CN116459358A - Rare earth radioactive medical nuclide labeled nano material and preparation method and application thereof - Google Patents

Rare earth radioactive medical nuclide labeled nano material and preparation method and application thereof Download PDF

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Publication number
CN116459358A
CN116459358A CN202310171212.5A CN202310171212A CN116459358A CN 116459358 A CN116459358 A CN 116459358A CN 202310171212 A CN202310171212 A CN 202310171212A CN 116459358 A CN116459358 A CN 116459358A
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rare earth
mln
earth ion
medical
nanomaterial
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刘永升
郑靖雯
陈皓
洪茂椿
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Fujian Institute of Research on the Structure of Matter of CAS
Mindu Innovation Laboratory
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Fujian Institute of Research on the Structure of Matter of CAS
Mindu Innovation Laboratory
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/025—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus inorganic Tc complexes or compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1262—Capsules
    • A61K51/1265—Microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to the technical field of biomedical nano-drugs, and particularly relates to a rare earth radioactive medical nuclide labeled nano-material, a preparation method and application thereof. The nanomaterial comprises a rare earth ion sensitizer core MLn 1 F 4 :Ln 2 3+ The rare earth ion sensitizer is sequentially coated with a rare earth ion luminescent shell layer MLn outside the inner core 1 F 4 :Ln 2 3+ Rare earth ion sensitizer shell layer MLn 1 F 4 :Ln 2 3+ And rare earth ion inert protective layer MLn 1 F 4 The nano material is distributed with rare earth radiomedical nuclides R Ln. The nanometer material can be excited by 808nm, 980nm and 1532nm excitation light simultaneously or respectively, and can generate strong fluorescence emission of rare earth ions in 400-1700nm wave band from the visible region to the near infrared region, and can be used as a radionuclides medical PET-CT or SPECT tumor imaging agent, and further can realize rare earth nanometer fluorescence and rare earth radionuclides medical nuclides under the combined guidance of the radionuclides medical SPECT or PET-CT multi-mode medical images R Application of Ln intratumoral irradiation treatment.

Description

Rare earth radioactive medical nuclide labeled nano material and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biomedical nano-drugs, in particular to a nano-material marked by rare earth radionuclides and a preparation method and application thereof, and particularly relates to a preparation method and application of a multi-mode medical image diagnosis and tumor radioactive internal irradiation treatment integrated nano-preparation for rare earth radionuclides PET-CT or SPECT and rare earth fluorescent tumors.
Background
In recent years, along with the continuous intersection and maturation of molecular imaging technology, nuclear medicine technology and molecular biology technology, accurate medical treatment is rapidly developed, and tumor diagnosis and treatment integration based on radionuclide tracing and therapeutic agents gradually becomes a research hot spot. The diagnosis and treatment integration can discover cancer in vivo, can realize targeted radioactive internal irradiation treatment of tumors, can monitor curative effect and adjust the dosing scheme at any time in the treatment process, and can effectively improve the diagnosis rate of early cancers and enhance the treatment effect.
Although the targeted radiotherapy based on the radiomedical nuclides has the advantages of local treatment and minimally invasive compared with other treatment modes such as surgery and chemotherapy, the current common radiotherapy drugs mostly load and mark the radiomedical nuclides on targeted biomolecules or antibodies, but the drugs have the defects of low stability, poor tumor retention capacity and shorter in vivo circulation time, so that the accumulation amount of nuclides at tumor focus positions is low, and the efficient tumor intra-radioactive irradiation treatment is difficult to realize. Therefore, a more proper radionuclide labeling carrier needs to be designed to improve the application efficiency of the radionuclide in the nuclear medicine field.
The rare earth doped inorganic nano fluorescent material has rare earth up-conversion and near infrared luminescence, and high-resolution fluorescent imaging of the rare earth doped inorganic nano fluorescent material can improve a short plate which cannot accurately position a tiny focus in the radionuclides medical PET-CT (positron emission tomography-computed Tomography, positron emission computed tomography and X-ray tomography) and SPECT (single photonemissioncomputed tomography ) tumor imaging. More importantly, the rare earth inorganic nano fluorescent material is easy to be doped with rare earth radionuclides (such as 90 Y、 177 Lu、 166 Ho、 153 Sm, etc.), combining the two is expected to develop a novel multifunctional nano-preparation integrating multi-mode medical image tumor diagnosis such as rare earth radionuclides PET-CT or SPECT, rare earth fluorescence, etc., and efficient radioactive internal irradiation treatment.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a rare earth radioactive medical nuclide labeled nano material, a preparation method and application thereof.
In a first aspect, the present invention provides a rare earth radiomedical nuclides-labeled nanomaterial comprising a rare earth ion sensitizer core MLn 1 F 4 :Ln 2 3+ The rare earth ion sensitizer core is sequentially coated with a rare earth ion luminescent shell layer MLn 1 F 4 :Ln 2 3+ Rare earth ion sensitizer shell layer MLn 1 F 4 :Ln 2 3+ And rare earth ion inert protective layer MLn 1 F 4 Distributed on the nanomaterialWith rare earth radionuclides for medical use R Ln；
The distribution in the present invention refers to the rare earth radiomedical nuclides R Ln may be doped at any position in the rare earth ion sensitizer core, the rare earth ion luminescent shell layer, the rare earth ion sensitizer shell layer, and the rare earth ion inert protective layer of the nanomaterial, for example, doped in the rare earth ion sensitizer core, and/or the rare earth ion luminescent shell layer, and/or the rare earth ion sensitizer shell layer, and/or the rare earth ion inert protective layer, for example, doped in the rare earth ion inert protective layer.
Wherein M is a metal element selected from one or more of Li, na, K, rb, cs, mg, ca, sr and Ba.
Ln 1 、Ln 2 Is a rare earth stable isotope selected from one or more of La, ce, pr, nd, po, sm, eu, gd, tb, dy, ho, er, tm, yb, lu, Y and Sc.
R Ln is a rare earth radioactive medical nuclide which can be any therapeutic and/or imaging rare earth radioactive medical nuclide which can be stably loaded on rare earth inorganic nanocrystals and is selected from yttrium # 90 Y, lutetium ] 177 Lu, & holmium ] 166 Ho) samarium 153 Sm), for example, capable of effecting radiation therapy and imaging 177 Lu。
According to the invention, the R The abundance of Ln in the corresponding core or shell of the nanomaterial is at least 0.1mCi/g, preferably at least 0.15mCi/g, e.g. as described R The abundance of Ln on the inert protective layer of rare earth ions is at least 0.1mCi/g.
According to the invention, the surface of the rare earth ion inert protective layer is provided with a functional tumor targeting biomolecule LIG.
According to an embodiment of the invention, M, ln in the nanomaterial 1 、Ln 2 、 R Ln exists in an ionic state.
According to the present invention, the rare earth ion sensitizer core has a crystal structure, preferably the core has a trigonal, cubic, tetragonal, hexagonal or monoclinic crystal phase structure, for example, a hexagonal crystal phase structure.
According to the invention, the structural general formula of the rare earth radionuclide labeled nano material is as follows: R Ln-MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 LIG, in the general formula, R the position of Ln has the definition described above.
For example, the structural general formula of the rare earth radiomedical nuclides marked nano material is MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 : R Ln@lig, wherein, R ln is located in an inert protective layer of rare earth ions.
According to the invention, the functional tumor-targeting biomolecule LIG is selected from water-soluble ligands without tumor specific recognition capability or molecules with tumor targeting function.
According to the present invention, the water-soluble ligand having no tumor-specific recognition ability is selected from one or more of methoxy polyethylene glycol alemthanate (MPEG-ALE), polyacrylic acid (PAA), distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and derivatives thereof, dioleoyl phosphatidylethanolamine-polyethylene glycol (DOPE-PEG) and derivatives thereof, dipalmitoyl phosphatidylethanolamine-polyethylene glycol (DPPE-PEG) and derivatives thereof, for example, distearoyl phosphatidylethanolamine-polyethylene glycol 2000-polypeptide (DSPE-PEG 2 k-SWKLPPS).
According to the invention, the tumor targeting functional molecules are selected from one or more of small organic molecules, monoclonal antibodies, polyclonal antibodies, polypeptides and small single or multi-target inhibitor biomolecules (for example) with tumor targeting functions, preferably the small multi-target inhibitor biomolecules are selected from one or more of polysaccharides, nucleic acids, folic acid, aspirin and vitamin C.
According to the invention, the nanomaterial is 10 to 200nm in size, preferably 20 to 100nm in size, for example 30 to 50nm in size.
According to the present invention, the nanomaterial has a transmission electron micrograph substantially as shown in fig. 1.
According to the invention, the nanomaterial has low biotoxicity.
In a second aspect, the present invention further provides a method for preparing the rare earth medical nuclide labeled nanomaterial, which may be one selected from a stepwise layer-by-layer epitaxial high temperature coprecipitation method, a thermal decomposition method, a hydrothermal method or a sol-gel method, and an example is a stepwise layer-by-layer epitaxial high temperature thermal decomposition method.
According to the invention, the nano material marked by the rare earth medical nuclide is prepared by adopting a stepwise layer-by-layer epitaxial high temperature thermal decomposition method, and the method comprises the following steps:
s1, preparing a rare earth ion sensitizer inner core MLn 1 F 4 :Ln 2 3+ ；
S2, in the rare earth ion sensitizer kernel MLn 1 F 4 :Ln 2 3+ Surface, growing rare earth ion luminous shell MLn according to shell epitaxial growth method 1 F 4 :Ln 2 3+ Obtaining MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ ；
S3, in a rare earth ion luminous shell MLn 1 F 4 :Ln 2 3+ Sequentially growing rare earth ion sensitizer shell MLnF on the surface according to a shell epitaxial growth method 1 :Ln 2 3+ Inert protective layer MLn of rare earth ion 1 F 4 Rare earth doped medical nuclide R Ln。
According to the invention, step S1 comprises the steps of:
(a) Adding a stable rare earth source and a metal source into a first solvent, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to obtain a precursor.
(b) Adding the precursor, the stable rare earth source and the metal source into a second solvent, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to obtain the rare earth ion sensitive compoundChemoattractant core MLn 1 F 4 :Ln 2 3+ 。
According to the invention, M, ln in the stabilized rare earth source and metal source of steps (a), (b) 1 、Ln 2 The molar ratio of (2) is 1: (0-1): (0-1).
According to the present invention, the first solvent comprises at least one of oleic acid, oleylamine and octadecene, preferably a mixture of oleic acid, oleylamine and octadecene, for example, 1 part of octadecene, (0.5 to 1) part of oleylamine and (0.5 to 1) part of oleic acid by mol.
According to the invention, the second solvent comprises at least one of oleic acid and octadecene, preferably a mixture of oleic acid and octadecene, for example, in molar parts, and the second solvent comprises 1 part oleic acid and (0.5-1.5) parts octadecene.
According to the present invention, before the temperature is raised in the step (a), the method further comprises the following steps: heating under vacuum condition to stabilize rare earth source and metal source to be dissolved in solvent.
According to the invention, after the reaction in step (a), the method further comprises the following steps: naturally cooling the reacted solution, precipitating, washing and dispersing.
According to the present invention, the shell epitaxial growth method in step S2 includes the steps of: the rare earth ion sensitizer core MLn 1 F 4 :Ln 2 3+ Adding a second solvent into the stable rare earth source and the metal source, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to grow the rare earth ion luminescent shell MLn 1 F 4 :Ln 2 3+ Obtaining MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ 。
According to the invention, M, ln in the alkali metal source and the stabilized rare earth source in the step S2 in terms of mole ratio 1 、Ln 2 Is 1: (0-0.9): (0 to 0.1).
According to the invention, step S3 comprises the steps of:
(c) MLn is first put into 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ Adding a second solvent into the stable rare earth source and the metal source, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to grow the rare earth ion sensitizer shell MLn 1 F 4 :Ln 2 3+ Obtaining MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ ；
(d) MLn is set 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ Adding a second solvent into the stable rare earth source, the metal source and the rare earth radioactive medical nuclide source, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to grow the rare earth ion inert protective layer MLn 1 F 4 Obtaining R Ln-MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @M Ln 1 F 4 。
According to the invention, M, ln in the stabilized rare earth source and metal source of step (c) 1 、Ln 2 The molar ratio of (2) is 1: (0-0.5): (0-0.5).
According to the invention, M, ln in the stabilized rare earth source and metal source of step (d) 1 The molar ratio of (2) is 1: (0.5 to 1.5) is, for example, 1:1.
According to the invention, the stabilized rare earth source is selected from one or more of the following: acetate, chloride, nitrate and trifluoroacetate salts of the rare earth ion stable isotope Ln, preferably trifluoroacetate and rare earth chloride salts of the rare earth ion stable isotope Ln, and also preferably trifluoroacetate and/or chloride salts of ytterbium, erbium, gadolinium, thulium, holmium, samarium, neodymium, yttrium and lutetium, examples being ytterbium trifluoroacetate, yttrium trifluoroacetate, erbium trifluoroacetate, thulium trifluoroacetate, gadolinium trifluoroacetate.
According to the invention, the alkali metal source provides the element M for the nanocrystals. For example, the alkali metal source is selected from one or more of M-containing hydroxide, oleate, acetate, trifluoroacetate, fluoride, and fluorohydride, preferably M-containing trifluoroacetate, fluoride, or fluorohydride, exemplified by sodium trifluoroacetate.
According to the invention, the rare earth radionuclide source provides radiomedical nuclides for the nanocrystals R Ln, which may be chosen from oxalates and/or chlorides of radioactive rare earth isotopes, is exemplified by radioactive rare earth chlorides R LnCl 3 。
According to the invention, step S3 is followed by the following steps:
at the position of R Ln-MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 Surface modification modified ligand LIG.
According to the invention, the modified ligand has the definition as described above.
As an example, the preparation of the nanomaterial comprises the steps of:
preparation of rare earth ion sensitizer inner core NaGdF 4 :Yb 3+ ；
NaGdF in rare earth ion sensitizer core 4 :Yb 3+ Surface, growing rare earth ion luminous shell NaErF according to shell epitaxial growth method 4 :Tm 3+ Obtaining NaGdF 4 :Yb 3+ @NaErF 4 :Tm 3+ ；
NaErF in rare earth ion luminous shell layer 4 :Tm 3+ Sequentially growing rare earth ion sensitizer shell NaYF on the surface according to a shell epitaxial growth method 4 :Yb 3+ Rare earth ion inert protective layer NaYF 4 Finally, in the rare earth ion inert protective layer NaYF 4 Surface modification ligand DSPE-PEG2k-SWKLPPS.
In a third aspect, the present invention also provides a developing radiation therapy formulation comprising a nanomaterial as described above.
According to the invention, the preparation can respectively or simultaneously take 808nm, 980nm and 1532nm lasers as light sources to emit light in the wavelength bands from 400-700 nm in the visible light red region to 1400-1700 nm in the near infrared IIb region.
In a fourth aspect, the invention also provides the use of the nanomaterial or the imaging radiotherapy preparation in tumor diagnosis and/or treatment.
According to the invention, the tumour diagnosis comprises medical imaging, including real-time fluorescence imaging and/or surgical navigation, preferably for PET-CT or SPECT imaging.
(1) The tumor multi-mode medical image diagnosis and radiotherapy integrated nano preparation marked by the rare earth radioactive medical nuclide can be applied to PET-CT or SPECT imaging of tumor-bearing mice through intratumoral injection or tail vein injection.
(2) The tumor multi-mode medical image diagnosis and radiotherapy integrated nano preparation marked by the rare earth radioactive medical nuclide can be injected in tumor or injected in tail vein, can be excited by one or more excitation lights with wavelength of 808nm, 980nm or 1532nm, simultaneously generates emitted lights with wave bands from 400-700 nm to 1400-1700 nm in near infrared IIb region, and can realize finer in-vivo real-time positioning diagnosis and imaging.
(3) The rare earth radioactive medical nuclide labeled tumor multi-mode medical image diagnosis and radiotherapy integrated nano preparation can be injected into tumor or injected into tail vein for administration and is used for radiotherapy of tumor-bearing mice. Specifically, when the tumor is positioned on the skin surface, the medicine can be directly injected into the tumor to realize the in-focus administration, the targeting function of the medicine is beneficial to the detention of the medicine at the focus, and the killing of the tumor is realized through local high-dose internal radiation; the tumor located in the deep body position can be administrated by tail vein injection, and drug delivery and tumor treatment are realized by specific targeting identification of the drug on tumor cells.
Advantageous effects
(1) The nano material marked by the rare earth radioactive medical nuclide has stable property, and after a layer of water-soluble ligand is modified on the outer surface of the nano material, the biocompatibility of the material is improved, the nano material is changed from lipophilicity to hydrophilicity, and the nano material can be dispersed in normal saline and serum for a long time to keep a monodisperse state without agglomeration.
(2) The rare earth radioactive medical nuclide marked nano material has a core-shell micro-nano structure, and is easy to dope with the rare earth radioactive medical nuclide R Ln, because of R Ln is homologous to the substitutional matrix cations in the nanocrystalline lattice R Ln stabilizes the Ln atom of the rare earth isotope, minimizes the influence on the microstructure of the material, and has stable combination and difficult target removal.
(3) The invention relates to a rare earth radiomedical nuclides marked nano material, wherein the loaded rare earth radiomedical nuclides such as 177 Lu has a long half-life (t1/2=6.7 days) and can simultaneously emit beta rays (498 keV) and gamma rays (208 keV), wherein the beta rays can be used for efficient intra-radioactive irradiation treatment of tumors, and the gamma rays can be used for SPECT imaging of tumors, so that diagnosis and treatment integrated application of tumors can be synchronously realized.
(4) The nano material marked by the rare earth radioactive medical nuclide has specific targeting recognition capability on tumor cells after the functional tumor targeting biomolecules are modified on the surface, and has strong detention capability after the tumor cells are targeted to tumor lesions, so that the rare earth radioactive medical nuclide can be fixed in the tumor lesions for a long time, the effect of intra-tumor irradiation and radiotherapy can be greatly improved, and the radioactive injury to other normal tissues and organs in the local radiotherapy process can be synchronously reduced.
(5) The rare earth radioactive medical nuclide labeled nano material has good biological safety and no toxic or side effect.
(6) The nanometer material marked by the rare earth radioactive medical nuclide can be excited by 808nm, 980nm and 1532nm excitation light simultaneously or respectively, generates the strong fluorescence emission of rare earth ions with 400-1700nm wave bands crossing the visible region to the near infrared two regions, and can realize the solid tumor focus or the small micro-metastatic tumor focus<1 mm) accurate rare earth fluorescence medical imaging; meanwhile, the fluorescent powder can be used as a radioactive nuclear medicine PET-CT or SPECT tumor imaging agent, and further can realize rare earth nano fluorescence and rare earth radioactivity under the combined guidance of radioactive nuclear medicine SPECT or PET-CT multi-mode medical imagesMedical nuclide R Application of Ln intratumoral irradiation treatment.
Drawings
FIG. 1 is a transmission electron microscope image of a core-shell structured nanomaterial dispersed in physiological saline prepared in example 1 of the present invention;
FIG. 2 shows the in vitro stability of the rare earth radiomedical nuclides of the nanomaterial in the physiological saline and fetal bovine serum, respectively, in example 2 of the present invention;
FIG. 3 shows the binding capacity of nanomaterial to human gastric cancer cell MGC-803 in example 3 of the present invention;
FIG. 4 is a diagram showing the up-conversion luminescence medical imaging of the cells under the excitation of 980nm and 808nm lasers, respectively, of the nanomaterial in example 3 of the present invention;
FIG. 5 is a fluorescence imaging diagram of near infrared IIb region of a tumor nanomaterial in example 4 of the present invention in a nude mouse with human gastric cancer subcutaneous tumor under excitation of 980nm and 808nm lasers, respectively;
FIG. 6 is a SPECT image of the nanomaterial of example 5 of the present invention in vivo in nude mice bearing human gastric carcinoma subcutaneous tumors at different time points;
FIG. 7 shows the in vitro killing effect of different drugs on human gastric cancer cells MGC-803 in example 6 of the present invention;
fig. 8 shows the distribution of nanomaterial on day 25 in nude mice bearing tumors (n=3) in example 7 of the present invention;
fig. 9 is a graph of the change in radiation dose in tumor-bearing nude mice of example 8 of the present invention (n=5);
fig. 10 is a graph of tumor volume change (n=5) of a tumor-bearing nude mouse according to example 8 of the present invention;
FIG. 11 is a graph showing survival of nude mice bearing tumors in example 8 of the present invention;
FIG. 12 is a photograph showing one nude mouse per group before, on days 7 and 14 of the administration of example 8 of the present invention;
FIG. 13 is a TUNEL test chart of tumor tissue on day 7 after administration in example 8 of the present invention;
fig. 14 is a graph showing the change in body weight (n=5) after administration to a tumor-bearing nude mouse according to example 9 of the present invention;
FIG. 15 is a chart showing HE staining of histopathological sections in example 9 of the present invention.
Detailed Description
The nanomaterial of the present invention, and the preparation method and application thereof will be described in further detail with reference to specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Comparative example:
preparation of core-shell structured nanomaterial NaGdF of unlabeled rare earth radiomedical nuclides 4 :Yb 3+ @NaErF 4 :Tm 3+ @NaYF 4 :Yb 3+ @NaYF 4 And surface modifying the nano material.
The preparation method of the core-shell-structured nanomaterial can be selected from a high-temperature coprecipitation method, a high-temperature thermal decomposition method, a hydrothermal method or a sol-gel method and other methods for preparing the nanomaterial conventionally in the field, and the preparation method is exemplified by the high-temperature thermal decomposition method in the comparative example.
Preparation of NaGdF by high-temperature thermal decomposition method 4 :Yb 3+ @NaErF 4 :Tm 3+ @NaYF 4 :Yb 3+ @NaYF 4 The nanomaterial comprises the following steps:
s101, weighing 0.1360g of sodium trifluoroacetate, 0.2481g of gadolinium trifluoroacetate and 0.2560g of ytterbium trifluoroacetate at room temperature, adding 3.17mL of oleic acid, 3.29mL of oleylamine and 6.4mL of octadecene as mixed solvents into a three-neck flask; heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain alpha-phase NaGdF 4 :50％Yb 3+ And (3) nanocrystalline.
S102, preparing alpha-phase NaGdF in the step S101 4 :50％Yb 3+ To a mixed solvent of 6.4mL of oleic acid and 6.4mL of octadecene, 0.0680g was addedSodium trifluoroacetate, 0.1241g gadolinium trifluoroacetate and 0.1280g ytterbium trifluoroacetate; heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain beta-phase NaGdF 4 :50％Yb 3+ The grain size of the nanocrystalline is about 8nm.
S103, preparing beta-phase NaGdF in the step S102 4 :50％Yb 3+ To a mixed solvent of 6.4mL of oleic acid and 6.4mL of octadecene, 0.1360g of sodium trifluoroacetate, 0.0025g of thulium trifluoroacetate and 0.5038g of erbium trifluoroacetate were added; heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ The grain size of the nanocrystalline is about 15nm.
S104, preparing NaGdF in the step S103 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ The nanocrystals were added to a mixed solvent of 6.4mL oleic acid and 6.4mL octadecene, and 0.1360g sodium trifluoroacetate, 0.0512g ytterbium trifluoroacetate and 0.3852g yttrium trifluoroacetate were added; heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ The grain size of the nanocrystalline is about 30nm.
S105, preparing NaGdF in the step S104 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ To a mixed solvent of 6.4mL of oleic acid and 6.4mL of octadecene, 0.1360g of sodium trifluoroacetate and 0.4280g of yttrium trifluoroacetate were added; heating to 110deg.C under vacuum, continuously heating to 300deg.C under inert atmosphere after the trifluoroacetate is dissolved, reacting for 0.5 hr, naturally cooling to room temperature, precipitating, and washing to obtain about 300mg NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 The grain size of the nanocrystalline is about 40nm.
S106, weighing 300mg distearoyl phosphatidylethanolamine-polyethylene glycol 2000-targeting polypeptide (DSPE-PEG 2 k-SWKLPPS) in a eggplant-shaped bottle, adding 30mL chloroform as solvent, ultrasonic mixing and dissolving, and 30mg NaGdF prepared in step S105 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 The nanocrystals were mixed and stirred overnight at room temperature. Removing chloroform in the bottle by rotary evaporation, adding ultrapure water for dispersion, and centrifuging to obtain precipitate beta-NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 @ DSPE-PEG2000 (surface modified core-shell structured nanomaterial) dispersed in physiological saline.
Example 1: preparation of rare earth medical nuclide labeled nano material NaGdF 4 :Yb 3+ @NaErF 4 :Tm 3+ @NaYF 4 :Yb 3 + @NaYF 4 : 177 Lu and surface modification
The preparation method can be selected from the methods for preparing the nano material by a high-temperature coprecipitation method, a high-temperature thermal decomposition method, a hydrothermal method or a sol-gel method and the like which are conventional in the art, and is exemplified by the high-temperature thermal decomposition method, and the preparation method comprises the following steps:
s201, weighing 0.1360g of sodium trifluoroacetate, 0.2481g of gadolinium trifluoroacetate and 0.2560g of ytterbium trifluoroacetate at room temperature to a three-neck flask, and adding 3.17mL of oleic acid, 3.29mL of oleylamine and 6.4mL of octadecene as mixed solvents; heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain alpha-phase NaGdF 4 :50％Yb 3+ And (3) nanocrystalline.
S202, preparing alpha-phase NaGdF in the step S201 4 :50％Yb 3+ To a mixed solvent of 6.4mL of oleic acid and 6.4mL of octadecene, 0.0680g of sodium trifluoroacetate, 0.1241g of gadolinium trifluoroacetate and 0.1280g of ytterbium trifluoroacetate were added; heating to 110 ℃ under vacuum condition, after the trifluoroacetate is dissolved,continuously heating to 300 ℃ in inert atmosphere, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain beta-phase NaGdF 4 :50％Yb 3+ The grain size of the nanocrystalline is about 8nm.
S203, preparing beta-phase NaGdF from the step S202 4 :50％Yb 3+ The nanocrystalline was added to a mixed solvent of 6.4mL oleic acid and 6.4mL octadecene, and 0.1360g sodium trifluoroacetate, 0.0025g thulium trifluoroacetate and 0.5038g erbium trifluoroacetate were added; heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ The grain size of the nanocrystalline is about 15nm.
S204, preparing NaGdF in the step S203 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ The nanocrystals were added to a mixed solvent of 6.4mL oleic acid and 6.4mL octadecene, and 0.1360g sodium trifluoroacetate, 0.0512g ytterbium trifluoroacetate and 0.3852g yttrium trifluoroacetate were added; heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ The grain size of the nanocrystalline is about 30nm.
S205, preparing NaGdF in the step S204 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ The nanocrystals were added to a mixed solvent of 6.4mL oleic acid and 6.4mL octadecene, 0.1360g sodium trifluoroacetate and 0.4280g yttrium trifluoroacetate were added, and a radiation dose of 5mCi was added 177 LuCl 3 The method comprises the steps of carrying out a first treatment on the surface of the Heating to 110 ℃ under vacuum, continuously heating to 300 ℃ under inert atmosphere after the trifluoroacetate is dissolved, naturally cooling to room temperature after reacting for 0.5 hour, precipitating and washing to obtain NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 Lu nanocrystalline, pelletThe diameter is about 40nm.
S206, weighing 300mg distearoyl phosphatidylethanolamine-polyethylene glycol 2000-targeting polypeptide (DSPE-PEG 2 k-SWKLPPS) in a eggplant-shaped bottle, adding 30mL chloroform as a solvent, ultrasonically mixing and dissolving, and 30mg NaGdF prepared in step S205 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 The Lu nanocrystals were mixed and stirred overnight at room temperature. Removing chloroform in the bottle by rotary evaporation, adding ultrapure water for dispersion, and centrifuging to obtain precipitate beta-NaGdF 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 Lu@DSPE-PEG2k-SWKL PPS is modified nanocrystalline, and the modified nanocrystalline is dispersed and stored in physiological saline.
The yield of the modified nanocrystals was measured to be 50-85% and the labeling rate was measured to be 30-60%.
Referring to fig. 1, a transmission electron microscope image of modified nanocrystals dispersed in physiological saline is prepared in this example, and it can be seen that the modified nanocrystals (hereinafter referred to as integrated agents) are uniformly dispersed in physiological saline without agglomeration, and the particle size of the modified nanocrystals is 30-50nm.
Example 2: evaluation of in vitro stability of rare earth radiomedical nuclides-labeled nanomaterials
The integrated preparation NaGdF prepared in example 1 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3 + @NaYF 4 : 177 Lu@DSPE-PEG2k-SWKLP PS is respectively dispersed in physiological saline and fetal bovine serum, a plurality of time points (0 h, 1h, 2h, 3h, 4h, 8h, 12h, 24h and 48 h) are selected for sampling, and the radiation stability of the integrated reagent in different media at different times is measured by using a gamma counter, and the modified nanocrystal has good stability in the fetal bovine serum and physiological saline within 48 hours, as shown in figure 2, wherein the radiation purity of 48h in the physiological saline is higher than 90%, and the radiation purity of 48h in the fetal bovine serum is higher than 85%.
Example 3: targeting verification of rare earth radionuclide marked integrated preparation on cancer cells
(1) In vitro cell binding
The specificity of the integrated formulation prepared in example 1 to human gastric cancer cells was evaluated by cell binding experiments. In 6-well plates, 10 is inoculated per well 5 ～10 6 MGC-803 cells (human gastric cancer cells) were incubated overnight, modified nanocrystals with a radioactive dose of 0.01mCi were added to the wells as the experimental group, rare earth radiomedical nuclides with the same radioactive dose were added as the control group, incubated with the cells separately, cells were rinsed with PBS at different incubation times for 12h, 24h, 48h, and all supernatants were collected, followed by digestion of the cells and collection. Radioactivity of the collected supernatant and cell fluid was recorded with a γ counter, and binding rate (%) =cell fluid count/(cell fluid count+supernatant count) ×100%.
Referring to fig. 3, the integrated preparation prepared in example 1 was increased with time, the binding rate with cells was gradually increased, and 32% at 48 hours was achieved; the binding rate of the pure nuclide and the cells is gradually reduced along with the increase of time, and the binding rate is less than 2 percent, which is far lower than that of the integrated preparation prepared in the embodiment, and the integrated preparation prepared in the surface embodiment 1 can be well combined with the cells.
(2) Confocal cell imaging experiments
The tumor multi-mode medical image and radiotherapy integrated preparation prepared in example 1 is mixed with human gastric cancer cells (MGC-803), incubated for 8 hours at 37 ℃ and then fixed (the concentration of the integrated preparation in the mixed solution is 200 ug/mL), nuclei are dyed by DAPI dye, and up-conversion luminescence medical imaging images of dark field green light emission (540 nm) and dark field red light emission (650 nm) in the cells can be simultaneously observed under confocal fluorescence microscopy under excitation of 980nm and 808nm lasers respectively, as shown in FIG. 4.
Example 4: assessing in vivo fluorescence imaging effects of integrated formulations
Intravenous injection of 0.2mL of multimode medical integrated preparation NaGdF prepared in example 1 with concentration of 30mg/mL into naked tail of human gastric cancer cell MGC-803 subcutaneous tumor 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 Lu@DSPE-PEG2k-SWKLP PS is subjected to fluorescence imaging under excitation of excitation light with wavelength of 808nm and 980nm respectively, and in-vivo fluorescence imaging effect of nude mice is observed, and as shown in FIG. 5, blood vessels at the head, back, leg and tumor of the mice are clearly visible under excitation light with two wavelengths, and a fluorescence imaging diagram of a near infrared IIb region (emitted at 1530 nm) with lower background and clearer than that under excitation of 980nm can be obtained under excitation of 808 nm.
Example 5: assessing SPECT imaging effect of an integral formulation
Selecting a tumor mass volume of about 100mm 3 Is prepared by injecting an integrated preparation NaGdF prepared in example 1 with radioactive dose of 0.1mCi into nude mice bearing human gastric cancer cell MGC-803 subcutaneous tumor 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 The Lu@DSPE-PEG2k-SWKLP PS, shown in FIG. 6, is SPECT (single photon emission computed tomography) at different times (1 h, 24h, 72 h) after injection, and the integral preparation prepared in example 1 has good retention effect at the tumor and no obvious diffusion occurs within 3 days.
Example 6: evaluating the in vitro cell killing effect of the integral formulation
MGC-803 cells were grown at 3X 10 4 The concentration of each mL is inoculated in a 96-well plate, and after adherence, the mixture is respectively mixed with different medicines: naGdF prepared in comparative example 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 @ DSPE-PEG2k-SWKLPPS, pure nuclide 177 Lu, naGdF prepared in example 1 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 Lu@DSPE-PEG2k-SWKLP PS (concentration of drug after addition was 0. Mu.g/mL, 25. Mu.g/mL, 50. Mu.g/mL, 100. Mu.g/mL, 200. Mu.g/mL, 400. Mu.g/mL, 800. Mu.g/mL, respectively) was co-cultured for 24 hours. The absorbance at 450nm was measured by CCK8 method, and the cell viability was calculated.
See fig. 7 for a different drugThe in vitro killing effect on human gastric cancer cells MGC-803 is different, the integrated preparation prepared in the example 1 has better killing effect than the comparative example with the same concentration, and simultaneously has better killing effect than the pure nuclide with the same radiation dose, namely free nuclide 177 Lu has more remarkable killing effect.
Example 7: in vivo distribution research of integrated preparation in nude mice with human gastric cancer subcutaneous tumor
Selecting a tumor mass volume of about 100mm 3 MGC-803 subcutaneous tumor-bearing nude mice (n=3), study of the integrated preparation NaGdF prepared in example 1 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 Biodistribution of Lu@DSPE-PEG2k-SWKLP PS.
Intratumoral injection of the integrated formulation NaGdF prepared in example 1 with a radioactive dose of 0.1mCi 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 Lu@DSPE-PEG2k-SWKLP PS or pure nuclides 177 Lu, mice were euthanized on day 25 post-dose, the required organs and tumors were removed, radioactivity was measured with a gamma counter and calculated as percentage of injected dose per gram of tissue (% ID/g).
On day 25 post-administration, the integrated formulation prepared in example 1 and pure nuclides 177 The distribution of Lu in the tumor-bearing nude mice is shown in fig. 8 (n=3), and it can be seen that the integrated preparation prepared in example 1 remains in the mice for a long time, and remains concentrated at tumor sites, thus having good retention effect; and free from 177 Lu is difficult to stay at the tumor after intratumoral injection, but instead tends to enrich the bone, and it is difficult to achieve the effect of directional therapy.
Example 8: treatment research of integrated preparation on nude mice with human gastric cancer subcutaneous tumor
Selecting a tumor mass volume of about 100mm 3 The nude mice bearing human gastric cancer cell MGC-803 subcutaneous tumor are grouped (n=5, namely 5 nude mice in each group), physiological saline and NaGdF without rare earth medical nuclide are respectively injected into the tumor 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 @ DSPE-PEG2k-SWKLPPS, pure nuclide 177 Lu, example 1 Integrated NaGdF production 4 :50％Yb 3+ @NaErF 4 :0.5％Tm 3+ @NaYF 4 :10％Yb 3+ @NaYF 4 : 177 Lu@DSPE-PEG2k-SWKLP PS。
Wherein, the radioactive dose of the integrated preparation is 0.1mCi, the mass concentration is 8mg/mL, the volume is about 0.05mL, and the administration is mainly based on the radioactive dose; pure nuclide 177 The radioactive dose and volume of Lu are the same as those of the integrated preparation; the mass concentration and volume of the comparative example are the same as those of the integrated preparation; the volume of the physiological saline is the same as that of the integrated preparation.
The in vivo radioactivity and tumor mass size of nude mice were recorded every two days.
Fig. 9 is a graph of the change in the internal radiation dose of the tumor-bearing nude mice (n=5), and it can be seen that the internal radiation dose of the mice corresponding to the group of example 1 gradually decreases with the lapse of time, but is higher than the internal radiation dose of the mice corresponding to the pure nuclide group.
Fig. 10 is a graph of tumor volume change (n=5) of a tumor-bearing nude mouse, and it can be seen from the graph that the integrated preparation prepared in example 1 has a remarkable inhibitory effect on tumor growth, and the inhibitory effect is remarkably higher than that of pure nuclide and nanomaterial of comparative example 1.
FIG. 11 is a graph showing survival under different drugs, in which mice were dead 35 days before administration of physiological saline, pure nuclide, and the nanomaterial of comparative example 1, and no death occurred by the end of observation in the integrally-prepared treatment group prepared in example 1.
Fig. 12 is a photograph of a representative nude mouse of each group before administration, at the 7 th and 14 th days of administration, and it can be intuitively seen from the photograph that the tumor growth rate of the mice of the treatment group to which the integrated preparation prepared in example 1 was administered is significantly slower than that of the other groups.
Fig. 13 is a graph of tumor tissue TUNEL assay at day 7 post-dose for assessing apoptosis of tumor cells. At this time, the tumor tissues of the normal saline group and the administration control group were in a rapid stateIn the fast growth phase, apoptosis is not seen basically, and pure nuclide is administered 177 While the Lu group expressed small areas of apoptosis due to the influence of a small amount of undiffused pre-radionuclide irradiation, the tumor tissue administered with the group of example 1 had significant massive apoptotic expression.
Changes in body weight of nude mice were also recorded along with tumor volumes to assess potential toxicity of the integrated formulations.
In the normal saline group, the comparative example group, the pure nuclide group, when tumor mass of a certain mouse in each group increases to the death standard (1500 mm 3 ) Mice were considered dead and dissected; example 1 group dissection was performed at 36 days due to the small tumor mass volume, heart blood of nude mice was left and plasma was centrifuged, and upper serum was taken to measure blood glucose and liver and kidney function; important tissue organs such as heart, liver, spleen, lung and kidney are taken, the tissue organs are fixed by 4% paraformaldehyde, and after paraffin embedding and slicing, the tissue organs are stained by HE (high-performance organic chemical) for histopathological examination.
Fig. 14 is a graph of body weight change (n=5), and the body weight of each of the 4 groups of nude mice was steadily increased, indicating that the administration did not adversely affect the body weight.
Fig. 15 shows pathological sections of the tissue organs of representative nude mice selected from each group, and it can be seen that the major tissue organs of 4 groups of nude mice have no obvious lesions.
Table 1 shows blood biochemical data at day 7 after administration, and shows that the values of Ala aminotransferase ALT, asp and lactose dehydrogenase LDH in nude mice in the comparative administration group and the example 1 group are higher, indicating that the drug containing the core-shell structure nanocrystal affects liver function of nude mice.
TABLE 1
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Table 2 is blood routine data (n=3) of day 25 nude mice after administration, and no significant difference was seen in the data of 3 groups of nude mice injected with the drug in tumor compared with physiological saline group.
TABLE 2
The foregoing description of the specific embodiments of the present invention has been presented by way of example. However, the scope of the present invention is not limited to the above exemplary embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the scope of protection of the claims of the present invention.

Claims (10)

1. A rare earth radioactive medical nuclide marked nano material is characterized in that the nano material comprises a rare earth ion sensitizer inner core MLn 1 F 4 :Ln 2 3+ The rare earth ion sensitizer is sequentially coated with a rare earth ion luminescent shell layer MLn outside the inner core 1 F 4 :Ln 2 3+ Rare earth ion sensitizer shell layer MLn 1 F 4 :Ln 2 3+ And rare earth ion inert protective layer MLn 1 F 4 The nano material is distributed with rare earth radiomedical nuclides R Ln；
Wherein M is a metal element selected from one or more of Li, na, K, rb, cs, mg, ca, sr and Ba;
Ln 1 、Ln 2 is a rare earth stable isotope selected from one or more of La, ce, pr, nd, po, sm, eu, gd, tb, dy, ho, er, tm, yb, lu, Y and Sc;
R ln is a rare earth radioactive medical nuclide selected from yttrium # 90 Y, lutetium ] 177 Lu, & holmium ] 166 Ho) samarium 153 Sm).
2. The rare earth radiomedical nuclides labeled nanomaterial of claim 1, wherein the R The abundance of Ln on the rare earth ion inert protective layer is at least 0.1mCi/g, the surface of the rare earth ion inert protective layer is provided with a functional tumor targeting biomolecule LIG, the functional tumor targeting biomolecule LIG is selected from water-soluble ligands without tumor specific recognition capability or molecules with tumor targeting function, and the structural general formula of the rare earth radioactive medical nuclide labeled nanomaterial is as follows: R Ln-MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 @LIG。
3. a method for preparing the rare earth medical nuclide labeled nanomaterial according to claim 1 or 2, wherein the preparation method is selected from one of a high-temperature coprecipitation method, a high-temperature thermal decomposition method, a hydrothermal method and a sol-gel method.
4. The method for preparing rare earth medical nuclide-labeled nanomaterial according to claim 3, wherein the high-temperature thermal decomposition method for preparing rare earth radionuclide-labeled nanomaterial comprises the following steps:
s1, preparing a rare earth ion sensitizer inner core MLn 1 F 4 :Ln 2 3+ ；
S2, in the rare earth ion sensitizer kernel MLn 1 F 4 :Ln 2 3+ Surface, growing rare earth ion luminous shell MLn according to shell epitaxial growth method 1 F 4 :Ln 2 3+ Obtaining MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ ；
S3, in a rare earth ion luminous shell MLn 1 F 4 :Ln 2 3+ Sequentially growing rare earth ion sensitizer shell MLn on the surface according to a shell epitaxial growth methodF 1 :Ln 2 3+ Inert protective layer MLn of rare earth ion 1 F 4 Rare earth doped medical nuclide R Ln。
5. The method for preparing rare earth medical nuclide labeled nanomaterial according to claim 4, wherein step S1 includes the steps of:
(a) Adding a stable rare earth source and a metal source into a first solvent, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to obtain a precursor;
(b) Adding the precursor, the stable rare earth source and the metal source into a second solvent, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to obtain a rare earth ion sensitizer core MLn 1 F 4 :Ln 2 3+ ；
M, ln in the stabilized rare earth source and the metal source in the steps (a) and (b) 1 、Ln 2 The molar ratio of (2) is 1: (0-1): (0-1).
6. The method for preparing rare earth medical nuclide labeled nanomaterial according to claim 4, wherein the shell epitaxial growth method in step S2 comprises the steps of: the rare earth ion sensitizer core MLn 1 F 4 :Ln 2 3+ Adding a second solvent into the stable rare earth source and the metal source, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to grow the rare earth ion luminescent shell MLn 1 F 4 :Ln 2 3+ Obtaining MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ ；
In the step S2, M, ln of the alkali metal source and the stable rare earth source are mixed according to the mole ratio 1 、Ln 2 Is 1: (0-0.9): (0 to 0.1).
7. The method for preparing rare earth medical nuclide labeled nanomaterial according to claim 4, wherein step S3 includes the steps of:
(c) MLn is first put into 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ Adding a second solvent into the stable rare earth source and the metal source, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to grow the rare earth ion sensitizer shell MLn 1 F 4 :Ln 2 3+ Obtaining MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ ；
(d) MLn is set 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ Adding a second solvent into the stable rare earth source, the metal source and the rare earth radioactive medical nuclide source, mixing, heating to 250-350 ℃ in an inert atmosphere, and reacting for 10-120 minutes to grow the rare earth ion inert protective layer MLn 1 F 4 Obtaining R Ln-MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @M Ln 1 F 4 ；
M, ln of the stabilized rare earth and metal sources of step (c) 1 、Ln 2 The molar ratio of (2) is 1: (0-0.5): (0 to 0.5);
m, ln of the stabilized rare earth and metal sources of step (d) 1 The molar ratio of (2) is 1: (0.5 to 1.5) is, for example, 1:1.
8. The method of preparing rare earth medical nuclide labeled nanomaterial according to any of claims 4-7, wherein the stabilized rare earth source is selected from one or more of the following: acetate, chloride, nitrate and trifluoroacetate salts of the rare earth ion stable isotope Ln, preferably trifluoroacetate and rare earth chloride salts of the rare earth ion stable isotope Ln;
the alkali metal source provides an element M for the nanocrystalline, and is selected from one or more of hydroxide, oleate, acetate, trifluoroacetate, fluoride and fluorohydride containing the M element;
the rare earth radioactive medical nuclide source provides radioactive medical nuclides for the nanocrystalline R Ln, oxalate and/or chloride selected from radioactive rare earth isotopes;
the step S3 further comprises the following steps:
at the position of R Ln-MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 :Ln 2 3+ @MLn 1 F 4 Surface modification modified ligand LIG.
9. A brachytherapy formulation comprising a nanomaterial according to any of claims 1-2 or a nanomaterial prepared by the method of any of claims 3-8;
the preparation can respectively or simultaneously take 808nm, 980nm and 1532nm lasers as light sources to emit light in the wave bands from 400-700 nm in the visible light red region to 1400-1700 nm in the near infrared IIb region.
10. Use of the nanomaterial of any one of claims 1-2 or the nanomaterial prepared by the method of any one of claims 3-8 or the imaging radiation therapy formulation of claim 9 in tumor diagnosis and/or treatment;
the tumor diagnosis includes medical imaging including real-time fluoroscopic imaging, surgical navigation, PET-CT or SPECT imaging.
CN202310171212.5A 2023-02-27 2023-02-27 Rare earth radioactive medical nuclide labeled nano material and preparation method and application thereof Pending CN116459358A (en)

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