Polymer radiotherapy particles, suspensions and methods of production thereof

Abstract

The present invention relates to polymer radiotherapy particles, compositions and methods of production thereof, wherein the radionuclides are alpha and / or beta-emitting radionuclides. The invention also relates to the use of said particles and compositions in the treatment of cancer and their use in localized region radiation therapy, brachytherapy and transarterial radioembolism.

Description

Technical Field

[0001] This invention relates to polymeric radiotherapy particles, compositions, and methods for their production, wherein the radionuclides are α- and / or β-emitting radionuclides. The invention also relates to the use of said particles and compositions in cancer treatment and their use in localized radiotherapy, brachytherapy, and transarterial radioembolization. Background Technology

[0002] Numerous attempts have been made to locally administer radioactive materials to cancer patients as a form of treatment. In some of these, the radioactive material has been incorporated into particles that can be directly applied to, for example, cancerous tumors, where the radioactive particles are delivered in the form of transarterial radioembolization (TARE) (also known as selective internal radiotherapy (SIRT)). In TARE, radioactive particles are administered directly via a catheter into the arterial blood supply to a target organ, such as the liver, allowing the radioactive dose to be delivered directly to the tumor site without systemic exposure of the patient to the radionuclide. This has the advantage of delivering a higher dose of the desired radioactive radiation to the target lesion without exposing “healthy” tissue to otherwise harmful radiation. Such stable radiotherapy particles, such as non-degradable glass spheres (TheraSphere™) or resin-based spheres (SIR-Spheres™), have been used for radioembolization to treat primary tumors and liver metastases.

[0003] For such radioactive exposure to be effective and confined to the target tissue, the emitted radiation should be high-energy and short-range, which can be obtained through alpha and / or beta radiation. Therefore, radionuclides with high-energy alpha and / or beta decay are highly preferred for such applications.

[0004] The clinical problem of radionuclide adsorption on particles is the potential leaching of radionuclides from the particles, which can lead to inappropriate radiation to non-target tissues, as well as the accumulation of daughter bodies in unfavorable locations and tissues.

[0005] To overcome leaching problems, phosphate precipitation has been used, for example, in WO2015168726, which... 90 Y, as an insoluble phosphate, precipitates onto the particles, thus fixing the radionuclide onto the polymer particles, thereby forming phosphate protrusions on the particle surface. This also leads to... 90 Inefficient utilization of raw material Y.

[0006] Able to adsorb more effectively on particles 90 The alternative that does not form such protrusions is very advantageous because it can form more stable and robust radioactive particles, which in turn can reduce the potential off-target harmful radiation to patients. Summary of the Invention

[0007] This invention relates to particles labeled with α- and / or β-emitting radionuclides, wherein the particles comprise or consist of a polymer resin conjugated with a sulfonic acid and ionically bound α- and / or β-emitting radionuclides, such as those selected from... 90 Y、 225 Ac、 89 Sr、 153 Sm、 159 Gd, 18 F, 68 Cu、 69 Cu、 67 Ga、 99m Tc, 201 Ti、 111 In、 161 Tb and 177 The group consisting of Lu, preferably selected freely 90 Y、 68 Cu、 69 Cu、 225 Ac、 212 Pb, 177 α- and / or β-emitting radionuclides of the group consisting of Lu, more preferably the radionuclides are... 90 Y. Therefore, such radionuclides are preferably selected from radionuclides that emit gamma radiation accounting for no more than 10% of the total decay radiation, and thus preferably, the primary decay is α and / or β decay. Furthermore, such radionuclides may have a decay half-life in the range of 1-300 hours, such as between 30-100 hours or such as 50-70 hours. In embodiments, the particles may, for example, have a size in the range of 5-400 μm, such as in the ranges of 10-300 μm, 25-250 μm, 50-200 μm, 100-150 μm, such as a size greater than 50 μm and less than 200 μm. Preferably, such particles are spherical with a smooth surface, such as a surface without protrusions, having low roughness. It is also preferred that such particles are substantially free of phosphates. The particles described herein are preferably polymeric, formed from a polymeric resin, which, for example, comprises one or more elements selected from the group consisting of: divinylbenzene, polystyrene, polyethylene glycol (PEG), polycaprolactone (PCL), polyurethane (PU), polyvinylpyrrolidone (PVP), poly(2-hydroxyethyl-methacrylate), polyglycolic acid, polylactide, polyhydroxybutyrate, chitosan, and hyaluronic acid. The polymeric resin may also be a copolymer, wherein multiple polymers constitute the polymeric particles. Preferably, the polymeric resin is a styrene-divinylbenzene copolymer.

[0008] The present invention also relates to pharmaceutical compositions comprising particles as disclosed herein. Such pharmaceutical compositions may, for example, further comprise diluents, carriers, surfactants, and / or excipients, and / or biocollagen components (such as, for example, albumin, such as, for example, bovine serum albumin), and / or glutaraldehyde, and / or buffers (such as, for example, acetate, citrate, or glutamate). The pharmaceutical compositions preferably comprise an amount of radionuclide from 1 kBq to 10 GBq per dose, or an amount of radionuclide from 50 MBq to 1000 GBq suitable for multi-dose industrial-scale production. Furthermore, the pharmaceutical compositions are suitable for intravenous, intratumoral, and / or intracavitary injection.

[0009] This invention also relates to the use of the particles and / or pharmaceutical compositions disclosed herein, preferably as pharmaceuticals, such as for treating or improving cancers, for example, by single or repeated administration, including squamous cell carcinoma of the head and neck, metastatic melanoma, sarcoma, non-small cell lung cancer, colorectal cancer, primary and secondary hepatocellular carcinoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, ovarian cancer, muscle-invasive bladder cancer, prostate cancer, and / or osteosarcoma, preferably unresectable hepatocellular carcinoma and / or locally advanced borderline resectable pancreatic ductal adenocarcinoma. The particles and / or compositions disclosed herein are also suitable for endovascular treatment, or radiation-induced synovectomy, radiation embolization (such as transarterial radioembolization (TARE)), and intratumoral injection, preferably for hepatocellular carcinoma, but also for other cancers disclosed herein. The particles as compositions disclosed herein are also suitable for radionuclide imaging. This invention further relates to a method of treating cancer, the method comprising administering an effective dose of α- and / or β-emitting radionuclide-labeled particles as disclosed herein.

[0010] The present invention further relates to a method for producing particles or pharmaceutical compositions labeled with α- and / or β-emitting radionuclides as disclosed herein. The method includes, for example, providing an α- and / or β-emitting radionuclide or a salt thereof; providing particles of a polymer resin having a sulfonic acid conjugation; mixing the α- and / or β-emitting radionuclide and the particles in an aqueous solution in the pH range of 6.5-9.5; and separating the α- and / or β-emitting radionuclide-labeled particles from the aqueous solution. Preferably, the mixing and separation steps are not spaced more than 60 minutes apart, such as no more than 30 minutes, such as no more than 15 minutes. Preferably, the aqueous solution has a pH in the range of 7-9, preferably less than pH 8.5, such as less than pH 7.5, such as about pH 7.4. Preferably, the method does not include immobilizing the radionuclide on the particles by phosphate precipitation.

[0011] The present invention also relates to a kit comprising: unlabeled particles comprising or consisting of a polymeric resin conjugated with sulfonic acid; optionally, reagents for preparing α- and / or β-emitting radionuclide-labeled particles or pharmaceutical compositions as disclosed herein; and optionally, instructions for preparing said particles or pharmaceutical compositions. The kit may further comprise an aqueous solution containing an uncured curable biocompatible adhesive and / or a non-polymeric hydrogel in an aqueous solution, and an aqueous solution containing a curing agent and / or a polymerizing agent, preferably, the curable biocompatible adhesive being albumin, preferably bovine serum albumin, and the curing agent and / or polymerizing agent being an amide crosslinking agent, preferably glutaraldehyde.

[0012] This invention further relates to a method for preparing cured 90 A method for providing a gamma-ray therapy composition, the method comprising: providing... 90 A suspension of Y-labeled particles, an uncured biocompatible adhesive and / or non-polymerized hydrogel in aqueous solution, and a curing agent and / or polymerizing agent, wherein the curing agent and / or polymerizing agent induces the curing of the biocompatible adhesive and / or the polymerization of the hydrogel when mixed with the adhesive or hydrogel; the components are then mixed to obtain cured product. 90 A gamma-ray therapy composition comprising a biocompatible adhesive and / or hydrogel embedding. 90 Y radioactive particles. Attached Figure Description

[0013] Figure 1

[0014] By 89 The polymer particles prepared by Y ion exchange adsorption onto polymer particles were analyzed by energy dispersive X-ray spectroscopy (EDS).

[0015] Figure 2

[0016] Scanning electron microscopy (SEM) analysis of AG 50W-X4 resin containing yttrium incorporated by adsorption.

[0017] Figure 3

[0018] SEM analysis of existing products on the market containing yttrium doped through precipitation.

[0019] Figure 4

[0020] SEM analysis (magnification) of existing products on the market containing yttrium doped through precipitation.

[0021] Figure 5

[0022] SEM analysis of AG 50W-X4 resin containing yttrium incorporated through adsorption.

[0023] Figure 6

[0024] EDS analysis showed that yttrium (Y) and phosphorus (P) were detected on AG 50W-X4 containing yttrium incorporated through phosphate precipitation.

[0025] Figure 7

[0026] SEM analysis of AG 50W-X4 containing yttrium incorporated via phosphate precipitation.

[0027] Figure 8

[0028] Contains adsorption-incorporated 90 SEM analysis of Y's AG 50W-X4 resin. Detailed Implementation

[0029] The inventors have identified a cancer treatment with a lower risk of off-target side effects based on local therapy using short-range α- and / or β-emitters, particularly suitable for localized radiotherapy, such as brachytherapy and transarterial radioembolization.

[0030] Radionuclide-labeled particles

[0031] One object of the present invention relates to particles comprising a polymer resin that allows for the adhesion of α- and / or β-emitting radionuclides, wherein the leaching of the radionuclides from the particles is sufficiently low to make the particles suitable for cancer therapy. Such particles can be obtained by conjugating polymer particles with one or more suitable functional groups capable of achieving strong binding of the radionuclides to the particles. Examples of strong cationic functional groups capable of strongly binding metal ions are, for example, sulfonic acids and phosphoric acids, which are commonly used in cation exchange resins such as Lewatit® TP 260, AG® 50W, and AG® MP-50 cation exchange resins.

[0032] Therefore, one aspect of the present invention relates to a particle labeled with an α- and / or β-emitting radionuclide, wherein the particle comprises or is composed of a polymer resin conjugated with a sulfonic acid and an ionically bound α- and / or β-emitting radionuclide.

[0033] Preferably, the particles are labeled by cation exchange, wherein the α- and / or β-emitting radionuclides are provided in the form of soluble salts (preferably chloride salts), but may also be provided with alternative anions such as, for example, bromide, iodide, sulfate, sulfite, nitrate, acetate, phosphate, carbonate or oxide, or other suitable alternative anions known to those skilled in the art.

[0034] Preferably, cation exchange is achieved via sulfonic acid groups on a polymer resin, which may be pre-loaded with counterions, such as Na+. + H + Fe 2+ Or similar counterions, to avoid, for example, acidification, the functional groups are preferably loaded with Na before cation exchange with salts that emit α- and / or β-radioactive nuclides. + .

[0035] Example 1 illustrates the preparation of yttrium (Y) labeled particles, wherein cation exchange is performed by using SO3 - Na with functional groups + Ions and from Cl - Released Y 3+ Ion exchange is performed to produce NaCl and yttrium bound to the particles. Therefore, Example 1 demonstrates an example of how α- and / or β-emitting radionuclides can be adsorbed onto the surface of suitable particles to produce particles labeled with α- and / or β-emitting radionuclides as described herein. Furthermore, as shown separately in… Figure 2 and Figure 3 As shown, particles prepared as described herein are generally smoother and have fewer protrusions than particles prepared using precipitation. Typically, smooth surfaces are characterized by their uniform and regular texture, without any noticeable irregularities or protrusions. In the context of this invention, such surfaces are typically spherical and provide a uniform and continuous contact area.

[0036] In contrast, surfaces with protrusions are characterized by raised or uneven elements, resulting in variations in height and texture. These protrusions can take various forms, from small bumps to more complex structures. Surfaces with protrusions are often designed for specific purposes, such as providing a grip, for example, in a patient's artery.

[0037] Surface protrusions can be quantified. Surface protrusion (or roughness) is a function of its measured length scale and the frequency response function of the instrument used to acquire the data. Protrusions with various tip widths and radii are identified by scanning or measuring the surface of particles using two-dimensional and three-dimensional probes. These can all be quantified and compared. Therefore, in the context of this invention, a particle having a smooth surface with few or no protrusions is defined as a particle having fewer than ten protrusions with a minimum height of 1 μm as determined by scanning electron microscopy (SEM). In one or more exemplary embodiments of this invention, a particle having a smooth surface with few or no protrusions is defined as a particle having fewer than ten protrusions with a minimum height of 1 μm as determined by scanning electron microscopy (SEM). In one or more exemplary embodiments of this invention, a particle having a smooth surface with few or no protrusions is defined as a particle having fewer than ten protrusions with a minimum height of 2 μm as determined by scanning electron microscopy (SEM). In one or more exemplary embodiments of the present invention, a particle having a smooth surface with few or no protrusions is defined as a particle having fewer than 50 protrusions with a minimum height of 1 μm as measured by scanning electron microscopy (SEM). In one or more exemplary embodiments of the present invention, a particle having a smooth surface with few or no protrusions is defined as a particle having fewer than 5 protrusions with a minimum height of 2 μm as measured by scanning electron microscopy (SEM).

[0038] In one or more exemplary embodiments of the invention, particles having a smooth surface with few or no protrusions are particles of the invention, wherein the smooth surface with few or no protrusions is defined by a particle surface having fewer protrusions compared to the same particles that have been labeled with phosphate precipitation. As described herein, the precipitation of radioactive nuclides onto particles is well known in the art.

[0039] This is particularly evident in Example 2, which demonstrates a process using 100 times the amount of Y in the preparation of particles, employing the novel process disclosed herein and previous phosphate precipitation methods. Figure 5 (Particles prepared using the new process) and Figure 7 A comparison with particles prepared by a previous phosphate precipitation process shows that the large amount of Y used in particle preparation results in the formation of multiple salt precipitation layers on the particles. Figure 7 This could cause γ-phosphate to peel off from the particles, leading to the unwanted migration of potentially radioactive material from the particles.

[0040] Example 3 further demonstrates that adsorbed on the particles 90The amount of Y exceeds 85%, and particularly exceeds 96%, of the initial radioactivity initially provided in the solution, thereby greatly optimizing the amount of Y transferred to the particles and thus significantly reducing radioactive waste from particle production. Example 4 further demonstrates that the particles exhibit only a very limited leakage of less than 1% under various temperature stresses.

[0041] In principle, the polymer particles can be composed of any suitable polymer or copolymer known to those skilled in the art, which enables them to be used as resins capable of binding functional groups of radionuclides, as described herein.

[0042] The particles shown in Examples 1-3 were produced using a styrene-divinylbenzene copolymer resin, which was activated by the addition of sulfates as described above.

[0043] Alternative polymeric materials include, for example, cellulose-based resins, agarose, polyacrylate resins, polystyrene, and silica gel. In one embodiment, the particles comprise styrene. In other embodiments, the particles comprise divinylbenzene.

[0044] Preferably, the polymer resin constituting the particles is a styrene-divinylbenzene copolymer.

[0045] In the context of this disclosure, "lattice" refers to the three-dimensional arrangement of polymeric components within a particle, preferably a spherical particle comprising cross-linked polymer molecules, as disclosed herein. This arrangement can involve a lattice structure formed by a single type of polymer molecules or by multiple different types of polymer molecules forming a lattice structure through, for example, cross-linking or covalent intermolecular or intramolecular bonding to provide spherical or substantially spherical particles. The components constituting the lattice structure will affect the properties of the particle. In this disclosure, the particles preferably comprise a cross-linked styrene-divinylbenzene copolymer lattice, which produces spherical particles having a specific size distribution and properties as disclosed herein. The lattice structure is preferably conjugated with functional groups (such as, for example, sulfonic acids or phosphoric acids), which allow the binding of radionuclides as disclosed herein.

[0046] Therefore, in this disclosure, the polymer molecules of the particles may comprise a cross-linked polymer lattice. In embodiments, the degree of cross-linking of the cross-linked polymer lattice is about 2%-10%, such as 3%-7%, such as 4%, 6% or 8%, preferably about 4%.

[0047] In the context of this disclosure, "resin" refers to a polymeric structure formulated as particles or beads to achieve desired properties, such as, for example, hardness, chemical resistance, thermal stability, pore size, and particle size. In this disclosure, the resin is preferably formulated as spherical particles having a specific size distribution as disclosed herein, combined with specific functional groups such as sulfonic acid or phosphoric acid, which allows the binding of radionuclides as disclosed herein. Examples of commercially available resins are, for example, Lewatit® TP 260, AG® 50W, and AG® MP-50 resins. In embodiments, the resin is a polystyrene-divinylbenzene sulfonic acid resin.

[0048] The resin of the present invention can have a lattice structure. Therefore, the polymer particle lattice of the present invention can refer to the polymer resin. These terms are used interchangeably. When the resin constituting the particles is a styrene-divinylbenzene copolymer, the resin can be a styrene-divinylbenzene copolymer lattice. Thus, an example of such a type of resin is polystyrene-divinylbenzene sulfonic acid resin.

[0049] In one embodiment, the particles have a size in the range of 5-400 μm, such as 25-250 μm, such as 50-200 μm, such as 100-150 μm, such as greater than 60 μm and less than 150 μm. In another embodiment, the particles have a size in the range of 70-150 μm. In a preferred embodiment, the particles have a size in the range of 20-50 μm, more preferably 30-35 μm. In yet another embodiment, the particles have a size in the range of 5-400 μm, wherein the average particle size is 20-50 μm, preferably 30-35 μm.

[0050] In a preferred embodiment, the particles are substantially phosphate-free. "Substantially phosphate-free" means that the preparation of the particles preferably does not involve a phosphate precipitation step of a radionuclide to immobilize the particles. The phosphate precipitation step is necessary to obtain smooth particles with few or no protrusions, which would otherwise be produced by phosphate precipitation. In the context of this invention, the term "substantially" means that the amount of phosphate is less than the amount of particles prepared using phosphate precipitation. Thus, one or more embodiments of the invention relate to particles of the invention in which the amount of phosphate is less than 100 ppm. Thus, one or more embodiments of the invention relate to particles of the invention in which the amount of phosphate is less than 10 ppm. Thus, one or more embodiments of the invention relate to particles of the invention in which the amount of phosphate is less than 1 ppm. The novel method of adsorbing Y-90 via ion binding rather than phosphate precipitation allows the product to be more stable under temperature-forced degradation conditions, thereby reducing the percentage of Y-90 leaching.

[0051] In a particular embodiment, the particles are composed of a divinylbenzene copolymer. In other embodiments, the divinylbenzene copolymer has a crosslinking degree of 2%-10%, such as 3%-7%, such as 4%, 6% or 8%, preferably about 4%.

[0052] Radionuclides

[0053] The radionuclide of the present invention can be any α- and / or β-emitting radionuclide.

[0054] The main advantage of alpha and / or beta particle emitting compounds in local treatment (e.g., in the liver) is their short duration, compared to other methods such as... 99m Tc, 111 In and 18 Compared to the gamma-emitting particles of F, for example... 212 Bihe 212 Pb α-emitters are typically smaller than 0.1 mm, and for those from sources such as 90 Y、 82 Br and 201 The β particles of Tl's medical β-emitter range from mm to cm.

[0055] The use of α-emitters and β-emitters reduces the risk of toxicity from irradiation of non-target areas (such as adjacent healthy tissues, including blood vessels or even other proximal visceral organs) within the tumor intratumoral environment. Therefore, in a preferred embodiment, the decay of the α- and / or β-emitting radionuclides is primarily α- and / or β-decay.

[0056] In the implementation scheme, α- and / or β-emitting radionuclides are selected from the group consisting of: 90 Y、 225 Ac、 89 Sr、 153 Sm、 159 Gd, 18 F, 68 Cu、 69 Cu、 67 Ga、 99m Tc, 201 Ti、 111 In、 161 Tb, 212 Pb and 177 Lu. More preferably, the α- and / or β-emitting radionuclides are selected from the group consisting of: 90 Y、 68 Cu、 69 Cu、 225 Ac、 177 Lu. Most preferably, the β-emitting radionuclide is... 90 Y. 90Y is preferred because it releases a large amount of β radiation (2.2 MeV) and has a low tissue penetration length (up to 11 mm). Barrio (e.g., etc.), making it particularly suitable for targeted radiotherapy of tumors, such as local area radiotherapy, brachytherapy, or radioembolization. 90 Y is a radioactive isotope of yttrium, with 39 protons and 51 neutrons, and an atomic mass of 90. 90 Y is a β-emitter that decays primarily through β-radiation and then into a stable form. 90 Zr has a half-life of 64.4 hours. 90 Y is from 90 The result of Sr decay, and therefore, 90 Y is 90 Sr's offspring, the 90 Sr decays into 90 Y has a half-life of 29 years, making it a good choice. 90 Y generator, in which the different ionic properties of two materials can be used to... 90 Y and 90 Sr separation. 90 Sr usually from 235 Obtained through the U fission process.

[0057] The emission of gamma radiation is critical for the clinical application of particles as described herein, as high doses of gamma radiation will irradiate patients and those preparing for and / or providing treatment. Therefore, it is preferred that the emission of alpha and / or beta-emitting radionuclides does not exceed 10% of the total decay radiation, such as less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than 0.1% of gamma radiation.

[0058] For radionuclides suitable for therapy, the half-life of the radionuclide is also very important, and preferably, the decay of the particle is within a range that allows for the rapid administration of the required dose of radiation while also allowing the practitioner to prepare and administer the treatment. Therefore, in embodiments, α- and / or β-emitting radionuclides have a decay half-life in the range of 1-300 hours, such as between 10-100 hours or such as 50-70 hours.

[0059] Depending on the type of cancer being treated, each patient uses [the following treatment / treatment] 90The amount of Y can range from 1 kBq to 10 GBq. In examples used for liver cancer such as hepatocellular carcinoma, the dose ranges from 20 MBq to 1 GBq. Therefore, the particles disclosed herein can be prepared in doses ranging from 1 kBq to 10 GBq, such as those between 100-500 MBq, such as approximately 10 MBq, 20 MBq, 30 MBq, 40 MBq, 50 MBq, 60 MBq, 70 MBq, 80 MBq, 90 MBq, 100 MBq, 110 MBq, 120 MBq, 130 MBq, 140 MBq, 150 MBq, 160 MBq, 170 MBq, 180 MBq, 190 MBq, 200 MBq, 210 MBq, 220 MBq, 230 MBq, 240 MBq, 250 MBq, 260 MBq, 270 MBq, 280 MBq, 290 MBq, 300 MBq, 310 MBq, 320 MBq, 330 MBq, 340 MBq, 350 MBq, 360 MBq, etc. 370 MBq, 380 MBq, 390 MBq, 400 MBq, 410 MBq, 420 MBq, 430 MBq, 440 MBq, 450 MBq, 460 MBq, 470 MBq, 480 MBq, 490 MBq, or such as about 500 MBq, may be considered appropriate. The dosage usually depends on the size of the tumor.

[0060] Pharmaceutical Composition

[0061] Another aspect of the invention relates to a pharmaceutical composition comprising particles as disclosed herein.

[0062] The composition may be a particle suspension containing monodisperse or polydisperse particles labeled with α- and / or β-emitting radionuclides.

[0063] The composition is preferably an aqueous composition.

[0064] In an embodiment, the composition comprises particles as disclosed herein, as well as diluents, carriers, surfactants, antiflocculators, and / or excipients.

[0065] Acceptable carriers and drug carriers include, but are not limited to, non-toxic buffer solutions, fillers, isotonic solutions, solvents and co-solvents, antimicrobial preservatives, antioxidants, wetting agents, defoamers, and thickeners. More specifically, drug carriers may be, but are not limited to, physiological saline (0.9%), semi-physiological saline, lactated Ringer's solution, dissolved sucrose, dextran (e.g., 3.3% dextran / 0.3% physiological saline), and water for injection (WFI). Physiologically acceptable carriers may contain radiodegradation stabilizers, such as ascorbic acid or human serum albumin, which protect the integrity of the radiopharmaceutical during storage and transport.

[0066] Pharmaceutical compositions may contain a large number of particles. These particles may be the same or different.

[0067] Therefore, in another embodiment of the invention, the pharmaceutical composition is a particle suspension comprising monodisperse or polydisperse particles labeled with α- and / or β-emitting radionuclides.

[0068] Furthermore, compositions containing particles as disclosed herein comprise a curable adhesive and / or a polymerizable hydrogel. Preferably, the adhesive or hydrogel is biocompatible, such that the adhesive or hydrogel component in the composition does not induce any adverse effects upon application. In the context of this disclosure, a hydrogel is a three-dimensional network of hydrophilic polymer chains capable of absorbing and retaining water or biofluids while maintaining its structural integrity. These materials are highly biocompatible, meaning they are well tolerated by living organisms and can interact with biological systems without causing harm or adverse reactions to the tissues to which they are applied or administered. Within the framework of this invention, hydrogels can be polymerized to form an adhesive structure in which radioactive particles are embedded. Typically, polymerized hydrogels are formed by crosslinking polymer chains, resulting in a stable three-dimensional network structure. These hydrogels are solid or gel-like materials that maintain their shape and integrity in the presence of moisture or biofluids. In contrast, unpolymerized hydrogels are in a liquid or semi-liquid state and lack the crosslinked structure of their polymerized counterparts. These hydrogels are commonly used as injectable biomaterials that allow for in-situ polymerization at the application site, making them suitable for minimally invasive medical procedures, such as intratumoral administration via image-assisted application.

[0069] Biocompatible curable adhesives / glues are specially formulated adhesives that bond biological materials together while protecting their integrity and biocompatibility. They typically provide precise control over the strength and speed of adhesion through a curing process initiated by UV light, controlled heat, or the addition of a curing agent, thereby minimizing damage to sensitive biological tissues. Examples of such biocompatible adhesives include, for instance, BIOGLUE®, composed of bovine serum albumin cross-linked and cured using glutaraldehyde; and fibrin glue containing the protein fibrinogen and the protein curing agent thrombin. Various suitable alternatives are known to those skilled in the art, such as collagen-based adhesives, alginate adhesives, and gelatin adhesives. In the context of this invention, a biocompatible adhesive is to be understood as an adhesive that is a specialized adhesive material designed for adhesion to biological tissues or medical devices while minimizing adverse reactions or harm to living organisms. Such adhesives are formulated to be substantially non-toxic, non-irritating, and compatible with the human body or other biological systems. This type of adhesive is formulated to be substantially non-toxic, non-irritating, and compatible with the human body or other biological systems. Biocompatible adhesives are commonly used in medical applications such as wound closure, tissue transplantation, and the assembly of implantable devices, where they provide strong and durable adhesion without causing inflammation, toxicity, or other adverse biological reactions. Therefore, it is preferable that biocompatible adhesives, as disclosed herein, have minimal toxicity or irritation to surrounding tissues (when such tissues are non-cancerous).

[0070] In one embodiment, the composition comprises a portion of a two-component adhesive, such as, for example, BIOGLUE® (Artivion Inc.; Atlanta, GA), which comprises a first component of bovine serum albumin and a second component of glutaraldehyde.

[0071] In one embodiment, the composition comprises a divinylbenzene copolymer resin. 90 Y-labeled particles. In embodiments, the composition also comprises bovine serum albumin and / or glutaraldehyde.

[0072] In another embodiment, the compositions disclosed herein are pharmaceutical compositions, injectable compositions, or pharmaceutical preparations.

[0073] In the implementation scheme, the pharmaceutical composition is prepared using a radionuclide in amounts ranging from 1 kBq to 10 GBq per administration.

[0074] For example, if 100 patient doses are produced in a batch per day, each of the 100 doses manufactured can consist of a total of 1-10 GBq.

[0075] In another embodiment of the invention, a pharmaceutical composition is prepared with a radionuclide in an amount (e.g., 50 MBq to 1000 GBq) suitable for multi-dose industrial-scale production.

[0076] A method for producing radiolabeled particles

[0077] The present invention also relates to a method for producing particles labeled with α- and / or β-emitting radionuclides.

[0078] First, α- and / or β-emitters are provided, for example in salt form or aqueous solution form, such as containing... 90 Aqueous solutions of Y or containing 90 Powdered YCl3, or another α- and / or β-emitting radionuclides or their salts as disclosed herein.

[0079] Subsequently, the α- and / or β-emitters are mixed with a particle suspension containing functionalized particles to bind to, for example, a solution. 90 The Y particle. Such functional groups can be, for example, phosphoric acid, sulfonic acid, or combinations thereof. Importantly, the functional group should be able to bind α- and / or β-emitters in aqueous solutions with pH within the physiological range.

[0080] After the radionuclide and particles are mixed, the suspension is preferably left to stand for a period of time (i.e., the labeling time), which allows the radionuclide to bind to the particles, for example, through cation exchange between ion-binding functional groups on the particles and cationic radionuclides. This can continue for, for example, about 60 minutes after the step, such as a duration not exceeding 30 minutes, such as a duration not exceeding 15 minutes. The mixing of the particles with the α- and / or β-emitters is typically followed by a separation step, which may also include several washing steps. For example, as shown in Examples 1 and 2, the mixing can be carried out, for example, in a reaction vessel, such as a chromatographic column or a tube containing a filter suitable for separating the particles and the aqueous solution containing the unbound radionuclide, such as, for example, a polypropylene assembly tray, column, or the like. Alternatively, separation and washing can be carried out, for example, by centrifugation, where the particles and the aqueous solution are separated into liquid-liquid and particle-liquid phases. Other alternative separation methods for separating labeled particles and unbound radionuclides are well known to those skilled in the art.

[0081] However, the optimal time for binding will depend on the specific radionuclide and its binding kinetics with the particle. The half-life of a particular radionuclide is crucial; therefore, the shorter the half-life of the radionuclide, the shorter the process steps should be to maintain the highest possible radiation dose.

[0082] The inventors have discovered herein that the method provided herein offers a faster and more efficient particle labeling method compared to available methods, which additionally include a precipitation step for ion fixation, a process that is both time-consuming and reduces the overall recovery rate of α- and / or β-emitting radionuclides because more ions will detach from the particles during the precipitation step. Therefore, the method proposed herein for producing radioactive particles generates less waste and consumes less raw material compared to particles produced according to currently available methods. Furthermore, precipitation, such as by rapidly adjusting the pH through the addition of phosphates (e.g., sodium phosphate), creates protrusions on the particle surface, which can lead to the accidental detachment of α- and / or β-emitting radionuclides from the particles. Therefore, by using phosphate precipitation, the amount of radioactivity in each particle is limited to an amount that does not lead to detachment. Therefore, in the preparation of the particles of the present invention, it is preferable that the method does not include fixing the radionuclides to the particles by phosphate precipitation. Thus, the method of the present invention is capable of preparing α- and / or β-emitting radionuclide-labeled particles that are substantially phosphate-free.

[0083] Therefore, as disclosed herein, the inventors have discovered that the amount of α- and / or β-emitting radionuclides that can be bound to particles using the methods disclosed herein is higher than that possible by conventional means. This yields the potential benefit that fewer particles are needed to produce the same or similar dose due to the higher loading capacity on each particle; furthermore, higher doses are also permitted because the effective amount of particles that can be delivered is substantially the same, while the radioactivity per particle may be higher compared to particles containing precipitated and fixed α- and / or β-emitting radionuclides.

[0084] Therefore, in embodiments, the present invention also relates to a method for producing particles labeled with α- and / or β-emitting radionuclides as disclosed herein and / or pharmaceutical compositions disclosed herein.

[0085] The method includes: - Provide α- and / or β-emitting radionuclides or their salts, - Provides particles of a polymer resin having sulfonic acid and / or phosphonic acid, preferably sulfonic acid conjugated. - The α- and / or β-emitting radionuclides and the particles are mixed in an aqueous solution with a pH range of 6.5-9.5. - Separate α- and / or β-emitted radionuclide-labeled particles from the aqueous solution.

[0086] Therefore, the methods disclosed herein may include providing a salt of a nuclide, preferably 90 Y, such as 90 YCl3 or 90Y2(SO4)3、 90 Y3(CH3CO2)3, Y(NO3)3, or other salts. Additionally, the particles provided by the method are preferably conjugated with sulfuric acid and preferably contain divinylbenzene copolystyrene. Examples of particles suitable for preparing α- and / or β-emitting radionuclide-labeled particles are, for example, AG® 50W or AP® MP-50 or Aminex 50W-X4, X6 resins (BioRad), SulfopropylSepharose™ resins (GE Lifescience), and other sulfopropyl or sulfate-conjugated agarose, dextran, or similar resins.

[0087] In other embodiments, the present invention relates to a method for producing α- and / or β-emitting radiolabeled particles and / or pharmaceutical compositions disclosed herein, the method comprising: - supply 90 Y salt, preferred 90 YCl3, - Provides sulfonate-functionalized styrene-divinylbenzene copolymer particles, said particles having a size of 5-400 μm, preferably in the range of 20-125 μm, more preferably in the range of 20-50 μm, and most preferably about 30-35 μm. - The salt and the particles are mixed in an aqueous solution with a pH range of 6.5-9.5, and - Separation from the aqueous solution 90 Y-labeled particles.

[0088] In the implementation plan, the mixing and separation steps are performed within 60 minutes of each other, such as no more than 30 minutes, such as no more than 15 minutes.

[0089] In solution, pH can be critical for some applications for several reasons, such as suitability for injection, where pH ranges far exceeding physiological pH can cause undesirable tissue irritation. For example, if the pH is greater than 9, this could lead to vascular irritation when the suspension is injected into an artery during a TARE (SIRT) procedure. For these reasons, the pH is preferably in the range of 7-9, preferably less than pH 8.5, such as less than pH 7.5, such as about pH 7.4.

[0090] As shown in Examples 1 and 2, the methods disclosed herein enable the labeling of particles with different radionuclide to particle ratios, and also enable the labeling of particles with a radionuclide to particle ratio that causes detachment from the particles when phosphate precipitation is used.

[0091] Therefore, in the embodiments, the weight ratio of the radionuclide to the particle is in the range of 1:40 to 1:6000 (mg / mg), such as in the range of 1:100 to 1:6000, such as in the range of 1:1000 to 1:6000, such as about 1:5000. The weight ratio of the radionuclide to the particle can be in the range of 1:40 to 1:6000, such as in the range of 1:50 to 1:5000, or such as in the range of 1:60 to 1:4000. Suitable subranges within this broad range include, but are not limited to, 1:50 to 1:3000, 1:75 to 1:2500, 1:100 to 1:2000, 1:150 to 1:1500, and 1:200 to 1:1000, with other exemplary subranges being 1:45 to 1:100, 1:100 to 1:1000, and 1:1000 to 1:6000. In an embodiment, the weight ratio of the radionuclide to the particle is approximately 1:5800. In an embodiment, the weight ratio of the radionuclide to the particle is greater than 1:5800, such as greater than 1:5000, 1:4000, 1:3000, 1:2000, 1:1000, 1:500, 1:250, 1:100, or such as greater than 1:75.

[0092] Therefore, in another embodiment, the weight ratio of the radionuclide to the particle is in the range of 1:40 to 1:1000, such as in the range of 1:50 to 1:100, 1:45 to 1:75, such as about 1:50. In another embodiment, the weight ratio of the radionuclide to the particle is about 1:53.

[0093] To prepare labeled particles for application, it is preferable to prepare the labeled particles in an aqueous suspension, wherein such an aqueous suspension may contain, for example, a buffer such as acetate, phosphate, citrate, or glutamate in addition to water for injection (WFI). Alternatively, the particle suspension may consist essentially of particles labeled with α- and / or β-emitting radionuclides and water for injection (WFI).

[0094] Furthermore, for several ions, water-soluble anionic hydroxides can be formed (such as, for example, [Y[OH]4)). - The possibility of this could lead to the removal of bound α- and / or β-emitting radionuclides from the particle.

[0095] Furthermore, the method may also include combining a suspension of particles labeled with α- and / or β-emitting radionuclides with a biocompatible adhesive. The adhesive may be, for example, a one-component adhesive or a two-component or multi-component adhesive, wherein the adhesive cures once applied to the intended site (such as, for example, a tumor). Curing of a one-component adhesive can be achieved by heating, oxygen, UV light, or similar methods. Curing of a two-component adhesive typically involves mixing a first component and a second component, and then the mixture of the two components initiates the curing of the adhesive. Examples of such curable two-component adhesives are, for example, BIOGLUE®, which contains two components: bovine serum albumin and glutaraldehyde; VISTASEAL™, which contains the components fibrinogen and thrombin; hyaluronic acid-based adhesives; and gelatin-based adhesives.

[0096] Therefore, the methods provided herein can be used to prepare compositions, pharmaceutical compositions, and / or injectable compositions containing particles labeled with α- and / or β-emitting radionuclides.

[0097] Furthermore, as shown in Example 8, the radionuclide-labeled particle suspension prepared according to the present invention has a low leaching rate, up to 150. After C heat treatment for 30 minutes, the leaching rate of radionuclides was as low as 0.005%.

[0098] In particular, this low leaching rate further enables the use of autoclaves and / or other heat-intensive sterilization methods after the preparation of radionuclide particle suspensions as disclosed herein.

[0099] Furthermore, the low leaching rate at high temperatures enables the radionuclide particle suspension produced according to the methods disclosed herein and the bioglue containing the radionuclide particle suspension to be used in procedures with heat-intensive components, such as laser surgery, without experiencing any significant increase in leaching of the radionuclide from the insertion site.

[0100] In another embodiment, the present invention relates to a method for preparing cured... 90 A method for preparing a gamma-ray radiation therapy composition, the method comprising: a) Provide, i. 90 Y-labeled particle suspension ii. Uncured biocompatible adhesives and / or nonpolymeric hydrogels in aqueous solution, iii. A curing agent and / or a polymerizing agent, which, when mixed with ii) or i) and ii), induces the curing of the biocompatible adhesive and / or the polymerization of the hydrogel, and b) Mix i, ii, and iii to obtain cured product. 90A gamma-ray radiotherapy composition, wherein the cured 90Y radiotherapy composition comprises a biocompatible adhesive and / or hydrogel embedding. 90 Y-ray radiotherapy particles.

[0101] In the context of this disclosure, "curing" refers to the state in which the adhesive has completed its transformation from a liquid or malleable form to a solid or semi-solid state. Depending on the type of adhesive, this transformation occurs through a chemical reaction, exposure to a specific catalyst, ultraviolet (UV) light, or high temperature. Once cured, the adhesive forms a strong, permanent bond between surfaces, exhibiting properties such as strength, stability, and resistance to external factors.

[0102] In one embodiment, the uncured biocompatible adhesive is albumin. In another embodiment, the nonpolymeric hydrogel comprises one or more components selected from the list of compositions including: chitosan, hyaluronic acid, collagen, gelatin, elastin, alginate, cellulose, and glycosaminoglycans. In yet another embodiment, the curing agent may be, for example, glutaraldehyde or similar amide crosslinking agents, such as NHS-based or imine ester-based crosslinking agents; or hydroxyl-targeted crosslinking agents, such as diglycidyl ether (DDE)-based crosslinking agents.

[0103] Reagent test kit

[0104] In another aspect, the present invention also relates to kits for producing particles and / or compositions as disclosed herein.

[0105] In particular, the present invention also relates to a kit comprising: unlabeled particles comprising or composed of a polymeric resin conjugated with or consisting of a sulfonic acid; optionally, reagents for preparing α- and / or β-emitting radionuclide-labeled particles or pharmaceutical compositions as disclosed herein; and optionally, instructions for preparing said particles or pharmaceutical compositions.

[0106] The kit may also contain an aqueous solution containing an uncured, curable biocompatible adhesive and / or a nonpolymer hydrogel in the aqueous solution.

[0107] The kit may also contain an aqueous solution containing a curing agent and / or a polymerizing agent.

[0108] In some embodiments, the curable biocompatible adhesive is preferably albumin, more preferably bovine serum albumin; in other embodiments, the curing agent and / or polymerizing agent is an amide crosslinking agent, preferably glutaraldehyde.

[0109] The kit enables practitioners to produce the particles and / or compositions disclosed herein directly, thereby greatly simplifying the process of providing appropriate therapeutic doses without requiring the large-scale and laborious preparation of radioactive particles.

[0110] Therefore, the present invention also relates to a method for preparing cured [material]. 90 A method for providing a gamma-ray therapy composition in an aqueous solution, the method comprising... 90 The method may further include providing a curing agent and / or a polymerizing agent that, when mixed with the biocompatible adhesive and / or nonpolymerized hydrogel, induces the curing of the biocompatible adhesive and / or the polymerization of the hydrogel. The curing or polymerization of the biocompatible adhesive and / or nonpolymerized hydrogel may also be initiated by other external factors such as, but not limited to, exposure to UV radiation, heat, and / or air. Therefore, the method may include using a curing agent and / or a polymerizing agent to cure and / or polymerize the... 90 A gamma-ray therapy composition wherein the curing agent and / or polymerizing agent induces the curing of the biocompatible adhesive and / or the polymerization of the hydrogel when mixed with the uncured biocompatible adhesive and / or non-polymerized hydrogel, or initiates curing by exposure to UV radiation, heat, and / or air, thereby obtaining a cured / polymerized product. 90 Y-ray radiotherapy composition.

[0111] Solidified or polymerized compositions can be particularly suitable, for example, for cancer treatment, where it is necessary that the radioactive components of the treatment be kept in a suitable location within a recessed environment to reduce the potential risk of particle migration, where particles may migrate to unintended tissues and result in unwanted and harmful irradiation.

[0112] Medical devices

[0113] In one aspect of the invention, the particle according to the invention is a medical device or is contained in a medical device.

[0114] A medical device is any instrument, equipment, appliance, software, material or other article, whether used alone or in combination, including software that the manufacturer intends specifically for diagnostic and / or therapeutic purposes and which is necessary for its proper application, and which the manufacturer intends for human use for the following purposes: diagnosis, prevention, monitoring, treatment or relief of disease; diagnosis, monitoring, treatment, relief or compensation of injury or disability; study, replacement or modification of anatomical structures or physiological processes; control of conception; and whose primary intended effect is not achieved in or on the human body by pharmacological, immunological or metabolic means, but may be aided by such means.

[0115] Medical devices vary depending on their intended use and indications. Examples range from simple devices such as tongue depressors, medical thermometers, and disposable gloves to advanced devices such as computers that assist in medical testing, implants, and prostheses.

[0116] According to the FDA, a medical device is "an instrument, apparatus, appliance, machine, device, implant, in vitro reagent or other similar or related article, including parts or accessories, which: are recognized in the United States National Formulary or the United States Pharmacopeia or any supplement thereof, are intended for the diagnosis of a disease or other ailment, or for the cure, relief, treatment or prevention of a disease in a human or other animal, or are intended to affect the structure or any function of the body of a human or other animal, and whose primary intended purpose is not achieved by chemical action in or on a human or other animal, and is not dependent on metabolism to achieve its primary intended purpose."

[0117] The particles are carriers of radioactive material, which are designed to have limited chemical effects (if any) in the body, and this allows radiotherapy to have very limited unwanted side effects, such as toxicity.

[0118] Therefore, in one implementation, the term "medical device" is understood to be the FDA definition above.

[0119] Medical use

[0120] In certain embodiments, the particles or compositions disclosed herein are used as pharmaceuticals.

[0121] In particular, medical uses of the particles or compositions disclosed herein include human or veterinary uses in the following areas: (1) localized radiotherapy such as brachytherapy, (2) radioembolization, particularly transarterial radioembolization, (3) endovascular treatment, and (4) radiotherapy for synovectomy.

[0122] In a preferred embodiment, the particle or pharmaceutical compositions disclosed herein are used for localized radiotherapy, such as brachytherapy and transarterial radioembolization (TARE). Transarterial radioembolization (TARE) is also known as selective internal radiotherapy (SIRT). Therefore, one embodiment of the invention relates to the use of the particle or pharmaceutical compositions disclosed herein for transarterial radioembolization (TARE). Another embodiment of the invention relates to the use of the particle or pharmaceutical compositions disclosed herein for brachytherapy.

[0123] Localized radiotherapy is a procedure that precisely directs ionizing radiation to eliminate or destroy cancer cells in specific local and regional areas, thereby avoiding off-target effects and / or systemic exposure to the radiation source. This approach primarily targets the tumor and its adjacent tissues, thus reducing the likelihood of local and regional recurrence. It can be administered externally or internally and is often used in combination with other cancer therapies such as surgery, chemotherapy, and targeted therapies (such as, but not limited to, immunotherapy) to provide optimal therapeutic benefit while minimizing adverse effects on surrounding healthy tissues and organs. Therefore, in preferred embodiments, particles such as those disclosed herein are used in localized radiotherapy.

[0124] Brachytherapy is a specialized and precise form of localized radiation therapy. It involves placing a fixed radiation source directly inside or very close to the tumor, allowing for the delivery of high doses of radiation to a more localized area. This helps minimize damage to surrounding healthy tissue. Brachytherapy is particularly effective for prostate, cervical, liver, and breast cancer, allowing for targeted therapy with fewer side effects. The precise nature of brachytherapy makes it a viable option for tumors located in critical body structures where precision is paramount.

[0125] Therefore, compositions containing radioactive particles and biocompatible adhesives, as disclosed herein, are particularly suitable for brachytherapy because they enable the delivery of high doses of radiation to specific areas (such as tumors), and because the adhesive cures once applied, the radiation dose is held in place. As mentioned, curing reduces the side effects associated with classic radiotherapy.

[0126] Therefore, in a preferred embodiment, particles such as those disclosed herein are used for brachytherapy.

[0127] TARE is a medical procedure used to treat liver tumors, such as primary hepatocellular carcinoma or secondary liver cancer. During TARE, radioactive microspheres are injected directly into the blood vessels supplying the tumor. These microspheres emit radiation that targets and destroys cancer cells while protecting healthy tissue. TARE can help shrink tumors, relieve symptoms, and improve the quality of life for patients who are not suitable for surgery (including hepatectomy and orthotopic liver transplantation) or other treatments, providing a targeted and well-tolerated option for controlling certain liver malignancies and other types of malignancies.

[0128] In embodiments, the particles of the present invention or compositions containing said particles are also suitable for transarterial radioembolization.

[0129] In other embodiments, the particles of the present invention or compositions containing said particles are used to treat or improve cancer.

[0130] Therefore, the use of the particles or compositions disclosed herein may also include the treatment or improvement of cancers, such as, for example, head and neck squamous cell carcinoma, metastatic melanoma, sarcoma, non-small cell lung cancer, colorectal cancer, primary and secondary hepatocellular carcinoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, ovarian cancer, muscle-invasive bladder cancer, prostate cancer, and / or osteosarcoma, preferably unresectable hepatocellular carcinoma and / or locally advanced borderline resectable pancreatic ductal adenocarcinoma. Preferably, the particles or compositions disclosed herein are used to treat unresectable hepatocellular carcinoma.

[0131] Transarterial radioembolization can include treating primary or metastatic cancer in an organ (e.g., the liver) by administering the particles of the present invention to blood vessels leading to a tumor in the liver or another solid organ infiltrated by tumor tissue.

[0132] Furthermore, depending on the size, density, location, and surrounding tissues of the tumor, different doses may be preferred for different types of metastatic cancer. 90 Y.

[0133] In radionuclide therapy, the gray (Gy) is the basic unit used to quantify radiation dose. This measurement represents the amount of ionizing radiation energy deposited within biological tissue. One gray is equivalent to one joule of energy absorbed per kilogram of tissue (1 Gy = 1 J / kg). Grays are crucial for determining the optimal radiation dose delivered to the targeted tissue or tumor while minimizing damage to surrounding healthy tissue.

[0134] Choosing the appropriate radiation dose (Gray) depends on factors such as the type and stage of the disease, the specific radionuclide used, the affected tissue or organ, and the individual patient's characteristics. Before treatment, practitioners typically calculate the required dose to be administered, tailored to each patient's unique medical condition.

[0135] Radionuclide therapy is a specialized field within nuclear medicine, where gray (Gy) plays a crucial role in ensuring safe and effective radiation therapy. By maintaining this balance, medical professionals can optimize treatment outcomes while minimizing potential side effects. For example, for HCC, 120 Gy is generally considered a reasonable minimum target dose, and the more precise the target of treatment, the higher the dose that can be administered. For other indications, lower or higher doses may be advantageous. Therefore, in implementation methods, the target absorbed dose is in the range of 1 Gy to 500 Gy, such as between 50 Gy and 400 Gy. Between Gy, such as approximately 50 Gy, 60 Gy, 70 Gy, 80 Gy, 90 Gy, 100 Gy, 110 Gy, 120 Gy, 130 Gy, 140 Gy, 150 Gy, 160 Gy, 170 Gy, 180 Gy, 190 Gy, 200 Gy, 210 Gy, 220 Gy, 230 Gy, 240 Gy, 250 Gy, 260 Gy, 270 Gy, 280 Gy, 290 Gy, 300 Gy, 310 Gy, 320 Gy, 330 Gy, 340 Gy, 350 Gy, 360 Gy, 370 Gy, 380 Gy, 390 Gy, or such as approximately 400 Gy. Preferably, the target absorbed dose is in the range of 40-300 Gy, such as about 40, 50, 60, 70, 80, 100, 150, 200, 250 or about 300 Gy.

[0136] In addition, MBq (megabecq) is also commonly used to measure the actual dose delivered to the patient, where the dose in the syringe can be easily measured and compared with the amount of radioactive material present in the syringe after injection, and the active dose delivered to the patient can be easily calculated.

[0137] In the implementation, the active dose delivered to the patient is in the range of 1 kBq to 10 GBq, such as in the range of 10-50 MBq, such as in the range of 50-500 MBq, such as in the range of 500 MBq to 1 GBq, or such as in the range of 1 GBq to 3 GBq, or such as in the range of 3-10 GBq.

[0138] In the implementation plan, the particles are applied directly to the tumor.

[0139] Another aspect of the invention relates to a treatment or improvement method comprising administering to an individual in need a particle or pharmaceutical composition as disclosed herein.

[0140] In the embodiments described herein, the particles and / or compositions are administered via the hepatic artery.

[0141] In certain embodiments, the particles and / or compositions are used to treat hepatocellular carcinoma, including but not limited to injection or application into the lesion, or injection or application to the treatment site after lesion resection. Furthermore, treatment may include intratumoral application or application to distant metastatic sites.

[0142] In implementation methods, the compositions disclosed herein are used for single treatment or repeated administration.

[0143] Imaging

[0144] Radionuclide imaging utilizes beta-emitting radionuclides to visualize internal structures and assess physiological functions within the human body. Beta-emitting radionuclides (such as...) 99m Tc and 131 I) They are commonly used in this imaging modality because they are capable of emitting beta particles (which are high-energy electrons or positrons). The particles of the present invention are preferably administered intratumorally, thereby allowing direct targeting to the target-specific tissue and / or organ of interest. Once administered, the beta-emitting radionuclide undergoes radioactive decay, emitting beta particles that can be detected by a gamma camera or a positron emission tomography (PET) scanner. Furthermore, radionuclide imaging can also be used to evaluate the injection site of the particles and / or compositions described herein.

[0145] Therefore, in the embodiments, the particles and compositions described herein can be used for radionuclide imaging.

[0146] It should be understood that any features and / or aspects of the compound discussion above in connection with the present invention are applicable by analogy to the methods described herein.

[0147] The following figures and embodiments are provided to illustrate the present invention. These embodiments are intended to be illustrative and should not be construed as limiting in any way.

[0148] Example

[0149] Example 1 - Incorporation of Yttrium into Cation Exchange Resin

[0150] Purpose

[0151] This embodiment aims to demonstrate that it is possible to incorporate yttrium into microspheres through adsorption at neutral pH without precipitating it as insoluble phosphate.

[0152] Material

[0153] raw materials

[0154] Anhydrous YCl3 from Sigma-Aldrich

[0155] AG 50W-X4 resin 200-400 from BioRad Laboratories, Inc.

[0156] method

[0157] 0.04 M dilute HCl contains 0.1-300 GBq of yttrium (90Y) per ml, which is equivalent to 0.005-15 micrograms of yttrium [90Y] (in the form of yttrium [90Y] chloride) at the reference date and time.

[0158] In this embodiment, 89Y is used instead of 90Y, and the amount of yttrium is calculated from the expected dose / mL in order to simulate the expected radiation dose required in the final vial.

[0159] Therefore, in order to achieve 1 mL 90 Y was used in a sterile solution of 0.04 M HCl to achieve a dose of 1.5 GBq (1 μmol). 90 Y reaches 1.5 Gbq 90 Y), calculated that approximately 90 μg of yttrium (89Y or 90Y) is required for every 530 mg of dry resin.

[0160] The program has been tested through four main steps: - Resin titration; - Prepare the resin as a sodium salt; - Prepare YCl3 solution; - Adsorb yttrium onto the resin.

[0161] Resin titration 1.6 g of AG 50W-X4 cation exchange resin (supplier: Bio-Rad Laboratories, Inc., code #1421351, sulfonic acid functional group) was added to a 5 ml syringe equipped with a polypropylene sintering pan and washed with 1.0 M NaOH to perform cation exchange until the pH of the collected aqueous phase was above pH 7 (alkaline), indicating that the ion exchange was terminated. The collected aqueous phase was titrated with 1.0 M HCl until the pH was neutral (approximately pH 7). 3.5 mmol of NaOH was required for cation exchange, indicating that the loading of dry resin corresponds to 6.5 mmol of active sites per 1.0 g of resin.

[0162] The resin is prepared as a sodium salt: This step aims to generate 530 mg of phosphate-free resin using a 1.5 GBq solution of 90-Y. 1.5 to 1.7 g of AG 50W-X4 cation exchange resin is added to a 5 ml syringe equipped with a polypropylene disc. The resin is washed; first with 3.5 ml of 1.0 M NaOH for cation exchange, then four times with 2 ml of water for injection (WFI) to condition the resin to sodium salt.

[0163] Preparation of YCl3 solution and adsorption of yttrium onto resin: First, 90 µg of anhydrous YCl3 was dissolved in 1 ml of 0.04 M HCl to obtain a homogeneous solution. Second, 0.4 ml of 0.1 M NaOH was added to the yttrium chloride solution to achieve a neutral pH.

[0164] Add the neutralized YCl3 solution to the syringe containing the resin, and rinse the yttrium vial and syringe with 1 ml of water. Then gently shake the mixture for 15 minutes to allow yttrium to adsorb onto the activated resin microspheres.

[0165] The final solution was filtered and the resin was washed multiple times with WFI.

[0166] Energy dispersive X-ray spectroscopy (EDS) was performed to verify the doping of yttrium into the particles.

[0167] Furthermore, the yttrium-labeled particles were imaged using scanning electron microscopy and compared with particles prepared by precipitating yttrium phosphate onto the particles.

[0168] result

[0169] like Figure 1As shown, energy-dispersive X-ray spectroscopy (EDS) analysis of the produced particles indicates that the procedure allows yttrium to be adsorbed onto the resin, verifying that yttrium adsorbs onto the cation exchange resin at neutral pH without the use of phosphate and without metal precipitation. The stoichiometry presented for yttrium adsorption can be replicated for other metals, such as, for example, holmium, lutetium, or actinium.

[0170] Figure 2 The product presented in the image is shown by scanning electron microscopy (SEM) and compared with particles prepared by phosphate precipitation according to existing techniques (see [link to image]). Figure 3 and Figure 4 (This shows a denser structure with a rough surface due to precipitation) compared to the uniform and thin surface of microspheres. This rough structure may be more easily leached under changing environmental conditions (such as, for example, changes in pH).

[0171] Therefore, the yttrium-90 produced according to the described process and bonded to biodegradable microspheres provides an improved and simplified labeling method.

[0172] Example 2 - Incorporation of high concentrations of YCl3 into cation exchange resin

[0173] Purpose

[0174] The purpose of this embodiment is to test the feasibility of doping particles with a large amount of yttrium. Experiments were conducted using a novel method and phosphate precipitation.

[0175] Material

[0176] raw materials

[0177] Anhydrous YCl3 from Sigma-Aldrich

[0178] AG 50W-X4 resin 200-400 from BioRad Laboratories, Inc.

[0179] Na3PO4 solution 1.25% w / v (weight / volume) (mm = 163,941 g / mol)

[0180] 0.1 M phosphate buffer solution, pH 7.5

[0181] method

[0182] New method: Resin titration: The resin was titrated as described in Example 1.

[0183] The resin is prepared as a sodium salt:Add 1.5 to 1.7 g of AG 50W-X4 cation exchange resin to a 5 ml syringe equipped with a polypropylene sintering plate. First, wash the resin with 3.5 ml of 1.0 M NaOH for cation exchange, then wash four times with 2 ml of WFI to condition the resin to sodium salt.

[0184] Preparation of YCl3 solution and adsorption of yttrium onto resin: 10 mg (10 mg) of anhydrous YCl3 was dissolved in 0.04 M HCl to obtain a homogeneous solution. 0.4 ml of 0.1 M NaOH was added to the yttrium chloride solution to achieve a neutral pH.

[0185] Add the neutralized YCl3 solution to the syringe containing the resin, and wash the yttrium vial and syringe with 1 ml of water. Then gently agitate the mixture for 15 minutes to allow yttrium to adsorb onto the activated resin microspheres. Filter the final solution and wash the resin several times with WFI.

[0186] Phosphate precipitation method: In short, the phosphate precipitate particles are prepared according to the following steps: - Dissolve 10 mg of YCl3 in 2.0 mL of 0.1 M H2SO4, and then add the yttrium sulfate solution into a syringe containing resin.

[0187] - Add 2.0 mL of Na3PO4 solution (1.25% w / v) to the reaction vessel to precipitate yttrium phosphate onto the resin (AG 50W-X4, as in Example 1).

[0188] - Wash the particles several times with 2.0 mL of 0.1 M phosphate buffer (pH 7.5) until the pH stabilizes. Wash the microspheres with 2.0 mL of water for injection.

[0189] result

[0190] To overemphasize the process and demonstrate that it is possible to combine more yttrium using the process disclosed in Example 1, yttrium in an amount 100 times greater than that commonly used in previous methods was adsorbed onto the AG 50W-X4 cation exchange resin using the current process. The resulting particles were compared with particles prepared using phosphate precipitation according to currently available methods, also using 100 times the amount of yttrium.

[0191] Scanning electron microscopy (SEM) of the product reveals a uniform and thin surface of microspheres. Figure 5The results show that the procedure allows yttrium to be adsorbed onto the resin, leading to the conclusion that it is possible to incorporate yttrium into the resin at neutral pH without the use of phosphates and without metal precipitation, even with more than 100 times the amount of yttrium.

[0192] Energy dispersive X-ray spectroscopy (EDS) analysis of phosphate precipitates Figure 6 The procedure allows yttrium to precipitate onto the resin in the form of phosphate.

[0193] from Figure 7 As can be seen, when using high yttrium amounts, particles prepared using the phosphate precipitation method with high yttrium amounts cannot ensure a stable structure due to the deposition of multiple layers of phosphate, which leads to the leaching and exfoliation of free yttrium from the particles. If the pH is maintained at 12.5, there is a risk of forming water-soluble anionic hydroxides [Y(OH)4], which may cause yttrium-90 to be removed from the surface of the microspheres. Furthermore, if the pH is greater than 9, this may cause vascular irritation when the suspension is injected into an artery. For these reasons, the pH is preferably less than 8.5, more preferably less than 7.5, but more preferably about 7.4.

[0194] This embodiment thus demonstrates that, compared to conventional processes, a process using more than 100 times the amount of yttrium still allows for the adsorption of a large amount of yttrium onto the microspheres, and that the adsorbed yttrium does not leach out of the particulate material under physiological conditions.

[0195] Example 3 - Measurement and Production of Radioactive Particles

[0196] Purpose

[0197] This embodiment aims to demonstrate that it is possible to measure and produce radioactive particles using the novel process described in Example 1, by incorporating radioactive yttrium (90 yttrium) into the spheres through adsorption at neutral pH without precipitating it as insoluble phosphate.

[0198] Material

[0199] raw materials

[0200] 90YCl3 from Eckert & Ziegler

[0201] AG 50W-X4 resin 200-400 from BioRad Laboratories, Inc.

[0202] method

[0203] The program has been tested through 6 main steps: - Resin titration; - Prepare the resin as a sodium salt; - Prepare a 90% YCl3 solution; - Adsorb 90 Yttrium onto the resin; - Extraction and elution stages are performed by washing Y-90 resin; - Calculation of process yield.

[0204] Resin titration: The resin was titrated as described in Example 1.

[0205] The resin is prepared as a sodium salt: Add 1.5 to 1.7 g of AG 50W-X4 cation exchange resin (AG 50W-X4 Resin 200-400 from BioRad Laboratories, Inc.) to the vacuum filter. Wash the resin with 4.0 mL of 1.0 M NaOH to perform cation exchange. Apply vacuum until the resin is dry. Check the pH of the collected fraction (acceptance standard pH 11-13). Then wash the resin four times with 50 mL of water for injection (WFI), for a total of 200 mL, to complete the resin conditioning to sodium salt. Apply vacuum until the resin is dry. Check the pH of the collected fraction (acceptance standard pH = 6.00-8.00).

[0206] Preparation of 90YCl3 solution and adsorption of 90YT onto resin: The resin was collected from the vacuum filter and transferred to a 50 mL polypropylene tube.

[0207] The radioactivity of a 0.1 mL original sample of 90YCl3 (from Eckert & Ziegler) was measured in a dosimeter.

[0208] A homogeneous solution was obtained by diluting 0.1 mL of 90YCl3 sample with 0.90 mL of 0.04 N HCl. 0.4 mL of 0.1 M NaOH was added to the yttrium chloride solution to achieve a neutral pH (acceptance standard: 6.00–8.00). The radioactivity of the diluted 90Y sample was measured using a dosimeter.

[0209] Using a syringe, transfer the neutralized 90YCl3 solution into a 50 mL propylene tube containing resin. Using the same syringe, wash all the 90YCl3 solution in the syringe with 1 mL of water and push it onto the resin tube. Then gently agitate the mixture for 15 minutes to allow 90YCl3 to adsorb onto the activated resin microspheres.

[0210] After the transfer was completed, the remaining radioactivity in the 90 yttrium vial was measured using a dosimeter.

[0211] The extraction and elution stages are performed by washing the Y-90 resin: Place the funnel containing polyethylene glass frit on the ring rack, and place a new 50 mL polypropylene tube below (elution stage tube). Transfer 90Y-resin from the 50 mL polypropylene tube into the funnel. Measure the residual radioactivity in the 50 mL polypropylene tube using a dosimeter.

[0212] Using a 10 mL syringe, push the product washing solution through the funnel and collect the fractions in a 50 mL polypropylene tube.

[0213] Wash the resin fraction four times with 1.6 mL of water. Using the plunger of a 10 mL syringe, push the water through the funnel until the resin is dry.

[0214] The radioactivity of the resin in the funnel and the radioactivity of the elution fraction were measured using a dosimeter.

[0215] Add 8 mL of WFI to the funnel to form a suspension. Place the suspension into a 10 mL syringe and empty the syringe into a final 10 mL vial. Measure the radioactivity in the vial, the residual radioactivity in the syringe, and the residual radioactivity in the funnel using a dosimeter. Process yield calculation: The yield of this process is calculated using the following formula: Yield = (Final radioactivity / Initial 90Y fraction) 100 Losses have also been calculated. Losses = Elution fraction + Unwashed 50 mL tube + Empty polyethylene funnel / glass charge.

[0216] result

[0217] As shown in Table 1, the yield obtained using the described process is very high (97%).

[0218]

[0219] Table 1 - Radioactivity measurements and yield and loss calculations.

[0220] In addition, the yttrium-labeled particles were imaged using scanning electron microscopy.

[0221] Scanning electron microscopy (SEM) of the product reveals a uniform and thin surface of microspheres. Figure 8 The results show that the procedure allows yttrium to be adsorbed onto the resin, leading to the conclusion that it is possible to incorporate yttrium into the resin at neutral pH without using phosphate and without metal precipitation.

[0222] Yttrium-90 decays with a half-life of 64 hours, emitting high-energy pure beta radiation. However, this process is also applicable to all other metals / radionuclides and can be used in place of yttrium-90 (i.e., but not limited to holmium, lutetium, actinium, and holmium), applying the same stoichiometry.

[0223] Example 4 - In vitro stability of radiolabeled particles

[0224] Purpose

[0225] This embodiment aims to demonstrate that 90-yttrium microspheres produced using the new method are stable at high temperatures, and therefore can be final sterilized using an autoclave.

[0226] In industry, the approved and widely used autoclave cycle is: - 121℃ for 30 minutes; - 132℃ for 7 minutes.

[0227] Further stress testing was conducted at a higher temperature: 150°C for 30 minutes.

[0228] A control group was also used at ambient temperature (25°C).

[0229] Material

[0230] The same materials were described and used in Experiment 3.

[0231] method

[0232] The initial radioactivity of 90 Yttrium differs, but the production and measurement steps for the radioactive microspheres are the same as described in Example 3: - Resin titration; - Prepare the resin as a sodium salt; - Prepare a 90% YCl3 solution; - Adsorb 90 Yttrium onto the resin; - Extraction and elution stages are performed by washing Y-90 resin; - Calculation of process yield.

[0233] After calculating the process yield, the collected resin was resuspended in 8 mL of water for injection.

[0234] The obtained suspension was divided into 4 equal portions (2 mL each) and placed in 10 mL glass vials with pressure caps and diaphragms.

[0235] Measure the following radioactivity levels in each vial: a. Radioactivity of vial A: 42.9 mCi @ 14:41 b. Radioactivity of vial B: 5.90 mCi @ 14:41 c. Radioactivity of vial C: 1.579 mCi @ 14:42 d. Radioactivity of vial D: 830 µCi @ 14:42 The vial was then subjected to the corresponding stress conditions described in Table 2 below:

[0236] Table 2 - Stress Temperature Conditions

[0237] As reported in Table 3, after equilibration at room temperature, the radioactivity of each vial was checked using a dose calibrator.

[0238]

[0239] Table 3 - Radioactivity measurements of each vial after T cycles

[0240] Each vial was resuspended by gentle vortexing, decapped, and transferred to a funnel containing polyethylene glass frit for individual filtration. The residual radioactivity in the elution fraction and decapped vials was checked using a dosimeter, and the results are reported in Table 4.

[0241]

[0242] Table 4 - Radioactivity Measurements of Elution Fractions and Vial Residues

[0243] result

[0244] As shown in Table 5, the 90Y loss percentage measured after temperature stress testing was very low (0.005%–0.7%). Furthermore, for two approved autoclave cycles (121°C for 30 minutes and 132°C for 7 minutes), the 90Y loss percentage measured after temperature stress testing was 0.005% and 0.04%, respectively.

[0245]

[0246] Table 5 - Summary of Results

[0247] During this experiment, the goal was to simulate the final sterilization process, heat the final product, and determine the amount of residual radioactivity attached to the microspheres and the 90% yttrium loss after the heating process.

[0248] In addition, the microspheres are subjected to excessive stress by exposing the composition to a temperature of 150°C for 30 minutes (which is higher than the normal conditions for autoclaving).

[0249] In summary, the use of high-temperature simulation of final sterilization of 90Y-resin showed that 90Y remained adhered to the resin when exposed to various temperatures for different durations. Even under overstress conditions, the measured percentage of Y90 loss was very low (0.005% and 0.04%, i.e., less than 1% (0.7%)).

[0250] Example 5 - Measurement and Production of Radioactive Particles Using Resin Conditioned with NaOH

[0251] Purpose

[0252] This embodiment aims to demonstrate the possibility of measuring and producing radioactive particles using the novel process described in this disclosure, employing Aminex 50W-X4 microspheres (25-37 μm) to incorporate radioactive yttrium (90 Yttrium) into the spheres through adsorption at neutral pH without precipitating it as insoluble phosphate. Although the resin was already present in sodium form, it was decided to evaluate the conditioning steps and seek results using NaOH anyway.

[0253] Material

[0254] raw materials

[0255] 90YCl3 from Eckert & Ziegler

[0256] Aminex 50W-X4 resin from BioRad Laboratories, Inc., 25-37 μm

[0257] method

[0258] The program has been tested through 6 main steps: - Resin titration; - Prepare the resin as a sodium salt; - Prepare a 90% YCl3 solution; - Adsorb 90 Yttrium onto the resin; - Extraction and elution stages are performed by washing Y-90 resin; - Calculation of process yield.

[0259] Resin titration: The resin was titrated as described in Example 1.

[0260] The resin is prepared as a sodium salt: Add 1.16 g of AG 50W-X4 cation exchange resin (Aminex 50W-X4 resin, 25–37 μm, from BioRad Laboratories, Inc.) to a vacuum filter. Wash the resin with 4.0 mL of 1.0 M NaOH to perform cation exchange. Apply vacuum until the resin is dry. Check the pH of the collected fractions (acceptance standard pH 11–13). Then wash the resin four times with 50 mL of water for injection (WFI), for a total of 200 mL, to complete the resin conditioning to sodium salt. Apply vacuum until the resin is dry. Check the pH of the collected fractions (acceptance standard pH = 6.00–8.00).

[0261] Preparation of 90YCl3 solution and adsorption of 90YT onto resin: The resin was collected from the vacuum filter and transferred to a 50 mL polypropylene tube.

[0262] The radioactivity of a 0.1 mL original sample of 90YCl3 (from Eckert & Ziegler) was measured in a dosimeter.

[0263] A homogeneous solution was obtained by diluting 0.1 mL of 90YCl3 sample with 0.90 mL of 0.04 N HCl. 0.4 mL of 0.1 M NaOH was added to the yttrium chloride solution to achieve a neutral pH (acceptance standard: 6.00–8.00). The radioactivity of the diluted 90Y sample was measured using a dosimeter.

[0264] Using a syringe, transfer the neutralized 90YCl3 solution into a 50 mL propylene tube containing resin. Using the same syringe, wash all the 90YCl3 solution in the syringe with 1 mL of water and push it onto the resin tube. Then gently agitate the mixture for 15 minutes to allow 90YCl3 to adsorb onto the activated resin microspheres.

[0265] After the transfer was completed, the remaining radioactivity in the 90 yttrium vial was measured using a dosimeter.

[0266] The extraction and elution stages are performed by washing the Y-90 resin: Place the funnel containing polyethylene glass frit on the ring rack, and place a new 50 mL polypropylene tube below (elution stage tube). Transfer 90Y-resin from the 50 mL polypropylene tube into the funnel. Measure the residual radioactivity in the 50 mL polypropylene tube using a dosimeter.

[0267] Using a 10 mL syringe, push the product washing solution through the funnel and collect the fractions in a 50 mL polypropylene tube.

[0268] Wash the resin fraction four times with 1.6 mL of water. Using the plunger of a 10 mL syringe, push the water through the funnel until the resin is dry.

[0269] The radioactivity of the resin in the funnel and the radioactivity of the elution fraction were measured using a dosimeter.

[0270] Add 8 mL of WFI to the funnel to form a suspension. Place the suspension into a 10 mL syringe and empty the syringe into a final 10 mL vial. Measure the radioactivity in the vial, the residual radioactivity in the syringe, and the residual radioactivity in the funnel using a dosimeter. Process yield calculation: The yield of this process is calculated using the following formula: Yield = (Final radioactivity / Initial 90Y fraction) 100 Losses have also been calculated. Losses = Elution fraction + Unwashed 50 mL tube + Empty polyethylene funnel / glass charge.

[0271] result

[0272] As shown in Table 6, the yield obtained using the described process is good (84%).

[0273]

[0274] Table 6 - Radioactivity measurements and yield and loss calculations.

[0275] Yttrium-90 decays with a half-life of 64 hours, emitting high-energy pure beta radiation. However, this process is also applicable to all other metals / radionuclides and can be used in place of yttrium-90 (i.e., but not limited to holmium, lutetium, actinium, and holmium), applying the same stoichiometry.

[0276] Example 6 - Measurement and Production of Radioactive Particles Using Resin Without NaOH Conditioning

[0277] Purpose

[0278] This embodiment is intended to demonstrate that it is possible to measure and produce radioactive particles using a novel process as described in this disclosure, using microspheres of Aminex 50W-X4 resin (25-37 μm) to incorporate radioactive yttrium (90 Yttrium) into the spheres through adsorption at neutral pH without precipitating it as insoluble phosphate.

[0279] Material

[0280] raw materials

[0281] 90YCl3 from Eckert & Ziegler

[0282] Aminex 50W-X4 resin from BioRad Laboratories, Inc., 25-37 μm

[0283] method

[0284] The program has been tested through 5 main steps: - Wash with water for injection; - Prepare a 90% YCl3 solution; - Adsorb 90 Yttrium onto the resin; - Extraction and elution stages are performed by washing Y-90 resin; - Calculation of process yield.

[0285] The resin is conditioned by washing with water: Add 1.13 g of AG 50W-X4 cation exchange resin (Aminex 50W-X4 resin, 25–37 μm, from BioRad Laboratories, Inc.) to the vacuum filtration apparatus. Since the resin is already in sodium form, wash it only with 4 mL of water for injection (WFI) without using NaOH. Apply vacuum until the resin is dry. Check the pH of the collected fraction (acceptance standard pH = 6.00–8.00).

[0286] Preparation of 90YCl3 solution and adsorption of 90YT onto resin: The resin was collected from the vacuum filter and transferred to a 50 mL polypropylene tube.

[0287] The radioactivity of a 0.1 mL original sample of 90YCl3 (from Eckert & Ziegler) was measured in a dosimeter.

[0288] A homogeneous solution was obtained by diluting 0.1 mL of 90YCl3 sample with 0.90 mL of 0.04 N HCl. 0.4 mL of 0.1 M NaOH was added to the yttrium chloride solution to achieve a neutral pH (acceptance standard: 6.00–8.00). The radioactivity of the diluted 90Y sample was measured using a dosimeter.

[0289] Using a syringe, transfer the neutralized 90YCl3 solution into a 50 mL propylene tube containing resin. Using the same syringe, wash all the 90YCl3 solution in the syringe with 1 mL of water and push it onto the resin tube. Then gently agitate the mixture for 15 minutes to allow 90YCl3 to adsorb onto the activated resin microspheres.

[0290] After the transfer was completed, the remaining radioactivity in the 90 yttrium vial was measured using a dosimeter.

[0291] The extraction and elution stages are performed by washing the Y-90 resin: Place the funnel containing polyethylene glass frit on the ring rack, and place a new 50 mL polypropylene tube below (elution stage tube). Transfer 90Y-resin from the 50 mL polypropylene tube into the funnel. Measure the residual radioactivity in the 50 mL polypropylene tube using a dosimeter.

[0292] Using a 10 mL syringe, push the product washing solution through the funnel and collect the fractions in a 50 mL polypropylene tube.

[0293] Wash the resin fraction four times with 1.6 mL of water. Using the plunger of a 10 mL syringe, push the water through the funnel until the resin is dry.

[0294] The radioactivity of the resin in the funnel and the radioactivity of the elution fraction were measured using a dosimeter.

[0295] Add 8 mL of WFI to the funnel to form a suspension. Place the suspension into a 10 mL syringe and empty the syringe into a final 10 mL vial. Measure the radioactivity in the vial, the residual radioactivity in the syringe, and the residual radioactivity in the funnel using a dosimeter. Process yield calculation: The yield of this process is calculated using the following formula: Yield = (Final radioactivity / Initial 90Y fraction) 100 Losses have also been calculated. Losses = Elution fraction + Unwashed 50 mL tube + Empty polyethylene funnel / glass charge.

[0296] result

[0297] As shown in Table 7, the yield obtained using the described process is very high (> 95%).

[0298]

[0299] Table 7 - Radioactivity measurements and yield and loss calculations.

[0300] Yttrium-90 decays with a half-life of 64 hours, emitting high-energy pure beta radiation. However, this process is also applicable to all other metals / radionuclides and can be used in place of yttrium-90 (i.e., but not limited to holmium, lutetium, actinium, and holmium), applying the same stoichiometry.

[0301] Example 7 - Measurement and Production of Radioactive Particles Without NaOH Conditioning – Scale-up of Radioactivity

[0302] Purpose

[0303] This embodiment is intended to demonstrate that it is possible to measure and produce radioactive particles using a novel process as described in this disclosure, using microspheres of Aminex 50W-X4 resin (25-37 μm) to incorporate radioactive yttrium (90 Yttrium) into the spheres through adsorption at neutral pH without precipitating it as insoluble phosphate.

[0304] Material

[0305] raw materials

[0306] 90YCl3 from Eckert & Ziegler

[0307] Aminex 50W-X4 resin from BioRad Laboratories, Inc., 25-37 μm

[0308] method

[0309] The program has been tested through 5 main steps: - Wash the resin with water for injection; - Prepare a 90% YCl3 solution; - Adsorb 90 Yttrium onto the resin; - Extraction and elution stages are performed by washing Y-90 resin; - Calculation of process yield.

[0310] The resin is conditioned by washing with water: Add 1.14 g of AG 50W-X4 cation exchange resin (Aminex 50W-X4 resin, 25–37 μm, from BioRad Laboratories, Inc.) to the vacuum filtration apparatus. Since the resin is already in sodium form, wash it only with 4 mL of water for injection (WFI) without using NaOH. Apply vacuum until the resin is dry. Check the pH of the collected fraction (acceptance standard pH = 6.00–8.00).

[0311] Preparation of 90YCl3 solution and adsorption of 90YT onto resin: The resin was collected from the vacuum filter and transferred to a 50 mL polypropylene tube.

[0312] The radioactivity of a 0.1 mL original sample of 90YCl3 (from Eckert & Ziegler) was measured in a dosimeter.

[0313] A homogeneous solution was obtained by diluting 0.1 mL of 90YCl3 sample with 0.90 mL of 0.04 N HCl. 0.4 mL of 0.1 M NaOH was added to the yttrium chloride solution to achieve a neutral pH (acceptance standard: 6.00–8.00). The radioactivity of the diluted 90Y sample was measured using a dosimeter.

[0314] Using a syringe, transfer the neutralized 90YCl3 solution into a 50 mL propylene tube containing resin. Using the same syringe, wash all the 90YCl3 solution in the syringe with 1 mL of water and push it onto the resin tube. Then gently agitate the mixture for 15 minutes to allow 90YCl3 to adsorb onto the activated resin microspheres.

[0315] After the transfer was completed, the remaining radioactivity in the 90 yttrium vial was measured using a dosimeter.

[0316] The extraction and elution stages are performed by washing the Y-90 resin: Place the funnel containing polyethylene glass frit on the ring rack, and place a new 50 mL polypropylene tube below (elution stage tube). Transfer 90Y-resin from the 50 mL polypropylene tube into the funnel. Measure the residual radioactivity in the 50 mL polypropylene tube using a dosimeter.

[0317] Using a 10 mL syringe, push the product washing solution through the funnel and collect the fractions in a 50 mL polypropylene tube.

[0318] Wash the resin fraction four times with 1.6 mL of water. Using the plunger of a 10 mL syringe, push the water through the funnel until the resin is dry.

[0319] The radioactivity of the resin in the funnel and the radioactivity of the elution fraction were measured using a dosimeter.

[0320] Add 8 mL of WFI to the funnel to form a suspension. Place the suspension into a 10 mL syringe and empty the syringe into a final 10 mL vial. Measure the radioactivity in the vial, the residual radioactivity in the syringe, and the residual radioactivity in the funnel using a dosimeter. Process yield calculation: The yield of this process is calculated using the following formula: Yield = (Final radioactivity / Initial 90Y fraction) 100 Losses have also been calculated. Losses = Elution fraction + Unwashed 50 mL tube + Empty polyethylene funnel / glass charge.

[0321] result

[0322] As shown in Table 8, the yield obtained using the described process is excellent (> 99%).

[0323]

[0324] Table 8 - Radioactivity measurements and yield and loss calculations.

[0325] In addition, the yttrium-labeled particles were imaged using scanning electron microscopy.

[0326] Scanning electron microscopy (SEM) of the product revealed a uniform and thin surface for microsphere analysis. The SEM also showed that the procedure allowed yttrium to be adsorbed onto the resin, concluding that it is possible to incorporate yttrium into the resin at neutral pH without the use of phosphates and without metal precipitation.

[0327] Yttrium-90 decays with a half-life of 64 hours, emitting high-energy pure beta radiation. However, this process is also applicable to all other metals / radionuclides and can be used in place of yttrium-90 (i.e., but not limited to holmium, lutetium, actinium, and holmium), applying the same stoichiometry.

[0328] Example 8 - In vitro stability of radiolabeled microparticles

[0329] Purpose

[0330] This embodiment aims to demonstrate that 90-yttrium microspheres produced using the new method are stable at high temperatures, and therefore can be final sterilized using an autoclave.

[0331] In industry, the approved and widely used autoclave cycle is: - 121℃ for 30 minutes; 132℃ for 7 minutes; - Further stress testing was conducted using a higher temperature: 150°C for 30 minutes.

[0332] Material

[0333] The same materials described and used in Example 7.

[0334] method

[0335] The initial radioactivity of 90 Yttrium differs, but the production and measurement steps for the radioactive microspheres are the same as described in Example 7: - Wash the resin with water for injection; - Prepare a 90% YCl3 solution; - Adsorb 90 Yttrium onto the resin; - Extraction and elution stages are performed by washing Y-90 resin; - Calculation of process yield.

[0336] After calculating the process yield, the collected resin was resuspended in 8 mL of water for injection.

[0337] The obtained suspension was divided into 4 equal portions (2 mL each) and placed in 10 mL glass vials with pressure caps and diaphragms.

[0338] Measure the following radioactivity levels in each vial: a. Radioactivity of vial A: 10.41 mCi @ 17:12 b. Radioactivity of vial B: 14.28 mCi @ 17:12 c. Radioactivity of vial C: 13.42 mCi @ 17:13 The vial is then subjected to the corresponding stress conditions described in Table 9 below:

[0339] Table 9 - Stress Temperature Conditions

[0340] As reported in Table 10, after equilibration at room temperature, the radioactivity of each vial was checked using a dose calibrator.

[0341]

[0342] Table 10 - Radioactivity measurements of each vial after T cycles

[0343] Each vial was resuspended by gentle vortexing, decapped, and transferred to a funnel containing polyethylene glass frit for individual filtration. The residual radioactivity in the elution fraction and decapped vials was checked using a dosimeter, and the results are reported in Table 11.

[0344]

[0345] Table 11 - Radioactivity Measurements of Elution Fractions and Vial Residues

[0346] result

[0347] As shown in Table 12, the 90Y loss percentage measured after temperature stress testing was very low (0.003%-0.005%). Furthermore, for two approved autoclave cycles (121°C for 30 minutes and 132°C for 7 minutes), the 90Y loss percentages measured after temperature stress testing were 0.004% and 0.003%, respectively.

[0348]

[0349] Table 12 - Summary of Results

[0350] During this experiment, the goal was to simulate the final sterilization process, heat the final product, and determine the amount of residual radioactivity attached to the microspheres and the 90% yttrium loss after the heating process.

[0351] In addition, the microspheres are subjected to excessive stress by exposing the composition to a temperature of 150°C for 30 minutes (which is higher than the normal conditions for autoclaving).

[0352] In summary, the use of high-temperature simulation of final sterilization of 90Y-resin showed that 90Y remained adhered to the resin when exposed to various temperatures for different durations. Even under overstress conditions, the measured percentage of Y90 loss was very low (0.003% and 0.005%, i.e., much less than 1% (0.005%)).

Claims

1. A particle labeled with an α- and / or β-emitting radionuclide, wherein the particle comprises or is composed of a polymer resin conjugated with a sulfonic acid and an ionically bound α- and / or β-emitting radionuclide, wherein the particle has a size in the range of 5-400 μm, and wherein the particle has a smooth surface with few or no protrusions.

2. The α- and / or β-emitting radionuclide-labeled particles according to claim 1, wherein the smooth surface having few or no protrusions is defined by a particle surface having fewer protrusions compared to the same particles that have been labeled with phosphate precipitation.

3. The α- and / or β-emitting radionuclide-labeled particles according to claims 1-2, wherein the smooth surface having few or no protrusions is defined by particles having fewer than 10 protrusions on the surface, each having a minimum height of 1 µm.

4. The α- and / or β-emitting radionuclide-labeled particles according to any one of the preceding claims, wherein the particles are substantially free of phosphates.

5. The α- and / or β-emitting radionuclide-labeled particles according to any one of the preceding claims, wherein the amount of phosphate in the particles is less than 1 ppm.

6. The α- and / or β-emitting radionuclide-labeled particles according to any one of the preceding claims, wherein the polymer resin is a styrene-divinylbenzene copolymer.

7. The α- and / or β-emitting radionuclide-labeled particles according to any one of the preceding claims, wherein the polymer resin is polystyrene-divinylbenzenesulfonic acid resin.

8. A particle labeled with an α- and / or β-emitting radionuclide according to any one of the preceding claims, wherein the α- and / or β-emitting radionuclide is selected from the group consisting of: 90 Y、 225 Ac、 89 Sr、 153 Sm、 159 Gd, 18 F, 68 Cu、 69 Cu、 67 Ga、 99m Tc, 201 Ti、 111 In、 161 Tb, 212 Pb and 177 Lu.

9. Particles labeled with α- and / or β-emitting radionuclides according to any one of the preceding claims, wherein the β-emitting radionuclide is 90 Y.

10. A particle labeled with an α- and / or β-emitting radionuclide according to any one of the preceding claims, wherein the decay emission of the α- and / or β-emitting radionuclide does not exceed 10% of the total decay radiation of gamma radiation.

11. A particle labeled with an α- and / or β-emitting radionuclide according to any one of the preceding claims, wherein the α- and / or β-emitting radionuclide has a decay half-life in the range of 1-300 hours, such as between 10-100 hours or such as 50-70 hours.

12. A particle labeled with an α- and / or β-emitting radionuclide according to any one of the preceding claims, wherein the decay of the α- and / or β-emitting radionuclide is primarily α- and / or β-decay.

13. A pharmaceutical composition comprising the particles according to claims 1-12.

14. The pharmaceutical composition according to claim 13, comprising a diluent, a carrier, a surfactant, an antiflocculation agent, and / or an excipient.

15. The pharmaceutical composition according to claim 13 or 14, further comprising a biocompatible binder or a component thereof.

16. The pharmaceutical composition according to any one of claims 13-15, further comprising albumin, such as, for example, bovine serum albumin.

17. The pharmaceutical composition according to any one of claims 13-16, wherein the radionuclide is prepared in an amount of 1 kBq to 10 GBq per dose or in an amount of 50 MBq to 1000 GBq suitable for multi-dose industrial production.

18. The pharmaceutical composition according to any one of claims 13-17, which is suitable for intratumoral, intracavitary and / or intra-arterial injection.

19. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, used as a pharmaceutical.

20. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for the treatment or improvement of cancer.

21. The α- and / or β-emitting radiolabeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for the treatment of head and neck squamous cell carcinoma, metastatic melanoma, sarcoma, non-small cell lung cancer, colorectal cancer, primary and secondary hepatocellular carcinoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, ovarian cancer, muscle-invasive bladder cancer, prostate cancer and / or osteosarcoma, preferably unresectable hepatocellular carcinoma and / or locally advanced borderline resectable pancreatic ductal adenocarcinoma.

22. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for the treatment of unresectable hepatocellular carcinoma.

23. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for use in localized radiotherapy.

24. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for use in transarterial radioembolization.

25. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for use in brachytherapy.

26. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for use in radionuclide imaging.

27. The α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or the pharmaceutical composition according to any one of claims 13-18, for single treatment or repeated administration.

28. A method for producing particles labeled with α- and / or β-emitting radionuclides according to any one of claims 1-12 or a pharmaceutical composition according to any one of claims 13-18, said method comprising: a) Provide α- and / or β-emitting radionuclides or their salts, b) Provide particles of a polymer resin with sulfonic acid conjugation. c) Mixing the α- and / or β-emitting radionuclides and the particles in an aqueous solution with a pH in the range of 6.5-9.5, and d) Separate α- and / or β-emitted radionuclide-labeled particles from the aqueous solution.

29. The method of claim 28, wherein the pH of the aqueous solution is in the range of pH 7-9, preferably less than pH 8.5, such as less than pH 7.5, such as about pH 7.

4.

30. The method according to claim 28 or 29, wherein the weight ratio between the radionuclide and the particle is in the range of 1:40 to 1:6000 (mg / mg), such as in the range of 1:100 to 1:6000, such as in the range of 1:1000 to 1:6000, such as about 1:5000.

31. The method according to any one of claims 28-30, wherein the weight ratio between the radionuclide and the particle is in the range of 1:40 to 1:1000, such as in the range of 1:50 to 1:100, 1:45 to 1:75, such as about 1:

50.

32. The method according to any one of claims 28-31, wherein the method does not include fixing the radionuclide onto the particle by phosphate precipitation.

33. The method according to any one of claims 28-32, wherein the aqueous suspension comprises a buffer, such as, for example, acetate, phosphate, citrate or glutamate.

34. The method according to any one of claims 28-33, wherein step d) is performed within 60 minutes, such as no more than 30 minutes, such as no more than 15 minutes, after step c).

35. A reagent kit comprising: a) Unlabeled particles, said unlabeled particles comprising or consisting of a polymer resin conjugated with sulfonic acid, optionally. b) A reagent for preparing α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or pharmaceutical compositions according to any one of claims 13-18, and optionally... c) Instructions for use in preparing α- and / or β-emitting radionuclide-labeled particles according to any one of claims 1-12 or pharmaceutical compositions according to any one of claims 13-18.

36. The kit according to claim 35, further comprising: d) An aqueous solution comprising an uncured, curable biocompatible adhesive and / or a nonpolymeric hydrogel in the aqueous solution, and e) An aqueous solution containing a curing agent and / or a polymerizing agent.

37. The kit according to claim 36, wherein the curable biocompatible adhesive is albumin, preferably bovine serum albumin, and the curing agent and / or polymerizing agent is an amide crosslinking agent, preferably glutaraldehyde.

38. A method for preparing cured 90 A method for preparing a gamma-ray radiation therapy composition, the method comprising: a) Provide, i. Containing particles according to any one of claims 1-13 90 Y-labeled particle suspension, ii. Uncured biocompatible adhesives and / or nonpolymeric hydrogels in aqueous solution, iii. A curing agent and / or a polymerizing agent, which, when mixed with ii) or i) and ii), induces the curing of the biocompatible adhesive and / or the polymerization of the hydrogel, and b) Mix i, ii, and iii to obtain cured product. 90 Gamma radiation therapy composition, the cured 90 The gamma-ray radiotherapy composition comprises a biocompatible adhesive and / or hydrogel embedding. 90 Y-ray radiotherapy particles.

Images