KR100530276B1 - Particulate radionuclide conjugated polymer, preparation method thereof and kit for manufacturing same - Google Patents

Abstract

The present invention relates to a particulate radionuclide conjugated polymer in which particulate radionuclide is encapsulated in a biodegradable polymer; A method for producing a particulate radionuclide conjugated polymer; And to kits for producing particulate radionuclide composite polymers.

The particulate radionuclide conjugated polymer of the present invention obtains the radionuclide particulate by mixing and combining the particulate radionuclide in the biodegradable polymer solution or by mixing the radionuclide solution, the radionuclide granulating agent and the biodegradable polymer solution. And at the same time as the biodegradable polymer can be prepared.

The particulate radionuclide conjugated polymer of the present invention can be used in kit form.

The particulate radionuclide conjugated polymer of the present invention is an internal radiation therapy for treating diseases such as cyst cancer or arthritis such as liver cancer, brain cancer, ovarian cancer, breast cancer, etc. by directly injecting directly into a lesion and releasing radiation therefrom. Can be used as.

Description

Particulate radionuclide conjugated polymer, preparation method thereof and kit for preparing same

The present invention relates to a particulate radionuclide conjugated polymer, a method for producing the same, and a kit for producing the same, wherein the particulate radionuclide is encapsulated in a biodegradable polymer.

The treatment of diseases such as cancer and arthritis using radioisotopes is not only simple and economical compared to surgery, but also less pain to patients and high therapeutic effect. Therefore, it is expected that the development of radioisotope therapies will be improved as a method that is widely used now and can be applied more frequently in the future.

Radioisotopes used in therapy are often radionuclides that emit beta rays, and sometimes radionuclides that emit alpha rays. Among these therapeutic nuclides, radionuclides that emit beta rays include ¹⁸⁶ Re, ¹⁸⁸ Re, ⁹⁰ Y, ³² P, ¹⁶⁵ Dy, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁶⁹ Er, ¹⁹⁸ Au, ⁸⁹ Sr, and the like. ²²⁴ Ra, ²¹¹ At, and the like. Beta rays or alpha rays have weak penetrating ability and strong ionizing ability, and thus have strong tissue breaking ability. Therefore, if a radioisotope is guided and administered to a lesion to be removed by radiation, such as by ultrasound or imaging, only the site can be selectively destroyed. The radioisotope should remain only at the site of administration and not move to other sites. If the radioisotope is transferred to another site, the tissue is destroyed by radiation, which causes side effects. In order to solve this problem, many radionuclides have been developed and put into practical use. Since particulate radionuclides generally have a size ranging from 50 nm to several tens of micrometers, they are larger than capillary gaps, and thus are difficult to transfer to other tissues when administered to one tissue. Examples of particulate radionuclides include ¹⁸⁶ Re-Rhenium colloid (Korean Patent Application No. 97-72445, filed by the present inventor), ¹⁸⁶ Re-Rhenium colloid (PP Venkatesan, S. Shortkorff, MR Zalutsky and CB Sledge, Rhenium heptasulfide : a potential carrier system for radiation synovectomy, Nucl.Med.Bio. , 17 , 357 ~ 362, 1990), ¹⁸⁸ Re-Lenium Tin Colloid (Korean Patent Application No. 97-72445, filed previously by the inventor), ¹⁸⁶ Re- Rhenium colloid (Venkatesan et al. , Ibid. , 1990; S.-J. Wang, W.-Y. Lin, B.-T. Hsieh, L.-H. Shen, Z.-T. Tsai, G Ting and FF Kanpp, Jr. Rhenium-188 sulphur collid as a radiation synovectomy agent, Eur. J. Nucl.Med. , 22 , 505-507, 1995), ¹⁸⁸ Re-hydroxyapatite (KG Grillenberger, S. Glatz) and SN Reske, Rhenium-188 labeled hydroxyapatite and rheinium-188 sulfur colloid: in vitro comparison of two agents for radiation synovectomy, Nuklearmedizin , 36 , 71-75 , 1997), ⁹⁰ Y-yttrium colloid (RJ Bayly, JA Peacegood and SC P eake, ⁹⁰ Y ferric hydroxide colloid, Ann.Rheum.Dis . , 32 , supplement 10, 1973), ³² P-chromicphosphate colloid (LJ Anghileri and R. Marques, New colloidal chromic radiophosphate ( ³² P) for local irradiation of the central nervous system, Int. J. Appl. Radiat. Isotopes. , 18 , 97-100, 1967), ¹⁹⁸ Au-colloid (BM Ansell, A. Crook, JR Mallard and EGL Bywaters, Ecalustion of intra-articular colloidal gold ¹⁹⁸ Au in the treatment of persistent knee effusion, Ann.Rheum.Dis . , 22 , 435-439, 1963), ²¹¹ At-Astatin Tellurium Colloid (WD Bloomer, WH Mc Laughlin, RD Neirinckx, SJ Adelstein, PR Gordon, TJ Ruth and AP Wolf, Astatine-211-tellurium radiocolloid cures experimental malignant ascites , Science , 212 , 340-341, 1981).

However, problems remain when treating diseases with these radionuclides. For example, when radioactive isotopes are administered and sutured to surgically removed tumor sites, such as brain tumors, radioactive isotopes are directly injected into the tumors when the radioisotopes are injected into the tumor, such as liver and breast cancers. It is desirable to release the radiation while maintaining the form, to have a therapeutic effect on the lesion, and to disappear naturally after sufficient time. In this case, the particulate radionuclide administered in the aqueous solution may spread to other body parts through the gap between the tissues and cause side effects when some of them come out of the tissues during administration, and do not stay at the site of administration. The form of the radioactive particles may not be suitable for treatment, such as only water is absorbed into the tissue after administration to the other side or after administration, and particulate radionuclides precipitate and collect on one side, resulting in uneven irradiation.

In Korean Laid-Open Patent Publication No. 96-33472, a complex of chitosan and radionuclide, which is a polymer, was prepared to compensate for this disadvantage. Chitosan is a linear polymer in which glucosamine has a β-(1-4) bond. It is made by hydrolyzing a substance called chitin, which is present in many shells of crabs and shrimp, and removing acetyl groups. It is used as a heavy metal antidote or radioactive decontamination agent because it can form complexes with various heavy metals or radionuclides due to its many amino groups. In addition, since a stable complex is formed with ¹⁶⁶ Ho, many researches using the same have been conducted.

^{The 166} Ho-chitosan complex has the advantage of being accurately and uniformly irradiated compared to the particulate radionuclides present in solution because they are turned into gels in the body after injection in liquid form and retain their form at that site. In addition, after sufficient time, the radioactivity disappears, and the chitosan administered as a complex is also broken down. After brain tumor surgery, even if the radioisotope is buried in the gel form at the surgical site, it is easy to be buried in the gel form due to its high viscosity. In addition, ¹⁶⁶ Ho has several advantages, such as being relatively inexpensive compared to other radionuclides, the energy of beta rays, and the half-life.

However, the method of preparing radioisotopes in the form of complexes with chitosan does not allow many radionuclides that are important for therapeutic use such as ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁹⁸ Au, ²¹¹ At, and ¹³¹ I to form stable complexes with chitosan. Because of this, there are limitations to the applicable nuclides. In other words, the complex is formed by chemically bonding the electron-receiving metal and the electron-giving ligand, and chitosan can act as a ligand because it is possible for a specific metal and only under specific conditions, so that the conditions for producing the complex are difficult. The disadvantage is limited.

In addition, there are a number of limitations in the polymers that can be used for complex formation. For example, alginic acid and polyglutamic acid, which are polymers generally known to be applicable to the human body, do not have enough amino groups and thus have a weak force to act as a ligand for electrons. There is a problem that does not form a complex with most radionuclides.

Accordingly, the present inventors have developed a new type of formulation capable of effectively administering the particulate radionuclide to the human body regardless of the types of biodegradable polymers such as chitin, chitosan, alginic acid, and polyamino acid, which are applicable to the human body. As a result of repeated studies, when the particulate radionuclide is prepared in an entrapment form in a biodegradable polymer, unlike the conventional complex form, there are problems caused by conventional complex formation (limitation of complex formable radionuclide, The present invention has been completed by discovering that the limitation of the biodegradable polymer that can be used can be effectively solved.

The present invention relates to a particulate radionuclide entraped polymer comprising particulate radionuclides in a biodegradable polymer; A method for producing a particulate radionuclide conjugated polymer; And to kits for producing particulate radionuclide composite polymers.

The first aspect of the present invention, the particulate radionuclide conjugated polymer is obtained by incorporating the particulate radionuclide into the biodegradable polymer, wherein the particulate radionuclide is in a state of being physically confined to the biodegradable polymer.

Particulate radionuclides of the particulate radionuclide conjugate polymer according to the present invention include (1) alpha rays and gamma rays, which are used for treating cancer or arthritis; (2) beta rays and gamma rays; Or (3) therapeutic radionuclides emitting alpha, beta and gamma rays, preferably ¹⁸⁶ Re, ¹⁸⁸ Re, ⁹⁰ Y, ³² P, ¹⁶⁵ Dy, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁶⁹ Er, ¹⁹⁸ Au, ⁸⁹ Sr , ²²⁴ Ra or ²¹¹ At.

The particulate radionuclides of the particulate radionuclide conjugate polymer according to the present invention may also directly use particulate radionuclides prepared according to the prior art. Examples of such particulate radionuclides include ¹⁸⁶ Re-Rhenium colloids, ¹⁸⁶ Re-Rhenium sulfur colloids and ¹⁸⁶ Re-microspheres; ¹⁸⁸ Re-Rhenium Colloid, ¹⁸⁸ Re-Rhenium Colloid and ¹⁸⁸ Re-Microsphere; ¹⁸⁸ Re-hydroxyapatite; ⁹⁰ Y-colloids and ⁹⁰ Y-microspheres; ³² P-chromic phosphate colloids and ³² P-chromic phosphate microspheres; ¹⁶⁵ Dy- colloid, ¹⁶⁵ Dy ₂ O ₃ ¹⁶⁵ Dy- oxides, represented by ¹⁶⁵ Dy- microspheres; ¹⁵³ Sm- colloid, ¹⁵³ Sm ₂ ^{153 153} Sm- oxide and represented by the O ₃ Sm- microspheres; ¹⁶⁶ Ho- colloid, ¹⁶⁶ Ho ₂ ^{166 166} Ho- oxide and represented by the O ₃ Ho- microspheres; ¹⁶⁹ Er- colloid, ¹⁶⁹ Er ₂ O ₃ ¹⁶⁹ Er- oxide and ¹⁶⁹ micro Er- represented by the spear; ¹⁹⁸ Au-colloids; ⁸⁹ Sr-peroxide colloid, ⁸⁹ Sr-phosphate colloid, ⁸⁹ Sr-sulphate colloid, ⁸⁹ Sr-carbonate colloid, ⁸⁹ Sr-selenide colloid, ⁸⁹ Sr-peroxide microsphere, ⁸⁹ Sr- Microspheres of phosphate, microspheres of ⁸⁹ Sr-sulfur oxide, microspheres of ⁸⁹ Sr-carbonate and microspheres of ⁸⁹ Sr-selenide; ²²⁴ Ra-peroxide colloid, ²²⁴ Ra-phosphate colloid, ²²⁴ Ra-sulphate colloid, ²²⁴ Ra-carbonate colloid, ²²⁴ Ra-selenide colloid, ²²⁴ Ra-peroxide microspheres, ²²⁴ Ra- Microspheres of phosphate, microspheres of ²²⁴ Ra-sulfur oxide, microspheres of ²²⁴ Ra-carbonate and microspheres of ²²⁴ Ra-selenide; ²¹¹ At-tellurium colloid and ²¹¹ At-tellurium microspheres.

The biodegradable polymers applicable to the particulate radionuclide conjugate polymers according to the invention are not only non-toxic and biocompatible.

1) Before administration to a human body, it may exist in a liquid state with high fluidity in an aqueous solution, and then harden in vivo after administration to change into a gel state.

2) both before and after administration to the human body, present as a liquid and can be injected into specific body parts;

3) All biodegradable polymers that can be present at the administration site for hours or days and then slowly biodegraded and absorbed are included. For example, chitin, chitosan, alginic acid, polyamino acids (polylysine, polyarginine, polyglutamic acid, polyhistidine, polyalphaglutamic acid, etc.) and salts thereof.

Accordingly, the particulate radionuclide conjugated polymer of the present invention may be prepared by changing the pH before and after injection (for chitin, chitosan, polyamino acid, etc.); The action of divalent ions such as calcium present in the body or administered externally (for alginic acid); Various methods such as mixing with plasma containing a large amount of platelets (for alginic acid) may be applied to the human body, and then converted into a gel state.

In the particulate radionuclide conjugate polymer according to the present invention, the particulate radionuclide is physically contained in the biodegradable polymer, i.e., in the conjugated state, and thus, the particulate radionuclide conjugate polymer of the present invention is capable of forming this conjugated state. It is prepared by the method.

The second aspect of the present invention, the method for preparing the particulate radionuclide conjugate polymer according to the present invention can be selected from the following two:

The first method is to obtain particulate radionuclides first and then mix them with the biodegradable polymer solution.

The second method involves the addition of 1) a biodegradable polymer solution, 2) an additive capable of converting the radionuclide into a particulate, i.e., a radionuclide granulating agent, and 3) a radionuclide solution in a suitable manner for chemical reactions. It is obtained at the same time and incorporated into a biodegradable polymer.

The first method can be applied to a combination of all particulate radionuclides and biodegradable polymers having the above characteristics, and is also prepared in advance with a suitable biodegradable polymer solution (e.g., by treatment such as lyophilization). Kit may be prepared and used to add particulate radionuclide immediately before use to make particulate radionuclide conjugate polymer.

The second method can be applied to various radionuclides which can be changed to particulate matter and biodegradable polymers having the above characteristics, and also by adding a radionuclide immediately before use by preparing a kit containing the biodegradable polymer and radionuclide granulating agent. Radioactive radionuclide conjugate polymers can be made. For example, when a radioactive rhenium solution is added to a solution in which chitosan and tin chloride are dissolved together, it becomes rhenium tin colloid and forms a conjugate with chitosan. In this case, it can be conveniently used by manufacturing a kit containing an appropriate amount of chitosan and tin chloride.

The radionuclide granulating agent may be appropriately selected depending on the radionuclide to be granulated, and examples thereof include tin dichloride, sodium thiosulfate, hydroxyapatite, etc. for ¹⁸⁶ Re or ¹⁸⁸ Re; Yttrium colloid for ⁹⁰ Y; Chromic phosphate colloid for ³² P; Disophorium colloid for ¹⁶⁵ Dy; Samarium colloid for ¹⁵³ Sm; Holmium colloid for ¹⁶⁶ Ho; Erbium colloid for ¹⁶⁹ Er; Gold colloid for ¹⁹⁸ Au; ^In the case of ⁸⁹ Sr, colloids such as peroxides, phosphorous oxides, sulfur oxides, carbonates, selenides and the like; ²²⁴ Ra for colloids such as peroxides, phosphates, sulfur oxides, carbonates, selenides and the like; ^In the case of ²¹¹ At, there may be mentioned asstatin tellurium colloid.

A third aspect of the invention, the kit for the preparation of the particulate radionuclide conjugate polymer according to the invention is:

1) a kit form comprising a lyophilized biodegradable polymer in one container and an aqueous particulate radionuclide solution in another container; or

2) It may be in the form of a kit comprising a lyophilized biodegradable polymer and radionuclide granulating agent in one container and an aqueous radionuclide solution in another container. The kit may include additional additives, such as gelatin, albumin, EDTA, for quality improvement, such as chemical and physical stability.

The particulate radionuclide conjugated polymer of the present invention is injected directly into a lesion locally and emits radiation therein to treat various diseases including cystic cancers such as liver cancer, brain cancer, ovarian cancer, breast cancer, arthritis and the like. It can be used as a radiation therapy.

The following examples and experimental examples specifically illustrate the present invention, but the scope of the present invention is not limited to these examples.

Example 1: Preparation of radioactive rhenium tin colloid conjugated chitosan

30 mg of chitosan was dissolved in 4 ml of 1% acetic acid, and then the pH was adjusted to 3.0. 10 mg of tin dichloride was added and 0.1 ml of 0.2 mCi equivalent was added to the ¹⁸⁸ Re solution, followed by reaction at 100 ° C. for 120 minutes. Chromatography was performed using Gelman's ITLC-SG as a stationary phase and acetone as a mobile phase to measure the production efficiency of radioactive rhenium colloid contained in chitosan. As a result, it was confirmed that the production efficiency was 99.8%.

Example 2 Preparation of a Kit for the Preparation of Radioactive Rhenium Colloidal Conjugate Chitosan

300 mg of chitosan was dissolved in 40 ml of 1% acetic acid, and then the pH was adjusted to 3.0. To this, 100 mg of tin dichloride was added, mixed, dispensed into 4 ml portions of sterile vials, and lyophilized to complete a container containing a lyophilized biodegradable polymer and a radionuclide granulating agent. In another vessel, 1 ml of a ¹⁸⁸ Re solution was added in an amount of 500 mCi equivalent, 1 ml to complete another vessel containing an aqueous radionuclide solution. The two containers were packed together in a paper box to complete the kit.

When using the kit prepared in this way, ¹⁸⁸ Re solution of ¹⁸⁸ Re was added to one vial according to the purpose, and distilled water for injection was added to make the whole about 4 ml, followed by reaction at 100 ° C. for 120 minutes.

Experimental Example 1 Particle Diagram of Radioactive Rhenium Colloidal Containing Chitosan

1 ml of the radioactive rhenium tin colloid conjugated chitosan prepared in Example 1 was taken, and diluted with 3 ml of distilled water. The fine pore size was filtered through a filter having 0.22, 1 and 5 μm, respectively, and the radioactivity remaining in each filter was measured to determine the distribution of particle size.

The results are shown in Table 1 and it can be seen that 75% of the radioactive rhenium tin colloid conjugated chitosan has a size between 1 μm and 5 μm. This particle size can be changed by adjusting the reaction temperature, concentration, pH and the like.

TABLE 1

Experimental Example 2: Stability of the radioactive rhenium tin colloid conjugated chitosan

In order to check how long the radioactive rhenium can be maintained at room temperature before administration, the radioactive rhenium tin colloid conjugate chitosan prepared in Example 1 was prepared at room temperature 18 Samples were taken at regular time intervals while standing for a period of time and chromatographed in the same manner as in Experimental Example 1 to separate the radioactive rhenium tin and the released radioactive rhenium tin and analyzed by TLC scanner.

As a result, as shown in Figure 1, the prepared radioactive rhenium tin colloid conjugated chitosan was confirmed to be very stable by maintaining a state in which 98% or more after 18 hours at room temperature.

Experimental Example 3: Stability in the Body Fluid of Radioactive Rhenium Colloidal Containing Chitosan

In order to confirm that the radioactive rhenium is not released even after administration of the radioactive rhenium tin colloid conjugated chitosan to the human body, the radioactive rhenium tin colloid conjugated chitosan prepared in Example 1 is 0.1 ml in 1 ml of human serum and synovial fluid, respectively. The sample was added at 37 ° C. in a 5% carbon dioxide gas incubator and incubated for 45 hours, taking samples at regular intervals. The collected samples were centrifuged at 3,000 rpm for 59 minutes, and the radioactivity of the supernatant and precipitate were measured by gamma counter, and the amount of free rhenium was calculated as a percentage of the total rhenium radioactivity. From this, the stability of the radioactive rhenium tin colloid-containing chitosan was measured. Evaluated.

As a result, as shown in FIG. 2, it was confirmed that the radioactive rhenium tin colloid conjugated chitosan was more than 90% stable in serum and synovial fluid even after 45 hours.

Experimental Example 4: Liver distribution pattern of radioactive rhenium tin colloid conjugated chitosan injected into normal rat liver

Intramuscular injection of 5 mg of ketamine in a normal white paper was anesthetized, and a portion of the diaphragm was excised from about 1.5 cm, and 0.05 ml of the radioactive rhenium tin colloid conjugate chitosan prepared in Example 1 was directly injected into the liver. After 1, 24 and 48 hours, livers were collected, frozen, slices were obtained to a thickness of 20 μm, and autoradiography was performed to obtain radioactive distribution photographs.

As a result, it was observed that the radioactive rhenium tin colloid conjugated chitosan administered as shown in FIG. 3 remained intact at the injection site even after 48 hours (c).

When the particulate radionuclide conjugated polymer of the present invention is administered to the human body, unlike the administration of the particulate radionuclide in aqueous solution, it does not escape at intervals between tissues, and thus does not cause side effects and does not precipitate the particulate radionuclide. It can be made uniformly on the treated area and effective treatment effect can be obtained.

In addition, unlike the preparation of the complex radionuclide conjugate polymer of the present invention, there is no limitation on the applicable radioactive radionuclides, and various biodegradable polymers other than chitosan can be used, and they can be manufactured and used as a kit for preparation. In addition, it can be widely used as an internal radiation therapy for the treatment of cystic cancer or arthritis, such as liver cancer, brain cancer, breast cancer, ovarian cancer.

1 shows the stability at room temperature indicated by the radioactive rhenium tin colloid conjugated chitosan of the present invention.

Figure 2 shows the stability of radiorenium tin colloid conjugated chitosan in human serum and synovial fluid.

Figure 3 shows the distribution of liver over time of the radioactive rhenium tin colloid conjugated chitosan injected into the normal rat liver. 3A shows the liver distribution after 1 hour of injection, FIG. 3B after 24 hours of injection, and FIG. 3C after 48 hours of injection.

Claims (10)

The chitosan biodegradable polymer which is in a liquid state in the aqueous solution state before administration to the human body, and then hardens to a pH state in the body after administration, or in the presence of divalent ions or mixed with plasma containing a large amount of platelets A particulate radionuclide conjugated polymer obtained by entrapment of particulate radionuclide in an alginic acid biodegradable polymer which is hardened and changed into a gel state. The method of claim 1, wherein the particulate radionuclide is alpha and gamma rays used for the treatment of cancer or arthritis; Beta rays and gamma rays; Or particulate radionuclide conjugate polymers obtained by granulating radionuclides emitting alpha, beta and gamma rays. 3. The particulate radionuclide of claim 2 selected from the group consisting of ¹⁸⁶ Re, ¹⁸⁸ Re, ⁹⁰ Y, ³² P, ¹⁶⁵ Dy, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁶⁹ Er, ¹⁹⁸ Au, ⁸⁹ Sr, ²²⁴ Ra and ²¹¹ At. A particulate radionuclide conjugated polymer obtained by granulating radionuclides. The method of claim 3, wherein the particulate radionuclide is selected from the group consisting of ¹⁸⁶ Re-Rhenium tin colloid, ¹⁸⁶ Re-Rhenium sulfur colloid and ¹⁸⁶ Re-microsphere; ¹⁸⁸ Re-Rhenium Colloid, ¹⁸⁸ Re-Rhenium Colloid and ¹⁸⁸ Re-Microsphere; ¹⁸⁸ Re-hydroxyapatite; ⁹⁰ Y-colloids and ⁹⁰ Y-microspheres; ³² P-chromic phosphate colloids and ³² P-chromic phosphate microspheres; ¹⁶⁵ Dy- colloid, ¹⁶⁵ Dy ₂ O ₃ ¹⁶⁵ Dy- oxides, represented by ¹⁶⁵ Dy- microspheres; ¹⁵³ Sm- colloid, ¹⁵³ Sm ₂ ^{153 153} Sm- oxide and represented by the O ₃ Sm- microspheres; ¹⁶⁶ Ho- colloid, ¹⁶⁶ Ho ₂ ^{166 166} Ho- oxide and represented by the O ₃ Ho- microspheres; ¹⁶⁹ Er- colloid, ¹⁶⁹ Er ₂ O ₃ ¹⁶⁹ Er- oxide and ¹⁶⁹ micro Er- represented by the spear; ¹⁹⁸ Au-colloids; ⁸⁹ Sr-peroxide colloid, ⁸⁹ Sr-phosphate colloid, ⁸⁹ Sr-sulphate colloid, ⁸⁹ Sr-carbonate colloid, ⁸⁹ Sr-selenide colloid, ⁸⁹ Sr-peroxide microsphere, ⁸⁹ Sr- Microspheres of phosphate, microspheres of ⁸⁹ Sr-sulfur oxide, microspheres of ⁸⁹ Sr-carbonate and microspheres of ⁸⁹ Sr-selenide; ²²⁴ Ra-peroxide colloid, ²²⁴ Ra-phosphate colloid, ²²⁴ Ra-sulphate colloid, ²²⁴ Ra-carbonate colloid, ²²⁴ Ra-selenide colloid, ²²⁴ Ra-peroxide microspheres, ²²⁴ Ra- Microspheres of phosphate, microspheres of ²²⁴ Ra-sulfur oxide, microspheres of ²²⁴ Ra-carbonate and microspheres of ²²⁴ Ra-selenide; And ²¹¹ At-tellurium colloid and ²¹¹ At-tellurium microspheres. The method of claim 1, wherein the biodegradable polymer is alginic acid, gelled by the action of Ca ²⁺ present in the body or Ca ²⁺ administered externally, or by mixing with plasma containing a large amount of platelets. A particulate radionuclide conjugated polymer. A method for producing the particulate radionuclide conjugate polymer according to claim 1, wherein the biodegradable polymer solution and particulate radionuclide are mixed. A method for producing the particulate radionuclide conjugated polymer according to claim 1, wherein the biodegradable polymer solution, radionuclide and radionuclide granulating agent are mixed. A first container containing lyophilized biodegradable polymer; And a second container containing an aqueous particulate radionuclide aqueous solution, the kit for producing the particulate radionuclide conjugate polymer according to claim 1. A first container containing lyophilized biodegradable polymer and radionuclide granulating agent; And a second container containing an aqueous solution of radionuclide, the kit for producing a particulate radionuclide conjugate polymer according to claim 1. An internal radiation therapy comprising the particulate radionuclide conjugated polymer of claim 1 as an active ingredient.