CN1368895A - 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. Preferre dsubstrates include carbon, particularly activated carbon. The sources may be useful for the treatment of restenosis.

Description

iodine radioactive source

This invention relates to radiation therapy. More particularly, the present invention relates to radiation sources for use in brachytherapy and methods of making such radiation sources.

Brachytherapy is a general term belonging to the field of medical treatment that involves placing a radiation source close to diseased tissue and can also include the temporary or permanent implantation or insertion of a radiation source into the patient's body. The radiation source is thereby positioned close to the body region to be treated. The advantage of this is that the required dose of radiation can be delivered to the treatment site while having a lower radiation dose surrounding or interfering with healthy tissue.

Brachytherapy has been recommended for the treatment of various diseases including arthritis and cancers such as breast, brain, liver and ovarian cancers, especially male prostate cancer (see e.g. J, C. Blasko et al. The Urological Clinics of North America, 23, 633-650 (1996), and H. Ragde et al. Cancer, 80, 442-453 (1997)). In the United States, prostate cancer is the most common malignancy in men, and more than 44,000 men died of prostate cancer in 1995 alone. Treatment methods may involve the temporary implantation of a radioactive source for a predetermined period of time, followed by its removal. Alternatively, the radioactive source may be permanently implanted in the patient for a predictable period of time to allow it to decay to an inert state. The use of temporary or long-term implants depends on the isotope chosen and the duration and intensity of treatment required.

Long-term implants for the treatment of the prostate include radioisotopes that have shorter half-lives and lower energy than temporary sources. Examples of long-term implantable sources include iodine-125 or palladium-103 as radioisotopes. The radioisotope is usually encapsulated in a titanium sheath to form a "seed" that can be implanted for later use. Temporary implants for the treatment of prostate cancer may use iridium-192 as the radioisotope.

More recently, brachytherapy has been recommended for the treatment of restenosis (restenosis) (see R. Waksman, Vascular Radiotherapy Monitor, 1998, 1, 10-18, and MedProMonth, January 1998, made in pp. 26-32 review). Restenosis is the renarrowing of blood vessels after initial treatment for coronary artery disease.

Coronary artery disease is a condition that results from narrowing or blockage of the coronary arteries (called stenosis), which can be caused by a number of factors, including the buildup of atherosclerotic plaque in the arteries. These blockages or narrowings can be treated by mechanically removing the atherosclerotic plaque or by inserting stents to keep the artery open. One of the most common treatments is percutaneous transluminal coronary angioplasty (PTCA), also known as balloon angioplasty. Currently, more than half a million PTCA procedures are performed annually in the United States alone. During PTCA, a catheter with an inflatable balloon on the tip is inserted into the coronary artery and positioned at the site of the blockage or stenosis. The balloon is then inflated, which flattens the sclerotic plaque against the arterial wall and stretches the arterial wall, resulting in dilation of the intraluminal passage and thereby increased blood flow.

PTCA has a high initial success rate, but 30-50% of patients self-report a recurrence of strictures of the disease, ie restenosis, within 6 months. One approach that has been proposed to treat restenosis is the use of intraluminal radiation therapy. Various isotopes have been suggested for use in the treatment of restenosis, including iridium-192, strontium-90, yttrium-90, phosphorus-32, rhenium-186, and rhenium-188.

Conventional radiation sources used in brachytherapy consist of so-called seed tubules, which are sealed containers (such as titanium or stainless steel) that contain the radioisotope in a sealed chamber, but allow radiation to penetrate out of the container/chamber wall ( US-A-4323055 and US-A-3351049). Only radioactive isotopes that emit radiation that penetrates the chamber/container wall can be used with these seed-shaped tubules. Therefore, these seed-shaped tubules usually employ radioisotopes that emit gamma rays or low-energy X-rays, rather than radioisotopes that emit beta rays.

Brachytherapy seeds comprising silver wires sealed in titanium containers with a radioactive silver iodide coating are known in the art (US-A-4323055). This seed-shaped tubule emits radiation corresponding to 0.1 to 100 millicuries of radioactivity. Such seed-shaped tubules are commercially available from Medi-Physics, Inc. under the trade designation I- ^125Seed_ , Model 6711.

Other conventional brachytherapy seeds include titanium containers sealed with ion exchange resin beads on which radioactive ions such as I-125 are adsorbed (US-A-3351049). A method for immobilizing radioactive powders within a polymer matrix has also been proposed (WO97/19706).

GB-A 1187368, US-A 4729903, WO99/41755 and WO99/40970 disclose the adsorption of molecular iodine-125 on various substrates including graphite and zeolites. However, due to the volatility of iodine molecules, there is a safety hazard when using iodine-125 in the form of iodine molecules. The use of volatile radioisotopes presents a radiological hazard, either from the manufacture of radioactive sources or if radioactive seed tubules rupture during handling.

US-A-4323055 discloses iodine-125 containing seed tubules up to 100 mCi/seed tubule, but does not show that metal wire-based iodine-125 containing seed tubules have very high radioactivity. Radioactive seed tubules based on metal wires also have the disadvantage of some radioactivity being absorbed by the wire itself. The amount of radioactivity absorbed by the wire increases with the atomic number of the metal used to form the wire. The exact amount of attenuation is a function of the size of the wire. Using 0.5 mm diameter silver wire coated with silver iodide-125, up to about 20% of the radioactivity is absorbed by the wire itself. When manufacturing a radioactive seed for a given dose of external radiation, additional radioactivity must be loaded onto the thread, taking into account that some of the radioactivity is absorbed by the thread and by the seed vial container. Due to the requirement to increase the activity of the seed tubule, an additional depleted percentage of radioactivity must be loaded onto the wire.

Attempts, as in US-A-3351049, to produce highly active radioactive seed-shaped tubes containing radioactive anions adsorbed on ion exchange resin beads were not entirely successful, which we believe is due to polymerization of the radiation on the beads themselves Physical bonds have an adverse effect. We have found that under high levels of radioactivity the beads tend to degrade leading to unstable results.

There remains a need for highly active radioactive sources suitable for use in brachytherapy that do not present the safety concerns inherent in the use of radioactive molecular iodine, and methods of making such sources. Such sources are useful for temporary brachytherapy of cancer and proliferative diseases, particularly for the prevention of restenosis after PTCA treatment.

It is therefore an aspect of the present invention to provide a radioactive source, preferably a sealed source, suitable for use in brachytherapy, said radioactive source comprising radioactive iodine in the form of iodine anions or iodine-containing compounds adsorbed on a substrate surface substantially free of radiation attenuation. isotopes, with the proviso that when the iodine is present in the form of an iodide anion, the matrix is not an ion exchange resin. Preferably the source has an activity of about 0.1 mCi to 1200 mCi. Preferably for use in the treatment of restenosis, the source has an activity of about 200 mCi to about 1200 mCi, preferably 300 mCi to 1000 mCi, more preferably 400 mCi to 600 mC. Preferably when used in prostate brachytherapy, the source has an activity of from about 0.1 mCi to about 5 mCi, more preferably from about 0.2 to about 2 mCi.

Suitable radioactive isotopes of iodine are iodine-125, iodine-131 and iodine-123. Iodine-125 is preferred due to its longer half-life. As used herein, wherever the term iodine-125 is used, it should be understood to apply equally to iodine-131 or iodine-123.

The iodine radioactive isotope can exist in the form of iodide anion or iodine-containing compound. As used herein, the term "iodine-containing compound" includes any compound containing covalently bonded iodine, wherein the iodine is bonded to at least one other non-halogen atom. Molecular iodine (I ₂ ) or iodohalogens such as ICl are thus excluded. Examples of suitable compounds include organic compounds containing carbon-iodine bonds, iodooxy compounds (such as iodosobenzene, phenyliodoso diacetate and o-iodosobenzoic acid), di Aryliodonium salt (diaryliodmium salt) (such as diphenyliodonium bromide and diphenyliodonium iodide (where one or two of the iodine atoms can be radioactive isotopes of iodine)), N-iodoamide (N -iodoamide) (such as N-iodosuccinimide), iodoxyaryl compounds (such as iodophenone) or covalently bonded inorganic iodine compounds (such as tributyltin iodide). Non-volatile iodine-containing compounds are preferred.

Preferably the source of the present invention comprises a sealed container, such as a substantially cylindrical tubular container made of metal or some other suitable material, having a cavity through which the appropriate amount of iodine-125 is present.

The container material should be corrosion resistant, compatible with the matrix fluid, non-toxic and not unduly absorb the X-rays emitted from the radioisotope. Suitable containers include those made of low atomic number metals such as titanium or stainless steel. High atomic number metals such as gold, copper or platinum cause too much attenuation of inherently useful radiation. However, they can be used as coatings for certain low atomic number metals, such as beryllium, which are otherwise too toxic to be used without an outer coating. Titanium, titanium alloys or stainless steel are preferred metals for the container. Other suitable container materials include inert synthetic materials such as Teflon ^™ . The interior of the container is preferably completely sealed to avoid the risk of leakage.

The source should be of an overall size and dimension suitable for its future use. For example, preferably the overall size of each radioactive source should be such that it can be delivered to the treatment site using conventional techniques, eg, the source can be loaded in a conventional catheter for delivery to the site of restenosis. For example, seed tubes used in the treatment of prostate cancer are generally substantially cylindrical in shape, about 4.5 mm in length and about 0.8 mm in diameter, so that they can be delivered to the treatment site using a hypodermic needle. For use in the treatment of restenosis, the source should be of suitable size for insertion into the interior of a coronary artery, for example about 10 mm in length and about 1 mm in diameter, preferably about 5 mm in length and about 0.8 mm in diameter, and most preferably about 3 mm in length and a diameter of approximately 0.6 mm. The source for treating restenosis is generally delivered to the treatment site using conventional catheter methods.

The matrix can be any substance capable of adsorbing iodine anions or iodine-containing compounds (physisorption or chemisorption) which is sufficiently stable to radiation to enable its processing into brachytherapy after adsorption of iodine radioisotopes source. Preferably the matrix is in the form of a substantially rigid matrix such as a rod, wire or sphere. Preferably the matrix has a relatively large surface area available for adsorption. The matrix may also be in powder form.

The matrix should be substantially free of radiation attenuation. Preferably the matrix contains at least 60% by volume, more preferably at least 80% by volume and most preferably at least 90% by volume of atoms of the low atomic number element. The atoms may be present in elemental form, or as a mixture or compound. As used herein, low atomic numbers with atomic numbers ≤ 30, more preferably ≤ 25 are preferred, and preferred substrates include minimal amounts (eg, coatings only) of high atomic number, radiation attenuating materials such as metallic silver, gold or palladium. In these substrates, the minimum amount is sufficient to produce a radioactive iodine coating. For example, the substrate may comprise a substantially non-radiation attenuating material coated with a thin layer of metal, such as silver.

The iodide anion or iodine-containing compound should only be coated on the surface of the substrate, rather than being uniformly distributed throughout the substrate. Applying the radioactive iodine as a coating to the surface of the substrate also helps to minimize radiation attenuation.

Traditionally, one of the main purposes of using substrates containing high atomic number materials such as seeds in brachytherapy has been to enable x-ray detection of the position of the seeds after they have been implanted in the body. Preferably the source of the present invention contains a biocompatible container that is sufficiently echogenic so that the source can detect its position in the body by ultrasound rather than X-ray. Therefore, the use of a matrix comprising a high atomic number material is no longer necessary in order to be able to detect the seed-shaped tubules.

The present invention therefore provides, in another aspect, a radioactive source suitable for use in brachytherapy comprising a radioactive isotope of iodine in the form of an iodide anion or an iodine-containing compound adsorbed on the surface of a substantially radioactive attenuating substrate, The radioisotope and matrix are sealed in a biocompatible echogenic container.

Iodide negative ions or iodine-containing compounds can be physically adsorbed on the surface of the substrate (physisorption) or there may be a certain degree of chemical bonding (chemisorption) between the substrate and iodide negative ions or iodine-containing compounds: chemical adsorption is better than physical adsorption. suck.

Suitable matrices include carbon, alumina, titania, silica and silicon oxide, zeolitic trivalent metal silicates, metal phosphates and hydroxyphosphates including hydroxyapatite, calcium hydroxyapatite, glassy materials, nitrided Aluminum, ceramics, radiation-resistant polymers, and natural materials such as bone, coral, coal, limestone, cellulose, starch, agar, gelatin, chitin, and hair alone or woven together into larger rods.

A preferred matrix is carbon, especially activated carbon. Suitable activated carbons are available from American Norit Co. under the commercial names ^Darco® and ^Norit® . It is preferred that the matrix comprises atoms of elements of low atomic number so that absorption of radioactivity by the matrix is minimized. Preferably the matrix also has a low density to help minimize absorption of radiation. For these reasons, carbon is particularly preferred.

For the adsorption of iodide anions, positively charged substrates are preferred. For example, a ceramic with a pH below its isoelectric point (ie, pI) will have a positive surface charge, which will attract negatively charged iodide ions.

If the matrix is carbon, it may be a filament, rod, powder, granule, powder, compressed powder, carbonized polymer (including starch, cellulose, chitin, agar or gelatin), carbon yarn from Alpha Aesar ( carbon yarn) and carbonized polymers derived from acetylene, carbon, soot, or graphite (including graphite fibers and rods) or clathrates, fullerenes, or other carbon cages.

Organic compounds adsorbed to the substrate of choice can be iodinated with ¹²⁵ I. The organic compound adsorbed to the desired substrate can be a compound known in the art or a compound that can be identified using routine experimentation.

Any known method for the iodination of organic compounds may be suitable for use of radionuclides of iodine in place of the "cold" isotopes. For example, iodide can react with an organic molecule to form a bond between the iodide atom and a carbon atom of the molecule. For example, radioactive sodium iodide can react with tyrosine to produce radiolabeled tyrosine. In addition, methods for the covalent attachment of radioactive isotopes of iodine to organic molecules are known in the art and described, for example, in Parker, C.W., "Radiolabeling of Proteins", Methods in Enzymology, Vol. 182, 721 (1990); Noel, J-P. "Radioactive synthesis of carbon 14, tritium, sulfur 35 and iodine 125", Actual. Chim (1997), (7), 5-13 ("La synthesize radioactive averc le carbone 14, le tritium , le soufre 35 et l'iodi 125, L'Act.Chim.(R), 1997, 7, 5-13."); Scherberg N.H. and Refetoff S." Radioactive iodine labeling of cells", Methods in Cell Biology (1957) 10, pp. 343-359 (Chapter 19); and Baldwin, R.M, "Radioiodine Chemistry", Appl. Radiat. Isot. Vol. 37, No. 8, pp. 817-821, 1986; all of which are hereby incorporated by reference. Reagents and methods useful for the radioiodination of organic molecules can also be found in, e.g., Pierce Catalog and Handbook, 1994-1995 edition, page T-335, Technical Section, "Iodination" (incorporated herein by reference). Organic compounds preferred for iodination include tyrosine, phenylalanine, tyrosine-, phenylalanine-containing polypeptides and proteins, phenols, and compounds with Aromatic molecules at the active site of iodination; hydroxyaromatic compounds capable of enol-keto tautomeric transitions, such as phenolic compounds with a hydrogen atom in the ortho or para position, such as catechol or poly( 3,4-dihydroxystyrene), in which poly(3,4-dihydroxystyrene) is free by emulsion polymerization (latex polymerization) of 1-vinyl-3,4-methoxystyrene or by limited coagulation limited coalescence freeradical polymerization, followed by treatment at low temperature with boron tribromide in dichloromethane; and aryldiazonium compounds, which are known to form aryl groups in the Sandmeyer reaction in the presence of potassium iodide Iodides (see Lucas HJ. and Kennedy E.R, Org Syn., Coll. Vol. 2, 351, 1943 (incorporated herein by reference)), for example according to Friedman L. and Logullo F M., Chem., 77 , 217, 1965 (incorporated herein by reference), the diazonium salt of anthranilic acid can provide diiodobenzene.

Preferably the base is of suitable size and dimension to fit the interior of the container to form a sealed source. For example, the matrix may be rod-shaped or substantially spherical. However, the matrix may be of any size or shape suitable for irradiating the lumen of a closed vessel to prevent restenosis, and the size and shape of the container may be selected based on the size of the matrix. The source may comprise one or more substrates, or a plurality of substrates bonded together, for example by compression and/or using a suitable adhesive.

A number of substrates can be joined together, optionally using adhesives. A binder is a material that binds two or more active substrates or many substrates together to form a larger composite.

The adhesive can be a cohesive agent such as glue such as crazy glue and its medical grade counterpart Dermabond ^™ (from Ethicon)), other polymeric cyanoacrylates, adhesives such as hot melt adhesives) or polymers (such as polyvinyl alcohol, polyethyl acetate, ethylene vinyl acetate copolymers and partially hydrolyzed ethylene vinyl acetate copolymers, polyvinylpyrrolidone or polyvinyl chloride). Also used as binders are carbohydrates such as sucrose, sorbitol, lactose, etc., dextran and cyclodextrin; amino acids and proteins such as albumin; and salts such as halides of alkali and alkaline earth metals , sulfates, phosphates and nitrates. Binders containing elements of low atomic mass are preferred to minimize attenuation of the binder by radioactivity.

Preferably, the base body is rod-shaped. A single container may contain only one substrate which occupies substantially the entire volume within the container. Alternatively each container may contain two or more substrates, optionally separated by a suitable partition, for example. Preferably the matrix is arranged such that there is a uniform field of radiation around the source.

The level of radioactivity of matrices prepared 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 source of a given activity will depend in part on the amount of radiation absorbed by the substrate and the container. The amount of attenuation under any given condition can be readily determined by a person skilled in the art, for example by successive approximation or by calculation.

The sources of the present invention can be prepared by exposing a suitable substrate to iodide anions or iodine-containing compounds such as ¹²⁵ I-containing organic compounds. For safety reasons, it is preferred not to use volatile radioiodine-containing compounds, or isotopic precursors thereof.

Accordingly, another aspect of the present invention provides a method of preparing a substrate suitable for use as a brachytherapy source, said method comprising exposing the substantially non-radiatively attenuating substrate to a source of iodine-125 negative ions or compounds containing iodine-125 , such that the iodide anion or iodine-125-containing compound is adsorbed on the surface of the matrix, provided that the matrix is not an ion exchange resin when the iodine is present in the form of iodide anion. Preferably, the iodine-125-containing compound is an organic compound containing ¹²⁵ I.

The iodide ion may be present as a solution of a soluble iodide salt in a suitable solvent, such as an aqueous solution of potassium or sodium iodide-125ide. Preference is given to using an aqueous solution of the iodine-125 anion.

Pegylated matrices such as Eichrom's ^ABEC® (Aqueous Biphasic Extraction Chromatography) resins can be used to selectively adsorb iodine (in the form of iodide) from concentrated solutions of certain salts. Once loaded with iodine and dried, the matrix can be sealed in a container to form a brachytherapy source.

The iodine-125-containing compound may be present in solution in a suitable solvent. Alternatively, if the compound is a liquid, it can be used directly. Alternatively, the substrate may be exposed to the vapor of an organic compound ^{containing125I} , but this is not preferred due to safety aspects of handling radioactive compounds.

The substrates should be exposed to iodide ions or iodine-containing compounds for a sufficient time so that the required amount of radioactivity is adsorbed to each substrate. Suitable exposure times can be determined by routine experimentation, for example by monitoring the amount of non-adsorbed radioactive iodine remaining in the reaction medium.

If the iodine is in the form of an iodine-containing organic compound, the adsorption can be carried out as an iodination reaction in the same reaction vessel. For example, the substrate can be added to the reaction mixture after the iodination reaction has taken place so that the iodinated product will adsorb to the substrate without any step of isolating the iodinated product. The iodine-125-adsorbed matrix may then be separated from the reaction mixture (eg, by filtration), dried (if desired) and packed in a suitable container to form a radioactive source for a brachytherapy source.

After adsorption, the substrate can be further processed if desired. For example, many substrates can be made into a composite by applying pressure and/or using adhesives. In one aspect of the present invention, the low-melting binder can be melted and mixed with the activated carbon matrix containing adsorbed iodine-containing molecules, and then molded, cast or formed into a certain shape, such as thin rods, pellets, bars, etc. , wire, ring or tube, followed by cooling. The temperature should be below any temperature at which any substantial iodine-125-containing compounds desorb from the activated carbon. In another aspect of the invention, the binder can be mixed with the activated carbon matrix containing adsorbed iodine-containing molecules, and then molded, cast or formed under pressure into a certain shape.

If the substrate comprises a coating of silver ions or some other metal ion, wherein the ions form an insoluble iodide salt, the substrate can be exposed to a solution of iodine-125, such as a ^Na125I solution, such that An insoluble iodide salt coating is formed on the substantially radioactively non-attenuating substrate surface. This method forms a further feature of the invention. Substrates containing silver ion coatings include substrates such as polyvinyl alcohol, agar, gelatin, silica, carbonaceous materials, or carbon yarns that have been previously exposed to a source of silver ions, such as a silver salt solution.

A suitable amount of radioactive iodine is preferably used in the method of the invention to produce a matrix having an activity level of from about 0.1 millicurie to about 1 Curie. Such a matrix can be incorporated into a radiation source, eg, used in brachytherapy, which has an activity of about 0.1 millicuries to about 900 millicuries.

In order for substantially all of the radioactive iodine to be adsorbed onto the surface of the substrate, the substrate and reaction medium are preferably stirred. Agitation is preferably performed by rotating the reaction vessel so that with each rotation the substrate "tumbles" or rolls in the reaction medium.

For example, if the reaction vessel comprises a self-contained sealed vial, the vial is rotated vertically from end to end such that the contents tumble from end to end of the vial with each rotation. A rotation speed of 20 to 60 rpm is suitable.

Alternatively, the reaction vessel may be rotated at an angle to the horizontal such that the substrate rolls repeatedly in the reaction medium with each rotation. An angle of about 30° is suitable.

Proper agitation of the reaction medium also helps to ensure that maximum iodine adsorption occurs and that adsorption occurs uniformly over the entire surface of the substrate.

The radioactive sources of the present invention are useful in the treatment of cancers, such as head and neck cancer, melanoma, brain tumor, non-small cell lung cancer, breast and ovarian cancer, uterine and cervical cancer, and other diseases such as proliferative diseases, arthritis, urinary tract Temporary implants for stenotic and fibrous uterine tumors. Due to the high radioactivity levels, the source is unlikely to be used for long-term implanted brachytherapy. The source may also be used to prevent restenosis following PTCA treatment.

Another aspect of the invention provides a method of treating a disease responsive to radiation therapy, such as cancer, especially restenosis, which method comprises temporarily placing a radiation source on the site of a patient to be treated for a period of time sufficient to deliver the A therapeutically effective dose, said radioactive source comprising an amount of iodine-125 in the form of an iodide anion or iodine-containing compound adsorbed on the surface of a substantially non-radiatively attenuating substrate, provided that said substrate is not an ion exchange resin.

Preferably, the method of treatment of the present invention is used to inhibit restenosis at a site within a patient's vasculature that has been treated with PTCA.

The invention is further illustrated by the following non-limiting examples.

The precipitation of embodiment 1 silver iodide on polyvinyl alcohol (Ivalon) particle

In a small beaker, evenly distribute 1 g of PVA particles (150-250 microns) in a 0.5 molar silver nitrate solution for 1 hour. After this hour, the particles were allowed to settle to the bottom of the beaker and the supernatant was decanted, instead 50ml of distilled water was added. In this way the particles were rinsed 3 times in preparation for final treatment. After the third rinsing, the water was poured off as much as possible, and the particles were evenly distributed in the potassium iodide solution for 1 hour. Thereafter, the particles were again rinsed with water and then suspended in a small amount of saline for further testing.

The samples were transferred to the Center for Imaging and Pharmaceutical Research (CIPR) at Massachusetts General Hospital using 1 ml HPLC sample tubes for image analysis using a Toshiba CT scanner at 80 kv. A starting sample of PVA precipitated with Agl in saline was tested at 441 Hounsfield Units (HU). Typically per 35 HU = 1 mg silver iodide or approximately 0.5 mg iodide, and thus the amount of iodide present in the sample can be estimated to be 6.6 mg iodide per ml of hermetically packaged particles or approximately 50 μg iodide per particle. With a specific activity of 12 Curies, then there will be about 600 millicuries of activity per particle in the container.

Example 2 Multilayer Precipitation on Polyvinyl Alcohol (Ivalon) Particles

A suspension of polyvinyl alcohol (PVA) particles was prepared as in Example 1 above. After the end of the water rinse after the addition of potassium iodide, the particles were again exposed to the silver nitrate solution for one 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. The operation was then repeated on a portion of the sample to precipitate a third layer of silver iodide onto the PVA particles. Image analysis of the particles at Massachusetts General Hospital gave the following results:

Preparation Comparison of saline Estimated activity ^*

  (Hounsfield unit) µg I/particle mCurie/particle

AgI(1) 441 50 600

AgI(2) 1758 200 2400

AgI(3) 2434 275 3300

^* Assumes a specific activity of ¹²⁵ I of 12 Curie/mg.

From this it is clear that a wide range of iodide loadings and activities can be obtained by precipitating multiple layers of silver iodide onto the PVA particles.

The precipitation of embodiment 3AgI on the zeolite

Zeolites containing silver ions were purchased from Aldrich as 1.6 mm pellets and 20 mesh balls with Ag _7.6 Na _0.4 [(AlO ₂ ) ₈ (SiO ₂ ) ₄₀ ] and Ag ₈₄ Na ₂ [(AlO ₂ ) ₈₆ ( SiO ₂ ) ₁₀₆ ]. Upon exposure of these ceramic materials to a sodium iodide solution, they changed from a silvery appearance to a yellow-green appearance, indicating the formation of AgI on the zeolite itself. The amount of iodide adsorbed was not determined, but theoretically the material contained 220 mg of Ag per gram of the zeolite pellets and 350 mg of Ag per gram of the zeolite pellets, which can be converted to an equivalent of Iodide in the form of silver iodide.

The precipitation of embodiment 4AgI on natural carbon source

Agar or gelatin of appropriate concentration is prepared using water and a silver salt (silver nitrate), packed in glass or fused silica tubes and allowed to solidify at room temperature. The glass tubes were cut to the desired length and soaked in sodium iodide solution so that the silver iodide was trapped in the agar or gelatin phase of the tube.

Example 5 Precipitation of AgI on solidified carbonaceous material and silica matrix

Solution A (7% sodium carbonate) was first coated with a silver coating by adding a natural carbon-containing source such as wooden toothpicks, rice grains, and glass tubes to Solution A (7% sodium carbonate) and mixing it well for several minutes. An equal amount of the following solution mixture was then added and mixed for 5 minutes at room temperature: Solution B: 0.72% nitrate, 0.72% ammonium nitrate and 1.31% formaldehyde. The product was removed and air dried. The product had a dull silver coating sheen. After drying, the product was immersed in NaI solution containing potassium ferricyanide and mixed well. After 10 minutes, the product was removed. The silver coating now had a yellow-green color, indicating the formation of silver iodide.

Example 6

Solution A was prepared as 7% sodium carbonate in water.

Solution B was prepared as 0.72% nitrate, 0.72% ammonium nitrate and 1.31% formaldehyde in water.

Solution C was prepared as a 1.0% NaI solution and 2.0% potassium ferricyanide in water and contained 600 mCi ^of125I .

A 5 mm long, 0.076 mm diameter section was removed from a 5 meter length of carbon yarn obtained from Alpha Aesar and placed in an aliquot of Solution A. To this solution was added an aliquot of solution B at room temperature. After approximately 5 minutes, the silver-coated carbon gauze was isolated by filtration, air dried and soaked in an aliquot of Solution C for no less than 30 minutes. Excess solution was removed by suction and the gauze, which had contained radioiodine, was dried in a stream of nitrogen.

Example 7

Using ¹²⁵ I ^- the method of Example 1 was repeated.

Example 8

Using ¹²⁵ I ^- the method of Example 2 was repeated.

Example 9

Using ¹²⁵ I ^- the method of Example 3 was repeated.

Example 10

Using ¹²⁵ I ^- the method of Example 4 was repeated.

Example 11

Using ¹²⁵ I ^- the method of Example 5 was repeated. Example 12

According to the method of Gershon et al. (J.Heterocycl.Chem., 1971, 8(1), 129-131), 7-iodo-8-hydroxyquinoline was prepared from 5-amino-8-hydroxyquinoline by Gattermann reaction, The method uses sodium nitrate to treat the amine ^{to achieve covalent attachment of 125 I in the presence of copper and H 125 I formed} from Na ¹²⁵ I at the pH of the reaction solution. The reaction product was extracted with a small amount of dichloromethane. A length of carbon yarn with a diameter of 0.076 mm and a length of 5 mm (from Alpha Aesar) was heated above 400°C in a tube furnace under an argon atmosphere, cooled in the absence of moisture and added to a dichloromethane solution. Evaporation of the solvent allows the reaction product to be adsorbed on the carbon yarn. The yarn was placed in a titanium canister and the canister was sealed to form a seed-shaped tubule suitable for brachytherapy.

Example 13

Anthranilic acid was diazotized and treated with ^K125I according to the method of Friedman L. and Logullo FM (Angew. Chem., 1965, 77, 217) to provide a product composition comprising radioiodinated aromatic organic compounds. The mixture was adsorbed onto carbon yarn according to the method of Example 12.

Example 14 Adsorption of Iodine-125 on Naturally Occurring Materials

Rice grain, a naturally occurring carbonaceous material, is subjected to silver plating followed by reaction with sodium iodide containing iodine-125. The grains showed uptake of radioactivity. experiment

1. Material selection. Four samples of rice were obtained (see Table 1 below for details), and each sample was weighed and placed into separate beakers. 10 ml of sodium carbonate solution (Solution 1, Table 2) was added to each beaker. The samples were mixed for 1 minute using a magnetic stirrer and fleeal. The samples were dried and weighed. The results are shown in Table 3. The agitation was repeated for 2 minutes using the same sample and a fresh solution; it was observed that all samples clearly exhibited deterioration, most notably in samples 1 and 4.

The experiment was repeated with fresh rice grains and solutions and manually stirred for 5 minutes using a plastic stirring rod to minimize damage. The samples were dried and weighed, and the results are shown in Table 4. Rice samples 1 and 4 were still the most damaged.

2. Non-radioactive method. Rice samples 2 and 3 were selected for this experimental part based on the results of part 1. Aliquots of the individual rice samples were weighed and placed in 25 ml beakers; 10 ml of solution 1 were added and they were manually stirred for 5 minutes. 10 ml of nitrate, ammonium nitrate, formaldehyde solution (solution 2) were added to each beaker and the mixture was stirred again for 5 minutes. The sample was observed to turn black, the sample was dried and weighed, the results are shown in Table 5. The sample was returned to a clean 25ml beaker, 10ml of solution 3 was added and the mixture was stirred for 5 minutes. The samples were dried and weighed, the results are shown in Table 5.

According to this experiment, rice sample 3 was selected for further testing. The sample has the greatest absorption of chemicals while maintaining the greatest physical integrity.

3. Radioactive methods. An aliquot of rice sample 3 was weighed and placed into a glass vial. Add 10 ml of solution 1 and spin the container on a vial rotator for 5 minutes. 10 ml of solution 2 was added and mixing was continued for 5 minutes. Remove the supernatant and keep it. The samples were dried and then weighed; the results are shown in Table 6. The sample was placed in a vial, and 10 ml of solution 3 containing 10 μl of iodine-125 solution having a radioactivity of 10 microcuries (μCi) per ml was added, and the mixture was rotated for 10 minute. Remove the supernatant and keep it. The samples were dried. Twenty independent kernels were selected and the radioactive content was determined in a gamma counter. The grains were weighed individually. The results are shown in Table 2.

4. Repeat

4.1 Repeat the above experiment, except that the radioactive content of solution 3 is increased by 10 times. The results are shown in Table 8.

4.2 Repeat experiment 3 with a smaller sample of rice, a reduced amount of solution 3 and the same radioactive content as in 4.1. The results are shown in Table 9.

Initial tests were designed to determine the most favorable matrix for the experiment. Brown rice was determined to be the most durable and absorb the greatest amount of iodide. The radioactivity test was used to study the uptake potential of iodine-125. Test 1. Nominal radioactive content 0.1 microcuries per 10ml iodide solution. Total activity of grains Total activity of iodide solution 1.0 microcurie grains 181574.4CPM (counts per minute) grain weight 0.4731g absorption of iodine-125 Curie microcurie of iodine solution per 5ml of iodine grains Total activity 760616.2CPM (counts per minute) grain weight 0.5189g absorption of iodine-125 1465824CPM/g

The uptake of iodine-125 showed a rise in three experiments. The specific activity ratio of the iodide solution is 1:10:20.

Studies have shown that the absorption of iodine-125 by the material is clearly related to the specific activity of the iodide solution used in the method. Table 1, rice sample 1. white Basmati 2. yellow Basmati 3. brown 4. Arborio table 2, reagent solution 1.7% sodium carbonate aqueous solution. 2. 0.72% nitrate, 0.72% ammonium nitrate and 1.31% formaldehyde solution. 3. 1.0% NaI solution and 2.0% potassium ferricyanide aqueous solution. Table 3. Absorption of sodium carbonate solution after stirring for 1 minute Type number Initial weight Increased after 1 minute of solution

After stirring 1 1.0050 1.0321 0.02712 1.0135 1.0743 0.06083 1.0745 0.06464 1.0178 1.0928 0.0750 Table 4. After 5 minutes of stirring, the initial weight of the absorption of sodium carbonate solution increased by 1 minute of the solution by 1 minute.

的搅拌后1             1.7358        1.7942                0.05842             1.8321        1.9682                0.13613             1.8010        1.9180                0.11704             1.8919        2.1339                0.2420表5、银和碘化物的吸收米类型       初始重量      加入银后             加入碘化物后2             1.6969        1.8403                1.99183             1.3952        1.5274                2.1464表6、在放射性测试前The weight of the silver absorption rice type The weight of the first weight of the silver 1.6372G 1.7845G Table 7. The results of the first radioactive test valley number (Identity) weight CPM1. 0.0202 594.12. 0.0285 758.13. 0.0185 626.14. .                      0.0201                564.17.                      0.0236                936.28.                      0.0166                486.19.                      0.0231                828.210.                     0.0225                656.211.                     0.0242                808.212.                     0.0211                714.213.                     0.0202                576.214.                     0.0212                814.215.                     0.0251                946.316.                     0.0115                498.117.                     0.0207                686.218.                     0.0221                692.219.                     0.0196                662.220.                     0.0188                576.2表8、第二次放射性测试的结果谷粒编号                 重量                  CPM1.                      0.0216                8257.72.                      0.0208                8821.83.                      0.0221                9151.94.                      0.0256                9141.65.                      0.0251                9186.96.                      0.0224                9267.97.                      0.0261               12606.18.                      0.0256                8781.19.                      0.0207                7105.410.                     0.0196                7865.411.                     0.0226                8272.212.                     0.0229                9474.713.                     0.0303               11221.814. 0.0241                8625.115.                     0.0217                7212.516.                     0.0265               10096.317.                     0.0204                9840.718.                     0.0261                9591.319.                     0.0208                7733.220.                     0.0281                9320.8表9、第三次放射性测试的结果谷粒编号                 重量                  CPM1.                      0.0016               20684.82.                      0.0208               33899.13.                      0.0169               29333.94.                      0.0226               31055.35.                      0.0135               16084.86 .                      0.0180               27555.57.                      0.0220               28080.88.                      0.0200               20936.99.                      0.0247               42486.610.                     0.0193               21551.111.                     0.0224               21912.712.                     0.0207               24429.913.                     0.0185               31040.814.                     0.0180               24250.115.                     0.0151               27447.416.                     0.0153               27522.117.                     0.0241               39403.918.                     0.0212               23690.719.                     0.0171               21406.320.                     0.0231               25611.521.                     0.0167               28079.122.                     0.0222

Claims (15)

1. A radioactive source suitable for brachytherapy, said radioactive source comprising iodine radioactive isotopes in the form of iodine anions or iodine-containing compounds adsorbed on the surface of a substrate substantially without radiation attenuation, provided that said When iodine is present in the form of iodide anion, then the matrix is not an ion exchange resin. 2. A radioactive source as claimed in claim 1, wherein the matrix and its adsorbed iodine are sealed in a biocompatible container. 3. A radioactive source as claimed in claim 2, wherein said container is capable of echogenicity. 4. A radioactive source as claimed in any one of claims 1 to 3, wherein the isotope of iodine is iodine-125. 5. A radioactive source as claimed in any one of claims 1 to 4 having an activity of from about 200 millicuries to about 1200 millicuries. 6. A radioactive source as claimed in any one of claims 1 to 4 having an activity of from about 0.1 mCurie to about 5 mCurie. 7. The radioactive source claimed in any one of claims 1 to 6, wherein said iodine-containing compound is an iodine halide compound, an organic compound containing a carbon-iodine bond, an iodine oxy compound, a diaryliodonium salt, N-iodoamides, iodosaryl compounds, or covalently bonded inorganic iodine compounds. 8. The radioactive source claimed in any one of claims 1 to 7, wherein the matrix is carbon, alumina, zeolite, titanium dioxide, silica and silicon oxide, zeolitic trivalent metal silicates, metal phosphates and Metal hydroxyphosphates, glassy materials, aluminum nitride, ceramics, radiation-resistant polymers, bone, coral, coal, limestone, cellulose, starch, agar, gelatin, chitin, or hair. 9. A radioactive source as claimed in any one of claims 1 to 7, wherein the matrix is carbon. 10. A radioactive source as claimed in any one of claims 1 to 9, further comprising a binder. 11. A method for preparing a radioactive substrate suitable for brachytherapy sources, said method comprising exposing a substrate substantially free of radioactive attenuation except ion exchange resins to a source of radioactive iodine anions, such that said iodide anions adsorb on the surface of the substrate. 12. A method of preparing a radioactive substrate suitable for use as a brachytherapy source, said method comprising exposing a substrate substantially free of radiation attenuation to a radioactive iodine-containing compound such that said iodine-containing compound is adsorbed on said substrate On the surface. 13. A method of treating a disease responsive to radiation therapy, said method comprising temporarily placing a radioactive source on an area of a patient to be treated for a sufficient period of time to deliver a therapeutically effective dose, said radioactive source comprising an adsorbent Radioactive isotopes of iodine in the form of iodine anions or iodine-containing compounds on the surface of a substrate substantially free of radioactive attenuation. 14. A method for inhibiting restenosis at a site within a patient's vasculature that has been treated with PTCA, said method comprising temporarily placing a radioactive source on the site of the patient to be treated for a period of time sufficient to deliver a therapeutically effective The radioactive source comprises iodine radioisotopes in the form of iodide anions or iodine-containing compounds adsorbed on the surface of a substantially non-radiatively attenuating substrate. 15. A radioactive source suitable for brachytherapy, said radioactive source comprising iodine radioactive isotopes in the form of iodine negative ions or iodine-containing compounds adsorbed on the substrate surface without radioactive attenuation, said radioactive isotopes and The matrix is sealed in a biocompatible echogenic container.