further testing. It gave the highest absorbency of chemicals while retaining the greatest physical integrity. Radioactive procedure. An aliquot of rice sample 3 was weighed and placed in a glass jar. 10 of solution 1 was added and the container rotated in a 10 bottle spinner for 5 minutes. 10 mis of solution 2 were added and the mixture continues for about 5 more minutes. The supernatant was removed and retained. The sample was allowed to dry and then weighed; The results are recorded in Table 6. The sample was replaced in 15 the vial, 10 ml of solution 3 containing 10 μl of an iodine-125 solution containing 10 μCi per ml were added and the mixture was rotated for 10 minutes. The supernatant was removed and retained. The samples were dried. 20 separate grains were selected, the Radioactive content was determined in a gamma counter. The grains were weighed individually. The results are given in Table 2. It is repeated. 4.1 The previous experiment was repeated but with the 25 radioactive content of solution 3 increased ten times. The results are recorded in Table 8. 4.2 The experiment in 3 was repeated with a smaller sample of rice, reduced volume of solution 3 and the same radioactive content as in 4.1. The results are recorded in Table 9. The initial tests were designed to identify the most favorable support for the experiments. Brown rice was indicated as the most robust while 10 absorbs the largest amount of iodide. The radioactive tests were intended to investigate the potential for iodine-125 absorption. Test 1. Nominal radioactive concentration. 0.1 μCi per 10 ml of Iodide Solution. fifteen 20 Test 2. Nominal radioactive concentration. 1.0 μCi per 10 ml of Iodide Solution. 25 £ ^ ^ ^ & g J ^ _ É ^^ * «» as ^^ a Test 3. Nominal radioactive concentration. 1.0 μCi for 5 mis of Iodide Solution.

The iodine-125 absorbance shows an increase in all three experiments. The specific activity of the iodide solutions is in the ratio 1: 10:20. The study indicates that the material absorbs iodine-125 in an apparent correlation in the specific activity of the iodine solution used by the process. Table 1 . Rice Samples 1. White Basmati. 2. Yellow Basmati. 3. Coffee. 4. Arborio. Table 2. Reagent Solutions 1. 7% Sodium Carbonate in aqueous. 2. 0.72% Silver Nitrate, 0.72% Ammonium Nitrate, 1.31% Formaldehyde in aqueous.

J? DtiMkaaiilht * ». **** > * < * '- * «- * - .yJkJL? ^ ?? ± ^ ?. 3. 1.0% Sodium Iodide, 2.0% Potassium Ferricyanide in aqueous. Table 3. Absorbency of Sodium Carbonate Solution of One Minute of Agitation. Rice Type No. Initial Weight After Solu. 1, Increase 1 Minute 1 1.0050 1.0321 0.0271 2 1.0135 1.0743 0.0608 3 1.0099 1.0745 0.0646 4 1.0178 1.0928 0.0750 Table 4. Absorbency of Sodium Carbonate Solution of; 5 Minutes of Agitation.

Table 5. Absorption of Silver and Iodide Table 6. Silver Absorption before the Radioactive test Table 7. Results of the Prime Identity of Grain Weight CPM 1 0.0202 594.1 2 0.0285 758.1 3 0.0185 626.1 4 0.0258 808.2 5 0.0204 848.6 6 0.0201 564.1 7 0.0236 936.2 8 0.0166 486.1 9 0.0231 828.2 10 0.0225 656.2 1 1 0.0242 808.2 12 0.021 1 714.2 13 0.0202 576.2 14 0.0212 814.2 15 0.0251 946.3 16 0.01 15 498.1 17 0.0207 686.2 8 0.0221 692.2 19 0.0196 662.2 0 0.0188 576.2 Table 8. Results of the Second Radioactive Test.

Grain Identity Weight CPM 1 0.0216 8257.7 2 0.0208 8821 .8 3 0.0221 9151 .9 4 0.0256 9141 .6 5 0.0251 9186.9 6 0.0224 9267.9 7 0.0261 12606.1 8 0.0256 8781 .1 9 0.0207 7105.4 10 0.0196 7865.4 11 0.0226 8272.2 12 0.0229 9474.7 13 0.0303 1 1221 .8 14 0.0241 8625.1 15 0.0217 7212.5 16 0.0265 10096.3 17 0.0204 9840.7 18 0.0261 9591 .3 19 0.0208 7733.2 0 0.0281 9320.8 Table 9. Results of the Third Radioactive Test.

Grain Identity Weight CPM 1 0.0016 20684.8 2 0.0208 33899.1 3 0.0169 29333.9 4 0.0226 31055.3 5 0.0135 16084.8 6 0.0180 27555.5 7 0.0220 28080.8 8 0.0200 20936.9 & 0.0247 42486.6 10 0.0193 21551.1 11 0.0224 21912.7 12 0.0207 24429.9 13 0.0185 31040.8 14 0.0180 24250.1 1 5 0.0151 27447.4 16 0.0153 27522.1 17 0.0241 39403.9 18 0.0212 23690.7 19 0.0171 21406.3 20 0.0231 35611.5 21 0.0167 28079.1 .iaitUiti: .. ^ Aaj 0.0222

Claims (1)

1. CLAIMS 1. A radioactive source suitable for use in brachytherapy comprising a radioactive iodine isotope in the form of iodide ions or an iodine-containing compound, absorbed onto the surface of an attenuating substrate substantially without radiation, provided that When the iodine is in the form of iodide ions, then the substrate is not an ion exchange resin. 2. A radioactive source according to claim 1, characterized in that the substrate plus the absorbed iodine is sealed inside a biocompatible container. 3. A radioactive source according to claim 2, characterized in that the container is ecogenic. 4. A radioactive source according to any of claims 1 to 3, characterized in that the isotope of iodine is iodine-125. 5. A radioactive source according to any of claims 1 to 4, characterized in that it has an activity in the range of about 200. mCi at approximately 1200 mCi. 6. A radioactive source according to any of claims 1 to 4, characterized in that it has an activity in the range of about 0.1 to about 5 mCi. 7. A radioactive source according to any one of claims 1 to 6, characterized in that the iodine-containing compound is an iodohalogen compound, an organic compound containing a carbon iodine bond, a iodo compound, a diaryliodo salt, an N-iodoamide, an aryl compound of iodoxy or a covalently bound inorganic iodide compound. A radioactive source according to any of claims 1 to 7, characterized in that the substrate is carbon, aluminum, a zeolite, a titanium oxide, silica, a silicon oxide, a trivalent metal silicate of the zeolite type, a phosphate of metal, a metal hydroxyphosphate, a crystalline material, aluminum nitride, a ceramic, a radiation-resistant polymer, bone, coral, coal, limestone, cellulose, starch, agar, gelatin, chitin, or filament. 9. A radioactive source according to any of claims 1 to 7, characterized in that the substrate is carbon. 10. A radioactive source according to any of claims 1 to 9, characterized in that it also comprises a binder. 1 1. A method for the preparation of a radioactive substrate suitable for use in a brachytherapy source, the method comprising exposing an attenuating substrate substantially without radiation unlike the ion exchange resin in a source of radioactive iodide ions with the result that iodide ions are absorbed on the surface of the substrate. 12. A method for the preparation of a radioactive substrate suitable for use in a brachytherapy source, the method comprising exposing an attenuating substrate substantially without radiation to a radioactive iodine-containing compound with the result that the iodine-containing compound is absorbed in the surface of the substrate. 13. A method of treating a condition which is a response to radiation therapy comprising the temporary placement of a radioactive source comprising a radioisotope of iodine in the form of iodide ions or a compound containing iodine absorbed on the surface of an attenuating substrate substantially free of radiation at the site to be treated within a patient for a sufficient period of time to deliver a therapeutically effective dose. 14. A method for the inhibition of restenosis at a site within the vascular system of a patient who has previously undergone PTCA, the method comprising the temporary placement of a radioactive source comprising a radioisotope of iodine in the form of iodide ions or a compound containing iodine absorbed on the surface of an attenuating substrate substantially without radiation at the site to be treated within a patient for a sufficient period of time to deliver a therapeutically effective dose. 15. A suitable radioactive source for use in brachytherapy comprising a radioactive isotope of iodine in the form of iodide ions or a compound containing iodine absorbed on the surface of an attenuating substrate substantially without radiation, the radioisotope and the substrate being sealed within a biocompatible ecogenic container. «... a ^, ... Í? ? i ^ iíi. t. "& uraii-tmÉ -atta