Medical isotope Ra-223 labeled high-photosynthetic-efficiency rare earth nano-drug as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biomedical nano-drugs, and particularly relates to a radioactive medical isotope labeled nano-material as well as a preparation method and application thereof. The rare earth nano drug comprises a rare earth nano fluorescent material and a biological modification layer, the rare earth nano fluorescent material comprises a rare earth ion luminous inner core MLn1F4: Ln23 +, wherein the rare earth ion luminous inner core is externally coated with a rare earth ion epitaxial growth shell layer MLn3F4: Ln43 + and a heterogeneous inert protective layer M1F2 in sequence; the rare earth nano fluorescent material further comprises a medical isotope Ra-223; the medical isotope Ra-223 is positioned in the heterogeneous inert protective layer M1F2; the biological modification layer is positioned on the surface of the rare earth nano fluorescent material. According to the rare earth nano-drug, the medical isotope Ra-223 can be fixed in a tumor focus for a long time, the effect of irradiation radiotherapy in a tumor can be greatly improved, and radioactive damage to other normal tissues and organs in the local radiotherapy process can be synchronously reduced.

Description

Technical Field

[0001] This invention belongs to the field of biomedical nanomedicine technology, and particularly relates to a medical isotope Ra-223 labeled high-efficiency rare earth nanomedicine, its preparation method and application. Background Technology

[0002] Cancer is a major disease threatening human health. In addition to traditional surgery, chemotherapy, and radiotherapy, internal radionuclide irradiation therapy, as an emerging strategy, is receiving widespread attention. Alpha-radionamide therapy utilizes radiopharmaceuticals that emit alpha particles, selectively delivering them to cancer cells and the tumor microenvironment, aiming to control tumor growth while minimizing toxicity. In recent years, this technology has shown great potential in cancer treatment, especially for small tumors widely distributed throughout the body, demonstrating excellent therapeutic effects. Radium-223 (Ra-223), as the world's first radiopharmaceutical to emit alpha particles, has an uptake mechanism similar to calcium, forming high concentrations in bones. Bone metastases accumulate more Ra-223 due to active bone metabolism, and the alpha rays released by Ra-223 have strong killing power, resulting in high concentrations in bone metastases, thus effectively inhibiting tumor growth. Furthermore, because Ra-223 has weak penetrating power and a range of less than 100 μm, normal tissue can effectively block alpha rays, limiting its killing effect to the deposition site and reducing toxicity to adjacent healthy tissues and bone marrow.

[0003] However, Ra-223 lacks selectivity in killing tumor cells, and it can also cause significant damage to normal tissues. Therefore, real-time monitoring of the biodistribution of Ra-223 is crucial for the treatment process. Unfortunately, therapeutic doses of the radionuclide Ra-223 do not produce enough imageable photons (gamma photons) or positrons (beta photons). + (Electrons), which hinders effective monitoring of the Ra-223 radiopharmaceutical. Although international colleagues have proposed using... 68 Ga、 64 Cu and lanthanide isotopes (such as Cu and lanthanides) 132 La, 133 La, 134 La, 134Ce) is used as a diagnostic and therapeutic pairing nuclide for Ra-223 to indirectly determine its distribution. However, this method has two major problems: first, radionuclide imaging techniques (such as PET / CT and SPECT) cannot achieve real-time monitoring; second, the resolution of these imaging techniques is only at the millimeter level, which is insufficient to meet the precise monitoring needs at the cell-tissue level. Increasing research indicates that, in addition to DNA, other sensitive sites such as the cell membrane and mitochondria may also be key targets for radionuclide therapy. Therefore, improving the detection technology of radionuclides at the subcellular level is particularly important to more accurately assess the spatial distribution of radionuclides in the nanometer to micrometer range, promote targeted therapy research of radionuclides at the cellular level, and develop nanoscale radionuclide localization and quantitative imaging techniques.

[0004] Therefore, real-time, multi-scale monitoring of Ra-223 biodistribution across cells, tissues, and animals remains an unresolved challenge, limiting the clinical application of Ra-223 medical radionuclides. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention proposes a medical-grade Ra-223-labeled high-efficiency rare-earth nanomedicine, its preparation method, and its applications. This drug employs a unique heterogeneous core-shell structure design. The core and middle layers are composed of rare-earth-based materials, providing high quantum yield rare-earth upconversion and near-infrared fluorescence signals. The outermost layer uses an alkaline earth metal from the same group as Ra-223 as the shell, achieving efficient Ra-223 loading. A targeting ligand is coupled externally to the heterogeneous core-shell nanoparticles. This design not only endows the drug with high-efficiency photomonitoring capabilities, supporting real-time, cross-scale, and targeted tracking of Ra-223 distribution in vivo, but also facilitates in-depth exploration of the interaction mechanisms between Ra-223 and tumor cells, tissues, and animal bodies. More importantly, this drug achieves integrated diagnosis and treatment, combining diagnostic and therapeutic functions into one, providing a precise and efficient solution for tumor treatment.

[0006] The technical solution of the present invention is as follows:

[0007] A rare-earth nanomedicine, comprising a rare-earth fluorescent nanomaterial and a biomodification layer; the rare-earth fluorescent nanomaterial comprises a rare-earth ion luminescent core MLn1F4:Ln2. 3+ The rare earth ion luminescent core is sequentially coated with a rare earth ion epitaxial growth shell MLn3F4:Ln4. 3+ and heterogeneous inert protective layer M 1 F2; The rare earth nanofluorescent material also includes the medical isotope Ra-223;

[0008] The medical isotope Ra-223 is located in the heterogeneous inert protective layer M. 1 In F2;

[0009] Wherein, M is a metallic element selected from one, two or more of Li, Na, K, Rb, Cs, Mg, Ca, Sr or Ba;

[0010] Ln1 and Ln3 may be the same or different, and are independently selected from rare earth stable isotopes, wherein the rare earth stable isotopes are selected from one, two or more of La, Ce, Pr, Nd, Po, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc;

[0011] Ln2 and Ln4 are rare earth luminescent ions, which may be the same or different, and are independently selected from one, two or more of Y, Sc, Yb, Er, Tm, Ho, Gd, Eu, Tb, Sm, Dy, Ce, Nd, La, Pr and Lu;

[0012] M 1 It is an alkaline earth metal element, selected from one, two or more of Mg, Ca, Sr or Ba;

[0013] The biomodification layer is located on the surface of the rare earth nanofluorescent material.

[0014] In this invention, the medical isotope Ra-223 can also be used... 223 Ra said.

[0015] According to an embodiment of the present invention, Ln2 and Ln4 may be the same or different, and are independently selected from one, two or more of Y, Yb, Er, Gd, Eu, and Lu, for example, two of Yb, Er and Ce.

[0016] According to an embodiment of the present invention, the biomodification layer is preferably located on the surface of the heterogeneous inert protective layer of the rare earth nanofluorescent material.

[0017] According to an embodiment of the present invention, in the rare earth nanofluorescent material, the abundance of the medical isotope Ra-223 in the rare earth nanofluorescent material is at least 0.1 μCi / g, preferably at least 0.15 μCi / g; in the present invention, the abundance refers to the ratio of the radiation dose of Ra-223 to the weight of the rare earth nanofluorescent material.

[0018] According to an embodiment of the present invention, in the rare earth nanofluorescent material, M, M 1 Ln1, Ln2, Ln3, Ln4, and Ra-223 exist in ionic form.

[0019] According to an embodiment of the present invention, the rare earth ion luminescent core has a crystal structure, preferably a trigonal, cubic, tetragonal, hexagonal, or monoclinic crystal structure, for example, a cubic crystal structure.

[0020] According to an embodiment of the present invention, the general formula of the rare earth nanomedicine is MLn1F4:Ln2. 3+ @MLn3F4:Ln4 3+ @M 1 F2: 223 Ra@BML, where BML refers to the biomodified layer; exemplarily, Ln1 and Ln3 are selected from Yb, and Ln2 and Ln4 are selected from Er. 3+ and Ce 3 + .

[0021] According to an embodiment of the present invention, the rare earth nanofluorescent material is designated as MLn1F4:Ln2. 3+ @MLn3F4:Ln4 3+ @M 1 F2: 223 Ra, for example, Ln1 and Ln3 are selected from Yb, and Ln2 and Ln4 are selected from Er. 3+ and Ce 3+ .

[0022] According to an exemplary embodiment of the present invention, the rare earth nanofluorescent material is NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra, of which 223 Ra is distributed in CaF2.

[0023] According to an embodiment of the present invention, the biomodified layer includes LIG, a functional tumor-targeting biomolecule.

[0024] According to an embodiment of the present invention, the functional tumor-targeting biomolecule LIG is selected from water-soluble ligands that do not have tumor-specific recognition capabilities and / or molecules that have tumor-targeting functions.

[0025] According to an embodiment of the present invention, the water-soluble ligand that does not have tumor-specific recognition capability is selected from one or more of the following: methoxy polyethylene glycol alendronate (MPEG-ALE), polyacrylic acid (PAA), distearate phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and its derivatives, dioleoylphosphatidylethanolamine-polyethylene glycol (DOPE-PEG) and its derivatives, and dipalmitoylphosphatidylethanolamine-polyethylene glycol (DPPE-PEG) and its derivatives.

[0026] According to an embodiment of the present invention, the tumor-targeting molecule is selected from one, two or more of the following: organic small molecules, monoclonal antibodies, polyclonal antibodies, polypeptides, and single or multi-target small molecule inhibitor biomolecules. Preferably, the multi-target small molecule inhibitor biomolecule is selected from one, two or more of the following: polysaccharides, nucleic acids, folic acid, aspirin, and vitamin C.

[0027] For example, the functional tumor-targeting biomolecule LIG is, for instance, distearylphosphatidylethanolamine-polyethylene glycol 2000-targeting polypeptide (DSPE-PEG2k-iRGD).

[0028] According to an embodiment of the present invention, the rare earth nanomedicine has a nanocrystal structure with a size of 5-200 nm, preferably 8-100 nm, for example 10-50 nm.

[0029] According to an embodiment of the present invention, the rare earth nanomedicine has the basic properties as follows: Figure 1 The transmission electron microscope image shown is a transmission electron microscope image.

[0030] According to an embodiment of the present invention, the rare earth nanomedicine has low biotoxicity.

[0031] According to an embodiment of the present invention, the rare earth nanomedicine can emit light in the visible red region (400-700nm) to the near-infrared IIb region (1400-1700nm) using a 980nm laser as a light source.

[0032] The present invention also provides a method for preparing the above-mentioned rare earth nanomedicine, the method comprising preparing a rare earth nanofluorescent material, modifying the surface of the rare earth nanofluorescent material to obtain the biomodified layer, and then obtaining the rare earth nanomedicine.

[0033] According to an embodiment of the present invention, the method for preparing the rare earth nanofluorescent material is selected from one of the following: thermal injection, stepwise layer-by-layer epitaxial high-temperature coprecipitation, high-temperature thermal decomposition, hydrothermal method, or sol-gel method, with the stepwise layer-by-layer epitaxial high-temperature thermal decomposition method being an example.

[0034] According to a preferred embodiment of the present invention, the method for preparing the rare earth nanofluorescent material is a stepwise layer-by-layer epitaxial high-temperature thermal decomposition method, specifically including the following steps:

[0035] S1. Preparation of rare-earth ion luminescent cores MLn1F4:Ln2 3+ ;

[0036] S2, in the rare earth ion luminescent core MLn1F4:Ln2 3+Surface growth (e.g., by shell epitaxial growth method) of rare earth ion epitaxial growth shell MLn3F4:Ln4 3+ We obtain MLn1F4:Ln2 3+ @MLn3F4:Ln4 3+ ;

[0037] S3, Rare earth ion epitaxial growth shell MLn3F4:Ln4 in step S2 3+ Surface-grown (e.g., by shell epitaxial growth method) heterogeneous inert protective layer M 1 F2 was used to dope the medical isotope Ra-223 to obtain rare earth fluorescent nanomaterials.

[0038] According to an embodiment of the present invention, when preparing the rare-earth nanofluorescent material, M in the heterogeneous inert protective layer 1 The molar ratio of M in the rare earth ion luminescent core is no greater than 4:1, for example (4-0.1):1, or (4-0.01):1, with examples of 3:1, 2:1, 1:1, and 0.1:1.

[0039] According to an embodiment of the present invention, in the preparation method of the rare earth nanomedicine, the surface modification treatment of the rare earth nanofluorescent material specifically refers to mixing the rare earth nanofluorescent material and the ligand forming the biomodified layer in an organic solvent, stirring at a temperature below 40°C for 1-24 hours, and then removing the organic solvent. Preferably, the organic solvent is one, two, or a mixture of two or more of cyclohexane, dichloromethane, trichloromethane, tetrahydrofuran, and N,N-dimethylformamide. Preferably, the removal of the organic solvent can be carried out using methods known in the art, such as rotary evaporation; furthermore, after removing the organic solvent, ultrapure water can be added for washing.

[0040] According to an embodiment of the present invention, the ligand is selected from LIGs, which are functional tumor-targeting biomolecules, and the LIGs have the meanings described above.

[0041] According to an embodiment of the present invention, the rare earth nanomedicine prepared by the above method has a yield of 50-90%, for example 60%, 70%, or 80%.

[0042] According to an embodiment of the present invention, the rare earth nanomedicine prepared by the above method has a Ra-223 labeling rate of 20-99%, preferably above 45%, for example 50%, 60%, 70%, or 80%. In this invention, the Ra-223 labeling rate refers to the percentage of Ra-223 in the rare earth fluorescent nanomaterials prepared in step S3. 223 The radiation dose of Ra and the amount added to the raw materials 223 The ratio of Ra to the total radiation dose.

[0043] According to an exemplary embodiment of the present invention, the preparation method of the rare earth nanomedicine includes the following steps:

[0044] (1) Preparation of rare earth ion luminescent core NaYbF4:Er 3+ Ce 3+ ;

[0045] (2) In the rare earth ion luminescent core NaYbF4:Er 3+ Ce 3+ Rare earth ion epitaxial growth shell NaYbF4:Er on the surface 3+ Ce 3+ We obtained NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ ;

[0046] (3) In NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ Surface growth contains 223 A heterogeneous inert protective layer of Ra, CaF2, yields NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra, of which 223 Ra is distributed in a heterogeneous inert protective layer CaF2, and is referred to as a rare earth nanofluorescent material;

[0047] (4) Add the rare earth nano fluorescent material and functional tumor-targeting biomolecule (such as DSPE-PEG2k-iRGD) from step (3) into chloroform to modify the surface heterogeneous inert protective layer CaF2 of the rare earth nano fluorescent material to obtain the rare earth nanomedicine.

[0048] The present invention also provides the use of the above-mentioned rare earth nanomedicines in the pharmaceutical field, such as for the preparation of tumor diagnostic agents and / or therapeutic agents, or for the preparation of tumor diagnostic and therapeutic agents.

[0049] The present invention also provides a diagnostic and therapeutic agent for the medical isotope Ra-223, wherein the diagnostic and therapeutic agent for the medical isotope Ra-223 comprises the above-mentioned rare earth nanomedicine.

[0050] According to an embodiment of the present invention, the diagnostic and therapeutic agent can be used for medical imaging of the medical isotope Ra-223, the medical imaging including real-time fluorescence imaging and / or surgical navigation, such as fluorescence imaging of the medical isotope Ra-223 in vivo.

[0051] According to an embodiment of the present invention, the diagnostic therapeutic agent can be excited by one, two or more excitation lights in the 980nm wavelength range, and simultaneously generate emitted light in the visible light region of 400-700nm to the near-infrared IIb region of 1400-1700nm, thereby enabling real-time localization diagnosis and / or imaging (e.g., localization diagnosis and / or imaging in tumor cells, tissues and animal bodies).

[0052] According to an embodiment of the present invention, the diagnostic and therapeutic agent can be administered by injection, for example, by intratumoral injection or intravenous injection.

[0053] According to embodiments of the present invention, the diagnostic therapeutic agent can be used for drug delivery and / or treatment of tumors (e.g., chemotherapy and / or radiotherapy).

[0054] According to an embodiment of the present invention, the diagnostic and therapeutic agent can be administered by at least one of the following methods: intravenous injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, rectal administration, etc.

[0055] Beneficial effects

[0056] (1) The rare earth nanomedicine labeled with medical isotope Ra-223 in this invention can be excited by 980nm excitation light to produce strong fluorescence emission of rare earth ions in the 400-1700nm band spanning the visible region to the near-infrared II region. It can track the distribution of Ra-223 in the body in real time and across scales. It also helps to explore the interaction mechanism between Ra-223 and tumor cells, tissues and animal bodies, and guide the application of medical isotope Ra-223 intratumoral irradiation therapy.

[0057] (2) The rare earth nanomedicine labeled with medical isotope Ra-223 in this invention has a core-shell-shell microstructure and is easy to dope with medical isotope Ra-223 because Ra-223 reacts with the cationic alkaline earth metal element M in the outermost lattice of the nanocrystal. 1 Being in the same main group (both are Group 2 elements), their influence on the core-shell-shell microstructure is minimized, and the medical isotope Ra-223 has a high loading capacity, stable binding, and is not prone to off-target effects.

[0058] (3) The rare earth nanomedicine labeled with the medical isotope Ra-223 in this invention, wherein Ra-223 has a relatively long half-life (t 1 / 2=11.43 days), thus enabling simultaneous and efficient radiotherapy for tumors.

[0059] (4) The rare earth nanomedicine labeled with medical isotope Ra-223 in this invention has a specific targeting recognition ability for tumor cells after its surface is modified with functional tumor-targeting biomolecules. After being targeted to the tumor lesion, it has a strong retention ability, thus it can fix the medical isotope Ra-223 in the tumor lesion for a long time, which can greatly improve the effect of intratumoral irradiation radiotherapy and simultaneously reduce the radiation damage to other normal tissues and organs during local radiotherapy. Attached Figure Description

[0060] Figure 1 This is a transmission electron microscope image of the rare earth nanomedicine prepared in Example 1 of the present invention dispersed in water.

[0061] Figure 2 This is a comparison chart of the near-infrared quantum yield and Ra-223 labeling rate of rare earth nanomedicines in Example 1 and Comparative Example 2 of the present invention.

[0062] Figure 3 This is a medical imaging image of upconversion luminescence in cells of rare earth nanomedicines excited by a 980nm laser in Example 1 of the present invention.

[0063] Figure 4 This is a near-infrared IIb region fluorescence image of rare earth nanomedicine in nude mice carrying human gastric cancer subcutaneous tumors under 980nm laser excitation, as shown in Application Example 2 of this invention.

[0064] Figure 5 This invention demonstrates the in vitro killing effect of different rare earth nanomedicines on human gastric cancer cells MGC-803 in Example 3 of this application.

[0065] Figure 6 The image shows the changes in tumor volume in nude mice bearing tumors in Example 4 of the present invention (the average tumor volume of each group is taken);

[0066] Figure 7 This is a TUNEL assay image of tumor tissue on day 7 after drug administration in Example 4 of the present invention.

[0067] Figure 8 The graph shows the changes in body weight of tumor-bearing nude mice after drug administration in Example 4 of the present invention (average body weight of each group is taken);

[0068] Figure 9 HE staining image of a tissue pathology section in Application Example 4 of this invention. Detailed Implementation

[0069] [Methods for preparing rare earth fluorescent nanomaterials]

[0070] The method for preparing the rare earth nano-fluorescent material of the present invention is selected from one of the following: hot injection method, stepwise layer-by-layer epitaxial high-temperature coprecipitation method, high-temperature thermal decomposition method, hydrothermal method, or sol-gel method. An example is the stepwise layer-by-layer epitaxial high-temperature thermal decomposition method.

[0071] According to a preferred embodiment of the present invention, the method for preparing the rare earth nanofluorescent material is a stepwise layer-by-layer epitaxial high-temperature thermal decomposition method, specifically including the following steps:

[0072] S1. Preparation of rare-earth ion luminescent cores MLn1F4:Ln2 3+ ;

[0073] S2, in the rare earth ion luminescent core MLn1F4:Ln2 3+ Surface growth (e.g., by shell epitaxial growth method) of rare earth ion epitaxial growth shell MLn3F4:Ln4 3+ We obtain MLn1F4:Ln2 3+ @MLn3F4:Ln4 3+ ;

[0074] S3, Rare earth ion epitaxial growth shell MLn3F4:Ln4 in step S2 3+ Surface-grown (e.g., by shell epitaxial growth method) heterogeneous inert protective layer M 1 F2 was used to dope the medical isotope Ra-223 to obtain rare earth fluorescent nanomaterials.

[0075] According to an embodiment of the present invention, in the method for preparing the rare earth fluorescent nanomaterial, surface modification treatment of the rare earth fluorescent nanomaterial specifically refers to mixing the rare earth fluorescent nanomaterial and the ligand in an organic solvent, stirring at a temperature below 40°C for 1-24 hours, and then removing the organic solvent. Preferably, the organic solvent is one, two, or a mixture of two or more of cyclohexane, dichloromethane, trichloromethane, tetrahydrofuran, and N,N-dimethylformamide. Preferably, the removal of the organic solvent can be carried out using methods known in the art, such as rotary evaporation; furthermore, after removing the organic solvent, ultrapure water can be added for washing.

[0076] According to an embodiment of the present invention, step S1 can be performed using methods known in the art. For example, step S1 includes the following steps: adding a rare earth source and a metal source to a first solvent, heating to 250–350°C in an inert atmosphere, and reacting for 10–120 minutes to obtain a rare earth ion luminescent core MLn1F4:Ln2. 3+ .

[0077] According to an embodiment of the present invention, in step S1, the molar ratio of M, Ln1, and Ln2 in the rare earth source and the metal source is 1:(0-1):(0-1).

[0078] According to an embodiment of the present invention, the first solvent includes at least one of oleic acid, oleylamine and octadecene, preferably a mixture of oleic acid, oleylamine and octadecene, for example, by molar part, the first solvent includes 1 part octadecene, (0.5 to 1) parts oleylamine and (0.5 to 1) parts oleic acid.

[0079] According to an embodiment of the present invention, before heating in step S1, the following step is further included: heating under vacuum until the rare earth source and the metal source dissolve in the solvent.

[0080] According to an embodiment of the present invention, after the reaction in step S1, the following steps are further included: allowing the reacted solution to cool naturally, precipitating, washing and dispersing.

[0081] According to an embodiment of the present invention, the shell epitaxial growth method in step S2 includes the following steps: growing a rare earth ion sensitizer core MLn1F4:Ln2... 3+ Rare earth source and metal source are added to a second solvent and mixed. The mixture is heated to 250–350 °C in an inert atmosphere and reacted for 10–120 minutes to grow a rare earth ion epitaxial shell MLn3F4:Ln4. 3+ We obtain MLn1F4:Ln2 3+ @MLn3F4:Ln4 3+ .

[0082] According to an embodiment of the present invention, in molar ratio, M, Ln3, and Ln4 in the metal source and rare earth source in step S2 are 1:(0-0.9):(0-0.1).

[0083] According to an embodiment of the present invention, the second solvent comprises at least one of oleic acid and octadecene, preferably a mixture of oleic acid and octadecene, for example, by molar amount, the second solvent comprises 1 part oleic acid and (0.5 to 1.5) parts octadecene.

[0084] According to an embodiment of the present invention, step S3 includes the following steps: mixing MLn1F4:Ln2 3+ @MLn3F4:Ln4 3+ An alkaline earth metal source and the medical isotope Ra-223 are added to a second solvent and mixed. The mixture is then heated to 250–350°C in an inert atmosphere and reacted for 10–120 minutes to grow a heterogeneous inert protective layer M. 1 F2, yielding MLn1F4:Ln2 3+ @MLn3F4:Ln4 3+ @M 1 F2.

[0085] According to an embodiment of the present invention, the rare earth source is selected from one, two or more of the following substances: at least one of the acetate, chloride, nitrate and trifluoroacetate salts of ytterbium, erbium, gadolinium, thulium, holmium, samarium, neodymium, yttrium and lutetium, preferably trifluoroacetate and chloride salt; more preferably at least one of the trifluoroacetate and / or chloride salts of ytterbium, erbium, gadolinium, thulium, holmium, samarium, neodymium, yttrium and lutetium, for example at least one of ytterbium trifluoroacetate, yttrium trifluoroacetate, erbium trifluoroacetate, thulium trifluoroacetate and gadolinium trifluoroacetate.

[0086] According to an embodiment of the present invention, the metal source provides element M to the nanocrystals, and the alkaline earth metal source provides element M to the nanocrystals. 1 For example, the metal source is selected from one, two, or more of hydroxides, oleates, acetates, trifluoroacetates, fluorides, and hydrofluorides containing element M, preferably trifluoroacetates, fluorides, or hydrofluorides containing element M, such as sodium trifluoroacetate. For example, the alkaline earth metal source is selected from those containing element M. 1 One, two, or more of the following: hydroxides, oleates, acetates, trifluoroacetates, fluorides, and hydrofluorides of the element, preferably containing M. 1 The trifluoroacetate, fluoride, or hydrofluoric acid salt of an element, for example, calcium trifluoroacetate.

[0087] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0088] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0089] Comparative Example 1:

[0090] Preparation of core-shell-shell structured nanomaterials with unlabeled radioactive medical isotopes

[0091] NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2, and the surface of the nanomaterial is modified.

[0092] The preparation method of the above-mentioned core-shell-shell structured nanomaterials can be selected from conventional methods for preparing nanomaterials in the field, such as hot injection, high-temperature co-precipitation, high-temperature thermal decomposition, hydrothermal method or sol-gel method. The example in this comparative example is the high-temperature thermal decomposition method.

[0093] Preparation of NaYbF4:Er by high-temperature thermal decomposition 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2 nanomaterials include the following steps:

[0094] S101. Weigh 0.1360 g sodium trifluoroacetate, 0.4962 g ytterbium trifluoroacetate, 0.0051 g erbium trifluoroacetate, and 0.0032 g cerium trifluoroacetate into a three-necked flask at room temperature. Add 3.17 mL oleic acid, 3.29 mL oleylamine, and 6.40 mL octadecene as a mixed solvent. Heat under vacuum until the sodium trifluoroacetate and ytterbium trifluoroacetate salts dissolve. Continue heating to 310 °C under an inert atmosphere. After reacting for 1 hour, allow to cool naturally to room temperature, precipitate, and wash to obtain α-phase NaYbF4:Er 3+ Ce 3+ Nanocrystals.

[0095] S102. The α-phase NaYbF4:Er prepared in step S101 is... 3+ Ce 3+ Add the following to a mixed solvent of 6.4 mL oleic acid and 6.4 mL octadecene: sodium trifluoroacetate, 0.4962 g ytterbium trifluoroacetate, 0.0051 g erbium trifluoroacetate, and 0.0032 g cerium trifluoroacetate. Heat under vacuum until the trifluoroacetates dissolve, then continue heating to 310 °C under an inert atmosphere. After reacting for 1 hour, allow to cool naturally to room temperature, precipitate, and wash to obtain NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ Nanocrystals with a particle size of approximately 11 nm.

[0096] S103. The NaYbF4:Er prepared in step S102 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ Add 0.1331 g of calcium trifluoroacetate to a mixed solvent of 6.4 mL oleic acid and 6.4 mL octadecene; then add the calcium trifluoroacetate; heat under vacuum until the calcium trifluoroacetate dissolves, then continue heating to 310 °C under an inert atmosphere, react for 1 hour, and allow to cool naturally to room temperature. The precipitate is then washed to obtain the desired product.

[0097] NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2 nanocrystals, with a particle size of approximately 13 nm.

[0098] S104. Weigh 300 mg of distearate phosphatidylethanolamine-polyethylene glycol 2000-targeting peptide (DSPE-PEG2k-iRGD, Xi'an Ruixi Biotechnology Co., Ltd.) into a gaiwan-shaped flask, add 30 mL of chloroform as a solvent, sonicate to mix and dissolve, and add 30 mg of NaYbF4:Er prepared in step S103. 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2 nanocrystals were mixed and stirred overnight at room temperature. The chloroform in the flask was removed by rotary evaporation, and the mixture was dispersed in ultrapure water and centrifuged to obtain the precipitate.

[0099] NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2@DSPE-PEG2000 (a core-shell-shell structured nanomaterial with surface modification) was dispersed and stored in physiological saline.

[0100] Example 1: Preparation of Ra-223-labeled rare-earth fluorescent nanomaterials NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra and its surface were modified to obtain rare earth nanomedicines.

[0101] The preparation method can be any conventional method in the art, such as hot injection, high-temperature co-precipitation, high-temperature thermal decomposition, hydrothermal method, or sol-gel method for preparing nanomaterials. The preparation method in this embodiment is the high-temperature thermal decomposition method, which includes the following steps:

[0102] S201. Weigh 0.1360 g sodium trifluoroacetate, 0.4962 g ytterbium trifluoroacetate, 0.0051 g erbium trifluoroacetate, and 0.0032 g cerium trifluoroacetate into a three-necked flask at room temperature. Add 3.17 mL oleic acid, 3.29 mL oleylamine, and 6.40 mL octadecene as a mixed solvent. Heat under vacuum until the sodium trifluoroacetate and ytterbium trifluoroacetate salts dissolve. Continue heating to 310 °C under an inert atmosphere. After reacting for 1 hour, allow to cool naturally to room temperature, precipitate, and wash to obtain α-phase NaYbF4:Er 3+ Ce 3+ Nanocrystals.

[0103] S202. The α-phase NaYbF4:Er prepared in step S201 is... 3+ Ce 3+Add the following to a mixed solvent of 6.4 mL oleic acid and 6.4 mL octadecene: sodium trifluoroacetate, 0.4962 g ytterbium trifluoroacetate, 0.0051 g erbium trifluoroacetate, and 0.0032 g cerium trifluoroacetate. Heat under vacuum until the trifluoroacetates dissolve, then continue heating to 310 °C under an inert atmosphere. After reacting for 1 hour, allow to cool naturally to room temperature, precipitate, and wash to obtain NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ Nanocrystals with a particle size of approximately 11 nm.

[0104] S203. The NaYbF4:Er prepared in step S202... 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ Add to a mixed solvent of 6.4 mL oleic acid and 6.4 mL octadecene, add 0.1331 g calcium trifluoroacetate, and add a radiation dose of 60 uCi. 223 RaCl3 was heated under vacuum until the calcium trifluoroacetate dissolved. The temperature was then increased to 310°C under an inert atmosphere. After reacting for 1 hour, the mixture was allowed to cool naturally to room temperature. The precipitate was then washed to obtain NaYbF4:Er. 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra nanocrystals have a particle size of approximately 13 nm.

[0105] S204. Weigh 300 mg of distearate phosphatidylethanolamine-polyethylene glycol 2000-targeted peptide (DSPE-PEG2k-iRGD) into a round-bottom flask, add 30 mL of chloroform as a solvent, and sonicate to dissolve. Then, mix with 30 mg of NaYbF4:Er prepared in step S203. 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra nanocrystals were mixed and stirred overnight at room temperature. The chloroform in the flask was removed by rotary evaporation, and the mixture was dispersed in ultrapure water and centrifuged to obtain the precipitate.

[0106] NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223Ra@DSPE-PEG2k-iRGD, which is a modified nanocrystal, is a rare earth nanomedicine. The modified nanocrystal is dispersed and stored in physiological saline.

[0107] See Figure 1 The image shown is a transmission electron microscope (TEM) image of the modified nanocrystals prepared in this embodiment dispersed in physiological saline. As can be seen from the image, the modified nanocrystals (hereinafter referred to as the integrated reagent) are uniformly dispersed in physiological saline without agglomeration, and the particle size of the modified nanocrystals is 10-50 nm.

[0108] Comparative Example 2

[0109] Medical isotopes were prepared according to the preparation method in Example 1. 223 Ra-labeled nanomaterials NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @NaYF4: 223 The preparation method of Ra and its surface modification to prepare rare earth nanomedicine is basically the same as in Example 1, except that:

[0110] In step S203, "0.1331g calcium trifluoroacetate" is changed to "0.4962g ytterbium trifluoroacetate" to prepare NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @NaYF4: 223 Ra nanocrystals with a particle size of approximately 13 nm; all other conditions were the same as in Example 1, and this is referred to as Comparative Rare Earth Nanomedicine 1.

[0111] See Figure 2 As shown, compared to the comparative rare earth nanomedicine 1 in Comparative Example 2, the NaYbF4:Er prepared in Example 1... 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra rare-earth nanomedicines exhibit significant performance advantages, with a near-infrared quantum yield as high as 45%, which is 2.25 times that of comparative rare-earth nanomedicine 1 in Example 2; meanwhile, in the rare-earth nanomedicine of Example 1... 223 The Ra labeling rate also reached 80%, which is twice that of the comparative rare-earth nanomedicine 1 in Comparative Example 2. (The text abruptly ends here, likely due to an incomplete sentence or missing information.) 223 Ra had a lower labeling rate and its therapeutic effect on tumor sites was not as good as in Example 1. Therefore, the following will not conduct experimental verification of the targeting of the drug in Comparative Example 2.

[0112] Application Example 1: Confocal cell imaging experiment to verify the targeting ability of medical isotope Ra-223-labeled rare earth nanomedicines against cancer cells.

[0113] The rare earth nanomedicine prepared in Example 1 was mixed with human gastric cancer cells (MGC-803, purchased from Fenghui Biotechnology) and co-incubated in 1640 complete medium at 37°C for 8 hours (the concentration of rare earth nanomedicine in the mixed solution was 100 μg / mL). After washing twice and fixing with paraformaldehyde fixative, the cell nuclei were stained with DAPI dye and excited by a 980 nm laser. (See [link to documentation]). Figure 3 As shown, upconversion luminescence medical imaging of cells can be observed simultaneously under a confocal fluorescence microscope, exhibiting both dark-field green light emission (~540 nm) and dark-field red light emission (~650 nm).

[0114] Application Example 2: Evaluation of the in vivo fluorescence imaging effect of medical isotope Ra-223 labeled rare earth nanomedicines

[0115] 0.2 mL of rare earth nanomedicine prepared in Example 1 was injected intravenously into nude mice with subcutaneous tumors of human gastric cancer cells MGC-803.

[0116] NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra@DSPE-PEG2k-iRGD was used for fluorescence imaging under excitation light at a wavelength of 980 nm. The fluorescence imaging effect in nude mice was observed. See [link to relevant documentation]. Figure 4 As shown, blood vessels in the mouse's head, back, legs, and tumor site are clearly visible, yielding a low-background, clear fluorescence image in the near-infrared IIb region (emitting at ~1530nm).

[0117] Application Example 3: Evaluation of the in vitro cell-killing effect of medical isotope Ra-223 labeled rare earth nanomedicines

[0118] MGC-803 cells were fed at a rate of 3 × 10⁻⁶ 4 Inoculated at a concentration of [number] cells / mL in 96-well plates, and after adhesion, were seeded with different drugs: NaYbF4:Er prepared in the comparative example. 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2@DSPE-PEG2k-iRGD (denoted as NPs), pure nuclide 223 Ra (Ra group, denoted as Ra), NaYbF4:Er prepared in Comparative Example 1 3+ Ce 3+@NaYbF4:Er 3+ Ce 3+ @CaF2@DSPE-PEG2k-iRGD and pure nuclides 223 Ra mixture (mixture group, denoted as NPs+Ra), NaYbF4:Er prepared in Example 1 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Cells were co-cultured with Ra@DSPE-PEG2k-iRGD (denoted as NPs-Ra) for 48 hours. The drug concentrations of NPs in Comparative Example 1 and NPs in NPs-Ra prepared in Example 1 were the same, at 0 μg / mL, 12.5 μg / mL, 25 μg / mL, 50 μg / mL, 100 μg / mL, and 150 μg / mL, respectively. The radiation doses in the Ra group and the mixed group were the same as those in NPs-Ra. Absorbance at 450 nm was measured using the CCK8 assay, and cell viability was calculated.

[0119] See Figure 5 As shown, different drugs exhibit varying in vitro killing effects on human gastric cancer cells MGC-803. The rare-earth nanoparticles prepared in Example 1 demonstrate better killing effects than the comparative drug at the same concentration, and also better than pure nuclides (i.e., free nuclides) at the same radiation dose. 223 Ra has a more significant killing effect.

[0120] Application Example 4: Study on the treatment of human gastric cancer subcutaneous tumors in nude mice using medical isotope Ra-223 labeled rare earth nanomedicines.

[0121] Animal experiments were approved by the Laboratory Animal Ethics Committee of Fujian Medical University. BALB / c nude mice (female, 4 weeks old) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. and housed in the animal facility of the New Drug Safety Evaluation Center of Fujian Medical University.

[0122] Select a tumor mass with a volume of approximately 100 mm. 3 Nude mice bearing human gastric cancer cell line MGC-803 subcutaneous tumors were divided into 5 groups (5 mice in each group) and injected intratumorally with:

[0123] The first group was injected with normal saline, which was the normal saline group and was designated as the control group.

[0124] The second group was injected with NaYbF4:Er, which was not loaded with rare earth medical nuclides, as in Comparative Example 1. 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+@CaF2@DSPE-PEG2k-iRGD, is the comparative example group, denoted as NPs;

[0125] The third group received injections of pure radionuclides. 223 Ra is a pure nuclide. 223 Group Ra, denoted as Ra;

[0126] Group 4 was injected with NaYbF4:Er prepared in Comparative Example 1. 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2@DSPE-PEG2k-iRGD and pure nuclides 223 A mixture of Ra is a mixture group, denoted as NPs+Ra;

[0127] Group 5: Rare earth nanomedicine from Example 1

[0128] NaYbF4:Er 3+ Ce 3+ @NaYbF4:Er 3+ Ce 3+ @CaF2: 223 Ra@DSPE-PEG2k-iRGD is the example group, denoted as NPs-Ra;

[0129] The administration of the rare earth nanomedicine was primarily based on the radioactive dose. In the fifth group, the radioactive dose was 0.3 uCi, the mass concentration was 16 mg / mL, and the volume was approximately 0.02 mL. In the third group, the administration was based on pure radionuclides. 223 The radioactive dose and volume of Ra were the same as those of rare earth nanomedicines; the mass concentration and volume of the second group of administration were the same as those of rare earth nanomedicines; the radioactive dose, mass concentration and volume of the fourth mixed group of administration were the same as those of rare earth nanomedicines; and the volume of physiological saline of the first group of administration was the same as that of rare earth nanomedicines.

[0130] The day of administration was recorded as day 1, and the radioactivity in the nude mice and the size of the tumor were recorded every three days thereafter.

[0131] Figure 6 This is a graph showing the changes in tumor volume in nude mice bearing tumors (average volume change for each group). Figure 6 It can be seen that the rare earth nanomedicine prepared in Example 1 has a significant inhibitory effect on tumor growth, and the inhibitory effect is significantly higher than that of pure radionuclides, mixed groups and nanomaterials in Comparative Example 1.

[0132] Figure 7This is a TUNEL assay image of tumor tissue on day 7 post-drug administration, used to assess tumor cell apoptosis. The gray areas in the image represent tumor cell apoptosis. Tumor tissue was obtained through in vivo sampling. The image shows that on day 7 post-drug administration, the tumor tissues in both the saline group and the control group were in a rapid growth phase with virtually no apoptosis. Pure radionuclide... 223 In the Ra group, a small area of ​​tumor cell apoptosis was observed due to the influence of a small amount of undiffused radionuclide irradiation in the early stages, while the tumor tissue in the Example group showed significant large-scale tumor cell apoptosis. Figure 7 The gray area in the intermediate embodiment group is the largest.

[0133] The tumor volume was recorded along with the weight changes of nude mice to evaluate the potential toxicity of rare earth nanomedicines.

[0134] In the saline group, comparative group, and pure radionuclide group, when the tumor size of a mouse in each group increased to the death standard (1500 mm), 3 The mice were considered dead and dissected. In Example 1, due to the small size of the tumor, the mice were dissected on the 36th day after administration. Important organs such as the heart, liver, spleen, lungs, and kidneys were taken. The organs were fixed with 4% paraformaldehyde, embedded in paraffin, sectioned, stained with hematoxylin and eosin (HE), and examined for histopathology.

[0135] Figure 8 The graph shows the weight changes (average weight of each group). The weight of all four groups of nude mice increased steadily, indicating that the drug administration did not have an adverse effect on weight.

[0136] After the experiment, the nude mice were dissected, and their organs and tumors were collected for testing. Figure 9 To select representative pathological sections of various tissues and organs from each group, as shown in the figure, no obvious lesions were found in the major tissues and organs of the four groups of nude mice.

[0137] The exemplary embodiments of the present invention have been described above. However, the scope of protection of this application is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A rare earth nanomedicine, characterized in that, The rare earth nanomedicine comprises a rare earth fluorescent nanomaterial and a biomodification layer; the rare earth fluorescent nanomaterial comprises a rare earth ion luminescent core MLn1F4:Ln2. 3+ The rare earth ion luminescent core is sequentially coated with a rare earth ion epitaxial growth shell MLn3F4:Ln4. 3+ and heterogeneous inert protective layer M 1 F2; The rare earth nanofluorescent material also includes the medical isotope Ra-223; The medical isotope Ra-223 is located in the heterogeneous inert protective layer M. 1 In F2; Wherein, M is a metallic element selected from one, two or more of Li, Na, K, Rb, Cs, Mg, Ca, Sr or Ba; Ln1 and Ln3 may be the same or different, and are independently selected from rare earth stable isotopes, wherein the rare earth stable isotopes are selected from one, two or more of La, Ce, Pr, Nd, Po, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc; Ln2 and Ln4 are rare earth luminescent ions, which may be the same or different, and are independently selected from one, two or more of Y, Sc, Yb, Er, Tm, Ho, Gd, Eu, Tb, Sm, Dy, Ce, Nd, La, Pr and Lu; M 1 It is an alkaline earth metal element, selected from one, two or more of Mg, Ca, Sr or Ba; The biomodification layer is located on the surface of the rare earth nanofluorescent material.

2. The rare earth nanomedicine according to claim 1, characterized in that, Ln2 and Ln4 may be the same or different, and are independently selected from one, two or more of Y, Yb, Er, Gd, Eu, and Lu. Preferably, in the rare earth fluorescent nanomaterial, the abundance of the medical isotope Ra-223 in the rare earth fluorescent nanomaterial is at least 0.1 μCi / g. Preferably, in the rare earth nanofluorescent material, M, M 1 Ln1, Ln2, Ln3, Ln4, and Ra-223 exist in ionic form. Preferably, the rare-earth ion luminescent core has a crystal structure. Preferably, the rare earth nanomedicine has the general formula MLn1F4:Ln2 3+ @MLn3F4:Ln4 3+ @M 1 F2: 223 Ra@BML, where BML refers to the biomodified layer. Preferably, the rare earth nanofluorescent material is designated as MLn1F4:Ln2. 3+ @MLn3F4:Ln4 3+ @M 1 F2: 223 Ra.

3. The rare earth nanomedicine according to claim 1 or 2, characterized in that, The biomodified layer includes LIG, a functional tumor-targeting biomolecule. Preferably, the functional tumor-targeting biomolecule LIG is selected from water-soluble ligands that do not have tumor-specific recognition capabilities and / or molecules that have tumor-targeting functions. Preferably, the water-soluble ligand that does not have tumor-specific recognition capability is selected from one or more of the following: methoxy polyethylene glycol alendronate (MPEG-ALE), polyacrylic acid (PAA), distearate phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and its derivatives, dioleoylphosphatidylethanolamine-polyethylene glycol (DOPE-PEG) and its derivatives, and dipalmitoylphosphatidylethanolamine-polyethylene glycol (DPPE-PEG) and its derivatives. Preferably, the tumor-targeting molecule is selected from one, two, or more of the following: organic small molecules, monoclonal antibodies, polyclonal antibodies, peptides, and single or multi-target small molecule inhibitor biomolecules.

4. The rare earth nanomedicine according to any one of claims 1-3, characterized in that, The rare earth nanomedicine has a nanocrystal structure with a size of 5–200 nm. Preferably, the rare earth nanomedicine can use a 980nm laser as a light source to emit light in the visible red region (400-700nm) to the near-infrared IIb region (1400-1700nm).

5. The method for preparing rare earth nanomedicine according to any one of claims 1-4, characterized in that, The preparation method includes preparing rare earth nanofluorescent materials, modifying the surface of the rare earth nanofluorescent materials to obtain the biological modification layer, and then obtaining the rare earth nanomedicine.

6. The preparation method according to claim 5, characterized in that, The method for preparing the rare earth nanofluorescent material is selected from one of the following: hot injection, stepwise layer-by-layer epitaxial high-temperature coprecipitation, high-temperature thermal decomposition, hydrothermal method, or sol-gel method. Preferably, the method for preparing the rare earth nano-fluorescent material is a stepwise layer-by-layer epitaxial high-temperature thermal decomposition method, specifically including the following steps: S1. Preparation of rare-earth ion luminescent cores MLn1F4:Ln2 3+ ; S2, in the rare earth ion luminescent core MLn1F4:Ln2 3+ Surface growth of the rare earth ion epitaxial growth shell MLn3F4:Ln4 3 + We obtain MLn1F4:Ln2 3+ @MLn3F4:Ln4 3+ ; S3, Rare earth ion epitaxial growth shell MLn3F4:Ln4 in step S2 3+ Surface growth of heterogeneous inert protective layer M 1 F2 was used to dope the medical isotope Ra-223 to obtain rare earth fluorescent nanomaterials.

7. The preparation method according to claim 6, characterized in that, When preparing the rare-earth nanofluorescent material, M in the heterogeneous inert protective layer 1 The molar ratio of M in the rare earth ion luminescent core is no greater than 4:

1.

8. The preparation method according to any one of claims 5-7, characterized in that, In the preparation method of the rare earth nanomedicine, the surface modification treatment of the rare earth nanofluorescent material specifically refers to mixing the rare earth nanofluorescent material and the ligand forming the biological modification layer in an organic solvent, stirring at a temperature below 40°C for 1-24 hours, and then removing the organic solvent.

9. Use of the rare earth nanomedicine according to any one of claims 1-4 in the pharmaceutical field.

10. A diagnostic and therapeutic agent for the medical isotope Ra-223, characterized in that, The diagnostic and therapeutic agents for the medical isotope Ra-223 include the rare earth nanomedicines according to any one of claims 1-4.

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