WO2024099251A1 - 一种包含杨梅素纳米材料的显影剂及其制备方法和用途 - Google Patents

一种包含杨梅素纳米材料的显影剂及其制备方法和用途 Download PDF

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WO2024099251A1
WO2024099251A1 PCT/CN2023/129857 CN2023129857W WO2024099251A1 WO 2024099251 A1 WO2024099251 A1 WO 2024099251A1 CN 2023129857 W CN2023129857 W CN 2023129857W WO 2024099251 A1 WO2024099251 A1 WO 2024099251A1
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myricetin
iii
preparation
nanomaterial
solution
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French (fr)
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甄崇礼
朱华
韩梅
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山东省创启先进材料研究院
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  • the invention belongs to the technical field of medical imaging, and particularly relates to a developer containing myricetin nanomaterials, a preparation method and application thereof.
  • Cancer metastasis is one of the main causes of death in patients.
  • Treatment methods such as surgery and radiotherapy can only remove the original tumor tissue, but cannot eradicate cancer cells that have spread and metastasized.
  • Chemotherapy as a means of systemic treatment, is often used in the treatment of cancer metastasis in clinical practice, but there is still a lack of efficient treatment methods.
  • Nanomaterial preparations have the advantages of high targeting, small side effects, long blood half-life and high biocompatibility. More and more studies are trying to apply them to cancer treatment to overcome the high toxic side effects and unstable blood drug concentration in cancer chemotherapy.
  • Myricetin is a kind of polyphenol compound. This compound has multiple biological activities such as anticancer activity, antioxidant activity, cardioprotective activity and neuroprotective activity, but due to its poor water solubility and low bioavailability, its application in clinical treatment is greatly limited.
  • PET Positron emission tomography
  • the present invention provides a developer containing myricetin nanomaterials, and a preparation method and use thereof.
  • the developer of the present invention is a radioactive element 64 Cu or 68 Ga labeled in the myricetin nanomaterial, which can be used as a radioactive tracer for clinical PET imaging, and can not only be used for tumor diagnosis and treatment, but also can be combined with chemotherapy drugs, nuclear magnetic resonance and the like for treatment.
  • the myricetin nanomaterial preparation (myricetin-Sm III -Cu II ) contains metal ions and multiple hydroxyl structures, the hydroxyl groups of myricetin have a strong coordination effect with radioactive metal nuclides such as 64 Cu and 68 Ga, so that the metal The ions form a chelate with the myricetin nanoformulation to complete the radioisotope labeling.
  • 64 Cu or 68 Ga can be stably and efficiently labeled into the prepared myricetin-Sm III -Cu II nanoformulation, and the corresponding labeling rate can be improved by simple mixing, and the signal is still clearly visible after 30 minutes and 60 minutes.
  • an object of the present invention is to provide a developer comprising myricetin nanomaterials.
  • Another object of the present invention is to provide a method for preparing the developer containing the myricetin nanomaterial.
  • Another object of the present invention is to provide a use of the developer containing the myricetin nanomaterial.
  • the present invention provides a developer comprising myricetin nanomaterials, wherein the developer is prepared from the following ingredients: a radioactive nuclide and a myricetin-Sm III -Cu II nanomaterial preparation.
  • the radionuclide is 64 Cu or 68 Ga.
  • the myricetin-Sm III -Cu II nanomaterial preparation is prepared from a myricetin-Sm III -Cu II solution and a polyethylene glycol aqueous solution.
  • the myricetin-Sm III -Cu II solution is prepared from myricetin, Cu II salt and Sm III salt.
  • the Cu II salt is selected from one or more of chloride, nitrate, acetate, chloride hydrate, nitrate hydrate and acetate hydrate of metallic copper;
  • the Cu II salt is selected from one or more of CuCl 2 , Cu(NO 3 ) 2 , (CH 3 COO) 2 Cu, CuCl 2 ⁇ 2H 2 O, Cu(NO 3 ) 2 ⁇ 3H 2 O, (CH 3 COO) 2 Cu ⁇ H 2 O.
  • the Sm III salt is selected from one or more of chloride, nitrate, acetate, chloride hydrate, nitrate hydrate and acetate hydrate of samarium metal;
  • the Sm III salt is selected from one or more of SmCl 3 , Sm(NO 3 ) 3 , (CH 3 COO) 3 Sm, SmCl 3 ⁇ 6H 2 O, Sm(NO 3 ) 3 ⁇ H 2 O, Sm(NO 3 ) 3 ⁇ 5H 2 O, Sm(NO 3 ) 3 ⁇ 6H 2 O, (CH 3 COO) 3 Sm ⁇ H 2 O.
  • the molar ratio of the myricetin to the metal ion Sm III in the Sm III salt is 1:0.1 to 1:10, preferably 1:2 to 1:6.
  • the molar ratio of the myricetin to the metal ion Cu II in the Cu II salt is 1:0.1 to 1:20, preferably 1:1 to 1:8.
  • the volume ratio of the myricetin-Sm III -Cu II solution to the polyethylene glycol aqueous solution is 1:0.1 to 1:10, preferably 1:0.5 to 1:3.
  • the solubility of the polyethylene glycol aqueous solution is 0.01-10 g/L, preferably 0.05-0.5 g/L.
  • the particle size of the myricetin-Sm III -Cu II nanomaterial preparation is 5-500 nm, preferably 50-300 nm.
  • the myricetin-Sm III -Cu II nanomaterial preparation comprises the following steps:
  • step (3) The myricetin-Sm III -Cu II solution prepared in step (2) and the polyethylene glycol aqueous solution prepared in step (1) are mixed and reacted to obtain a myricetin-Sm III -Cu II nanomaterial preparation.
  • the solubility of the polyethylene glycol aqueous solution is 0.01-10 g/L, preferably 0.05-0.5 g/L.
  • the solvent includes but is not limited to water, methanol, ethanol, propanol, ethylene glycol, and glycerol.
  • the volume ratio of the myricetin-Sm III -Cu II solution prepared in step (2) to the polyethylene glycol aqueous solution prepared in step (1) is 1:0.1 to 1:10, preferably 1:0.5 to 1:3.
  • the present invention provides a method for preparing a developer comprising a myricetin nanomaterial preparation, the method comprising the following steps:
  • step (2) adding 68 GaCl 3 solution or 64 CuCl 2 solution to the mixed solution prepared in step (1), adjusting the pH with ammonium acetate, and reacting at 40° C. for 30 min;
  • step (3) After the reaction in step (2) is completed, the system is cooled to room temperature, and a solid phase extraction column is used for separation and purification to obtain the labeled product 68 Ga-myricetin-Sm III -Cu II nanomaterial preparation.
  • step (1) the preparation method of the myricetin-Sm III -Cu II nanomaterial preparation is as described above.
  • the pH is 3.5-4.2.
  • the solid phase extraction column is a PD-10 column
  • the mobile phase is an 80% ethanol solution
  • washed with pure water and the liquid is collected to obtain.
  • the present invention provides a developer comprising a myricetin nanomaterial preparation for use in the preparation of tumor Application in tumor fluorescence and PET imaging agents.
  • the present invention provides a use of a developer comprising a myricetin nanomaterial preparation in the preparation of a tumor photothermal therapy agent.
  • the present invention provides a use of a developer comprising a myricetin nanomaterial preparation in the preparation of an integrated tumor diagnosis and treatment reagent.
  • the present invention provides a use of a developer comprising a myricetin nanomaterial preparation in the preparation of an integrated reagent for radioactive diagnosis and treatment of cancer and metastatic cancer.
  • the cancer includes melanoma, breast cancer, and prostate cancer;
  • the metastatic cancer includes breast cancer lung metastasis and breast cancer brain metastasis.
  • the present invention provides a method for diagnosing and treating cancer and metastatic cancer, the method comprising administering to a subject in need thereof a diagnostically and therapeutically effective amount of the above-mentioned imaging agent comprising the myricetin nanomaterial preparation or the imaging agent comprising the myricetin nanomaterial preparation prepared by the above-mentioned method;
  • the cancer includes melanoma, breast cancer, and prostate cancer;
  • the metastatic cancer includes breast cancer lung metastasis and breast cancer brain metastasis.
  • the developer containing the myricetin nanomaterial preparation of the present invention is used for integrated cancer diagnosis and treatment, has high sensitivity to cancer, high specific activity and radiochemical purity, good stability, and can ensure the final imaging effect.
  • FIG1 is a UV-visible absorption spectrum of myricetin (Mc) and myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc);
  • FIG2 is an infrared spectra of myricetin (Mc) and myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc);
  • FIG3 is a particle size distribution diagram of myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc) in PBS buffer;
  • FIG4 is a particle size distribution diagram of myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc) in normal saline;
  • FIG5 is a morphological image of the myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc) taken at different angles under a transmission electron microscope (TEM);
  • FIG6 is a morphological image of the myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc) taken at different angles under a scanning electron microscope (SEM);
  • FIG7 is a scanning electron microscope energy dispersive spectrometry (SEM-EDS) analysis of myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc);
  • FIG8 is a transmission electron microscope energy dispersive spectroscopic analysis (TEM-EDS) of the myricetin-Sm III -Cu II nanomaterial preparation (Sm-Mc).
  • TEM-EDS transmission electron microscope energy dispersive spectroscopic analysis
  • FIG9 is the 30-min in vivo imaging result of 68 Ga-myricetin-Sm III -Cu II ;
  • FIG. 10 shows the 60-min in vivo imaging results of 68 Ga-myricetin-Sm III -Cu II .
  • Test materials Sm(NO 3 ) 3 ⁇ 6H 2 O, cupric chloride, myricetin, ethanol, sodium carbonate, DP-polyethylene glycol, physiological saline, PBS phosphate buffer; all materials used were of analytical or chemical purity.
  • Ultraviolet absorption spectrum test method The myricetin solution and the myricetin nano-preparation were subjected to full-wavelength absorption spectrum scanning analysis using an ultraviolet-visible spectrophotometer with a scanning range of 200-800nm.
  • Infrared visible spectrum test method the myricetin nanoparticles were dried in an oven for about 3 hours to prepare solid samples, ground under an infrared drying lamp for 5 minutes, and evenly compressed using a tablet press. The samples were then scanned by near infrared spectroscopy in the range of 4000 cm -1 to 475 cm -1 .
  • Particle size distribution determination method Take 1.5 mL of the sample of the myricetin nanoformulation to be tested and place it in a cuvette, place it in the instrument slot, and determine the average particle size and particle size distribution of the myricetin nanoformulation by dynamic light scattering.
  • myricetin has a strong absorption at about 400 nm, while the myricetin nanoformulation of the present invention has an absorption peak disappearing at 400 nm.
  • the characteristic peaks of myricetin and the myricetin nanomaterial preparation of the present invention are different. Compared with myricetin, the characteristic peak of the myricetin nanomaterial preparation of the present invention at the position of 2500-3500 nm almost disappears.
  • the ultraviolet absorption spectrum and the infrared spectrum show that the myricetin nanomaterial preparation of the present invention is completely prepared without any residual myricetin monomer.
  • the average particle size of the myricetin nanomaterial preparation of the present invention in PBS buffer and physiological saline is basically the same, and the myricetin nanomaterial preparation of the present invention has no agglomeration and no precipitation in PBS buffer or physiological saline within three months, indicating that the preparation has good uniformity and stability.
  • the morphology of the myricetin-Sm III -Cu II nanomaterial preparation of the present invention can be seen from FIG. 5 and FIG. 6 .
  • Example 2 The proliferation inhibition effect of the myricetin nanomaterial preparation of the present invention on different types of cancer cells
  • mice tumor cells of different origins were selected: estrogen receptor-positive human breast cancer cells (MCF-7), estrogen receptor-negative human breast cancer cells (MDA-Mb-231), human breast cancer brain metastasis cells (MDA-Mb-231Br), mouse breast cancer cells (4T-1), mouse breast cancer brain metastasis cells (4T-1Br), human prostate cancer highly metastatic cells (PC-3M-IE8), human melanoma metastasis cells (WM983a);
  • DMEM high glucose medium, 1640 basal medium, fetal bovine serum, penicillin-streptomycin (Gibco), trypsin, ATP detection kit, dimethyl sulfoxide, myricetin.
  • MCF-7, MDA-Mb-231, MDA-Mb-231Br, PC-3M-IE8, WM983a and 4T-1Br cells from the incubator take cells in the logarithmic growth phase, digest, count, dilute to 5 ⁇ 10 4 cells/mL, use a spray gun to inoculate into a 96-well plate, 100 ⁇ L per well (5 ⁇ 10 3 cells/well), and place the well plate in the incubator for culture overnight.
  • a drug administration group and a control group were set up, 100 ⁇ L PBS was added to each well of the control group, and 100 ⁇ L myricetin nanomaterial preparation (prepared by Example 1) or myricetin was added to each well of the drug administration group, so that the final concentration of the myricetin nanomaterial preparation was 1, 3, 10, 30, 100, 300 ⁇ g/mL, and the final concentration of myricetin was 1, 3, 10, 30, 100, 300 ⁇ M.
  • the 96-well plate was placed in a 37°C, 5% CO2 incubator. After 48 hours, the drug effects were observed under an inverted microscope and photographed.
  • the culture medium was aspirated with a pipette, and 90 ⁇ L of DMEM basal culture medium and 10 ⁇ L of 5 mg/mL MTT detection reagent were added to each well.
  • the cells were incubated in an incubator for 4 hours, and the centrifuge speed was 2000 rpm for 10 minutes. After centrifugation, the supernatant was discarded, 150 ⁇ L of DMSO was added to each well, and the cells were shaken for 10 minutes using a multifunctional microplate reader. The luminescence value at a wavelength of 570 nm was detected to calculate the cell survival rate.
  • Each group of experiments was repeated three times.
  • the MTT method was used to determine the effect of the myricetin nanomaterial preparation of the present invention on the activity of MCF-7, MDA-Mb-231, MDA-Mb-231Br, PC-3M-IE8, WM983a, 4T-1 and 4T-1Br cells, and the IC 50 values were calculated by GraphPad Prism software, and the IC 50 values were 174.7, 190.0, 305.0, 202.8, 123.1, 51.3, and 69.3 ⁇ g/mL, respectively. This indicates that the nanomaterial preparation has a good inhibitory effect on the above cell lines.
  • Example 3 Inhibitory effect of the myricetin nanomaterial preparation of the present invention on melanoma in mice
  • Test cells human melanoma metastatic cells (WM983a);
  • DMEM basal culture medium special grade fetal bovine serum; penicillin-streptomycin; phosphate buffered saline (PBS); trypsin; isoflurane; 0.9% sodium chloride injection; myricetin.
  • PBS phosphate buffered saline
  • mice Forty 6-8 week old NuNu nude mice were randomly divided into a myricetin nanomaterial preparation group (prepared in Example 1, 10 mg/kg), a myricetin group (20 mg/kg) and a model group, with 12 mice in each group and 4 mice in the blank group.
  • Each mouse in the myricetin nanomaterial preparation group, myricetin group and model group was subcutaneously injected with 0.1mL (about 1 ⁇ 10 6 cells) cell suspension, the blank group was injected with 0.1mL PBS, and after injection, a medical cotton swab was used to press the injection hole for 30s to prevent liquid from flowing out. Seven days after the injection of cells, the drug was administered every other day.
  • the myricetin nanomaterial preparation group and the myricetin group were intraperitoneally injected with drugs of corresponding concentrations, and the model group and the blank group were intraperitoneally injected with normal saline.
  • the experimental period was 13 days.
  • Test materials the myricetin nanomaterial preparation of the present invention (prepared in Example 1), heparin sodium (250 U/mg), methanol, and water.
  • Test instrument Agilent 1100; Detector: VWD; C18 chromatographic column: 250mm ⁇ 4.6mm ⁇ 0.5 ⁇ m;
  • Blood was collected through the orbital vein at 5min, 10min, 30min, 1h, 2h, 4h, 6h, 8h, 11h, 14h, 24h, 48h, 72h and other time points after administration through tail vein injection (15mg/kg) or oral gavage (50mg/kg).
  • the experimental rats can be supplemented with physiological saline of the corresponding blood volume as appropriate.
  • the blood samples were collected in heparin sodium anticoagulant tubes, placed in a centrifuge, centrifuged at 15000rpm for 5min, and the supernatant was aspirated and placed in a -80°C refrigerator for storage.
  • the test sample was compared with the standard myricetin sample peak to obtain the drug concentration of each sample. It was calculated that the oral bioavailability of the myricetin nanomaterial preparation of the present invention was about 21.38%, which was increased by about 11.76% compared with the oral bioavailability of myricetin.
  • Test materials myricetin- Sm III -Cu II nanomaterial preparation (prepared in Example 1), sodium acetate solution, ammonium acetate, ethanol, hydrochloric acid, etc.; all materials used are of analytical or chemical purity.
  • Radio-TLC Rapid identification and analysis by Radio-TLC: 5 ⁇ L of the reaction product was dropped to about 1 cm below the bottom of the silica gel plate, and the silica gel plate was placed in a developing system, which was a mixed solution of methanol and ammonium acetate in equal proportions. When the product was developed to about 10 cm from the bottom, it was taken out and dried before Radio-TLC analysis. The radiochemical purity was about 57%.
  • Test materials 68 Ga-myricetin-Sm III -Cu II nanomaterial preparation (prepared in Example 5), nude mice.
  • mice Three nude mice were taken for the experiment and 100 ⁇ Ci 68 Ga-myricetin- Sm III -Cu II nanomaterial preparation was injected through the tail vein.
  • the nude mice were pre-anesthetized with a 3% volume fraction of isoflurane-oxygen mixture, and then placed on the small animal micro-PET/CT scanning bed, and anesthetized with a 1.5% volume fraction of isoflurane-oxygen mixture, and breathing was detected at the same time.
  • Micro-PET/CT static scanning imaging was performed 30min and 60min after injection, and images were collected.
  • Test materials myricetin-Sm III -Cu II nanomaterial preparation (prepared in Example 1), sodium acetate solution, ethanol, hydrochloric acid, etc.; all materials used are of analytical or chemical purity.
  • Radio-TLC Rapid identification and analysis by Radio-TLC: 5 ⁇ L of the reaction product was dropped to about 1 cm below the bottom of the silica gel plate, and the silica gel plate was placed in a developing system, which was a mixed solution of methanol and ammonium acetate in equal proportions. When the product was developed to about 10 cm from the bottom, it was taken out and dried before Radio-TLC analysis. The radiochemical purity was about 33%.
  • Test method Myricetin was dissolved in 75% ethanol to prepare a 0.3mM solution; FeCl 3 ⁇ 6H 2 O powder was dissolved in distilled water to prepare a 0.1mM solution, Fe III solution was added to the myricetin solution at room temperature until the reaction was complete, the obtained solution was centrifuged, and washed three times with ethanol and distilled water respectively to wash away the unreacted myricetin and Fe III , and the obtained solid was observed under a microscope.
  • the myricetin and Fe III solutions were diluted 10 times, 100 times, and 1000 times respectively, reacted overnight in an ice bath, and vortexed.
  • the myricetin solution is light yellow, and the Fe III solution is light yellow.
  • the two solutions are mixed, they immediately turn into a black turbid liquid. After standing for a period of time, a black solid is obtained by centrifugation. After washing with ethanol and distilled water respectively, it is observed by microscope and electron microscope scanning. It is found that the reaction of myricetin and Fe III fails to obtain a stable nano preparation.
  • Test materials Sm(NO 3 ) 3 ⁇ 6H 2 O, myricetin, ethanol, sodium carbonate, DP-polyethylene glycol; All materials used were of analytical or chemical purity grade.
  • Test materials copper chloride, myricetin, ethanol, sodium carbonate, DP-polyethylene glycol; all materials used were of analytical or chemical purity.
  • Test materials Sm(NO 3 ) 3 ⁇ 6H 2 O, ferric chloride, myricetin, ethanol, sodium carbonate, DP-polyethylene glycol; all materials used were of analytical or chemical purity.
  • Test materials cupric chloride, ferric chloride, myricetin, ethanol, sodium carbonate, DP-polyethylene glycol; all materials used were of analytical or chemical purity.

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Abstract

一种包含杨梅素纳米材料的显影剂及其制备方法和用途。所述的显影剂由如下成分制备而成：放射性核素及杨梅素-Sm III-Cu II纳米制剂。所述放射性标记的杨梅素纳米制剂可在癌症诊疗一体化中发挥重要作用。

Description

一种包含杨梅素纳米材料的显影剂及其制备方法和用途 技术领域
本发明属于医学显像技术领域，具体涉及一种包含杨梅素纳米材料的显影剂及其制备方法和用途。
背景技术
目前，癌症仍是世界范围内的公共健康问题。癌症转移是引起患者死亡的主要原因之一，手术、放疗等治疗手段仅能去除原位肿瘤组织，但不能根除已发生扩散转移的癌细胞。化疗作为一种全身治疗的手段，临床上常用于癌症转移的治疗，但目前仍缺乏高效的治诊疗手段。纳米材料制剂具有靶向性高、副作用小、血液半衰期长和生物相容性高等优势，越来越多的研究尝试将其应用于癌症治疗，以克服癌症化疗中的毒副作用高，血药浓度不稳定等缺陷。杨梅素(Myricetin)是多酚类化合物的一种。该化合物具有抗癌活性、抗氧化活性、心脏保护活性和神经保护活性等多种生物活性，但由于其水溶性差、生物利用度低等缺点，极大地限制了在临床治疗中的应用。
与传统的诊疗方法相比，发明一种兼具诊断和治疗功能的诊疗一体化试剂是实现协同癌症诊断及治疗的重要途径，对癌症的早期诊断和有效治疗具有重要意义。正电子发射型计算机断层显像(Positron Emission Tomography，PET)是核医学领域常用的临床检查影像技术，能够为癌症等疾病提供实时监测和定量分析，在合适的放射性显影剂匹配下已能广泛应用于临床诊断和治疗。
发明内容
为了克服现有技术的缺陷，本发明提供一种包含杨梅素纳米材料的显影剂及其制备方法和用途。本发明的显影剂是在杨梅素纳米材料中标记了放射性元素64Cu或68Ga，可以作为临床PET成像的放射性示踪剂，不仅能用于肿瘤诊疗，另外能与化疗药物、核磁共振等组合治疗。本发明中，由于杨梅素纳米材料制剂(杨梅素-SmIII-CuII)中含有金属离子、以及多个羟基结构，通过杨梅素的羟基与64Cu、68Ga等放射性金属核素发生强配位作用，使金属 离子与杨梅素的纳米制剂形成螯合物，完成放射性同位素标记。发明人发现64Cu或68Ga能够稳定、高效地标记到所制备的杨梅素-SmIII-CuII纳米制剂中，只需通过简单混合即可提升相应标记率，且30min、60min后信号仍清晰可见。
因此，本发明的一个目的是，提供一种包含杨梅素纳米材料的显影剂。
本发明的另一个目的是，提供一种上述包含杨梅素纳米材料的显影剂的制备方法。
本发明的又一个目的是，提供一种上述包含杨梅素纳米材料的显影剂的用途。
本发明的上述目的是采用如下技术方案来实现的。
一方面，本发明提供一种包含杨梅素纳米材料的显影剂，该显影剂由如下成分制备而成：放射性核素及杨梅素-SmIII-CuII纳米材料制剂。
优选地，所述放射性核素为64Cu或68Ga。
优选地，所述杨梅素-SmIII-CuII纳米材料制剂由杨梅素-SmIII-CuII溶液和聚乙二醇水溶液制备而成。
优选地，所述杨梅素-SmIII-CuII溶液由杨梅素与CuII盐和SmIII盐制备而成。
优选地，所述CuII盐选自金属铜的氯化盐、硝酸盐、醋酸盐、氯化盐水合物、硝酸盐水合物、醋酸盐水合物中的一种或多种；
优选地，所述CuII盐选自CuCl2、Cu(NO3)2、(CH3COO)2Cu、CuCl2·2H2O、Cu(NO3)2·3H2O、(CH3COO)2Cu·H2O中的一种或多种。
优选地，所述SmIII盐选自金属钐的氯化盐、硝酸盐、醋酸盐、氯化盐水合物、硝酸盐水合物、醋酸盐水合物中的一种或多种；
优选地，所述SmIII盐选自SmCl3、Sm(NO3)3、(CH3COO)3Sm、SmCl3·6H2O、Sm(NO3)3·H2O、Sm(NO3)3·5H2O、Sm(NO3)3·6H2O、(CH3COO)3Sm·H2O中的一种或多种。
优选地，所述杨梅素与所述SmIII盐中的金属离子SmIII的摩尔比为1:0.1至1:10，优选为1:2至1:6。
优选地，所述杨梅素与所述CuII盐中的金属离子CuII的摩尔比为1:0.1至1:20，优选为1:1至1:8。
优选地，所述杨梅素-SmIII-CuII溶液与所述聚乙二醇水溶液的体积比为 1:0.1至1:10，优选为1:0.5至1:3。
优选地，所述聚乙二醇水溶液的溶度为0.01-10g/L，优选为0.05-0.5g/L。
优选地，所述杨梅素-SmIII-CuII纳米材料制剂的粒径为5-500nm，优选为50-300nm。
优选地，所述杨梅素-SmIII-CuII纳米材料制剂包括如下步骤：
(1)制备聚乙二醇水溶液；
(2)将杨梅素和SmIII盐及CuII盐分别溶解在溶剂中，得到杨梅素-SmIII-CuII溶液；
(3)将步骤(2)制备得到的杨梅素-SmIII-CuII溶液与步骤(1)制备得到的聚乙二醇水溶液混合反应，得到杨梅素-SmIII-CuII纳米材料制剂。
优选地，在步骤(1)中，所述聚乙二醇水溶液的溶度为0.01-10g/L，优选为0.05-0.5g/L。
优选地，在步骤(2)中，所述溶剂包括但不限于水、甲醇、乙醇、丙醇、乙二醇、丙三醇。
优选地，在步骤(3)中，所述步骤(2)制备得到的杨梅素-SmIII-CuII溶液与所述步骤(1)制备得到的聚乙二醇水溶液的体积比为1:0.1至1:10，优选为1:0.5至1:3。
另一方面，本发明提供一种包含杨梅素纳米材料制剂的显影剂的制备方法，该方法包括如下步骤：
(1)将杨梅素-SmIII-CuII纳米材料制剂用1M的醋酸钠溶液制成1mg/mL的混合溶液；
(2)将68GaCl3溶液或64CuCl2溶液加入至步骤(1)中制备得到的混合溶液中，并用乙酸铵调节pH，于40℃条件下反应30min；
(3)将步骤(2)中反应结束后，待体系降至室温，采用固相萃取柱进行分离纯化获得标记后的产物68Ga-杨梅素-SmIII-CuII纳米材料制剂。
优选地，在步骤(1)中，所述杨梅素-SmIII-CuII纳米材料制剂的制备方法如上所述。
优选地，在步骤(2)中，所述pH为3.5-4.2。
优选地，在步骤(3)中，所述固相萃取柱为PD-10柱，流动相为80％乙醇溶液，纯水洗涤，收集液体，即得。
再一方面，本发明提供一种包含杨梅素纳米材料制剂的显影剂在制备肿 瘤荧光和PET显像试剂中的应用。
优选地，本发明提供一种包含杨梅素纳米材料制剂的显影剂在制备肿瘤光热治疗试剂中的应用。
优选地，本发明提供一种包含杨梅素纳米材料制剂的显影剂在制备肿瘤诊疗一体化试剂中的应用。
优选地，本发明提供一种包含杨梅素纳米材料制剂的显影剂在制备癌症及转移性癌症放射性诊疗一体化试剂中的应用。
优选地，所述癌症包括黑色素癌、乳腺癌、前列腺癌；
优选地，所述转移性癌症包括乳腺癌肺转移癌、乳腺癌脑转移癌。
再又一方面，本发明提供一种诊断和治疗癌症及转移性癌症的方法，该方法包括向有需要的受试者给予诊断和治疗有效量的上述的包含杨梅素纳米材料制剂的显影剂或上述方法制备得到的包含杨梅素纳米材料制剂的显影剂；
优选地，所述癌症包括黑色素癌、乳腺癌、前列腺癌；
优选地，所述转移性癌症包括乳腺癌肺转移癌、乳腺癌脑转移癌。
本发明包含杨梅素纳米材料制剂的显影剂用于癌症诊疗一体化，对癌症灵敏度高，比活度和放射化学纯度高，稳定性较好，可以保证最终的显像效果。
附图说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1为杨梅素(Mc)及杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)的紫外可见吸收光谱图；
图2为杨梅素(Mc)及杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)的红外光谱图；
图3为杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)在PBS缓冲液中的粒径分布图；
图4为杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)在生理盐水中的粒径分布图；
图5为杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)在透射电镜(TEM)下不同角度拍摄的形态图；
图6为杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)在扫描电镜(SEM)下不同角度拍摄的形态图；
图7为杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)的扫描电镜能谱分析(SEM-EDS)；
图8为杨梅素-SmIII-CuII纳米材料制剂(Sm-Mc)的透射电镜能谱分析(TEM-EDS)。
图9为68Ga-杨梅素-SmIII-CuII的30min体内显像结果；
图10为68Ga-杨梅素-SmIII-CuII的60min体内显像结果。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
实施例1本发明的杨梅素纳米材料制剂的制备方法
1、材料与方法
试验材料：Sm(NO3)3·6H2O，氯化铜，杨梅素，乙醇，碳酸钠，DP-聚乙二醇，生理盐水，PBS磷酸缓冲液；所用材料均为分析纯或化学纯级别。
试验方法：杨梅素-SmIII-CuII纳米材料制剂的制备：将适量浓度为2mM的杨梅素、浓度为8mM的Sm(NO3)3·6H2O、以及浓度为10mM的CuCl2分别溶解于乙醇中，通过离心收集混合物，并用去离子水洗涤几次，随后将棕色的杨梅素-SmIII-CuII悬浮于1mL去离子水中，得到杨梅素-SmIII-CuII溶液；将200μL杨梅素-SmIII-CuII，200μL DP-聚乙二醇(0.1g/L)和200mL去离子水混合，离心、洗涤，即得到杨梅素-SmIII-CuII纳米材料制剂。
紫外吸收光谱测试方法：将杨梅素溶液和杨梅素纳米制剂利用紫外-可见光分光光度计进行全波长吸收光谱扫描分析，扫描范围200-800nm。
红外可见光谱测试方法：将杨梅素纳米制剂在烘箱内烘3h左右后制备成固体样品，在红外干燥灯下研磨5min，使用压片机均匀压片，后将样品在4000cm-1至475cm-1范围内进行近红外光谱扫描。
粒径分布测定方法：取1.5mL杨梅素纳米制剂的待测样品置于比色皿中，置于仪器卡槽中，通过动态光散射法测定杨梅素纳米制剂的平均粒径及粒径分布。
其他表征测试方法：将得到的杨梅素纳米制剂经喷金处理，使用SEM、TEM在10kV的加速电压下进行表面形貌分析、并拍摄图片，同时结合EDS进行能谱分析，以分析杨梅素纳米制剂元素组成及分布。
2、实验结果
结果见图1-8。
由图1可知，杨梅素在400nm左右有强吸收，而本发明的杨梅素纳米制剂在400nm吸收峰消失。
由图2可知，杨梅素与本发明的杨梅素纳米材料制剂的特征峰不同，与杨梅素相比，本发明的杨梅素纳米制剂在2500-3500nm位置的特征峰几乎消失。
通过紫外吸收光谱图和红外光谱图，可知本发明的杨梅素纳米材料制剂制备完成，无杨梅素单体残余。
由图3、图4可知，本发明的杨梅素纳米材料制剂在PBS缓冲液、生理盐水中平均粒径都基本一致，且本发明中的杨梅素纳米材料制剂在PBS缓冲液或生理盐水中，三个月内无团聚，无沉淀析出，说明该制剂均匀性和稳定性均较好。
由图5、图6可见本发明中杨梅素-SmIII-CuII纳米材料制剂的形貌。
由图7、图8可知，其中SmIII和CuII特征峰清晰可见，证实了本发明杨梅素-SmIII-CuII纳米材料制剂的成分。
实施例2本发明的杨梅素纳米材料制剂对不同种类癌细胞的增殖抑制作用
1、材料与方法
试验细胞：选用不同来源的人源与鼠源肿瘤细胞：雌激素受体阳性人乳腺癌细胞(MCF-7)，雌激素受体阴性人乳腺癌细胞(MDA-Mb-231)，人乳腺癌脑转移细胞(MDA-Mb-231Br)，鼠源乳腺癌细胞(4T-1)，鼠源乳腺癌脑转移细胞(4T-1Br)，人前列腺癌高转移性细胞(PC-3M-IE8)，人黑色素瘤转移细胞(WM983a)；
试验材料：DMEM高糖培养基，1640基础培养基，胎牛血清，青-链霉素(Gibco)，胰酶，ATP检测试剂盒，二甲基亚砜，杨梅素。
试验方法：
从培养箱中取出MCF-7、MDA-Mb-231、MDA-Mb-231Br、PC-3M-IE8、WM983a和4T-1Br细胞，取对数生长期细胞，消化，计数，稀释为5×104个/mL，使用排枪接种于96孔板，每孔100μL(5×103个细胞/孔)，将孔板置于培养箱中培养过夜。
给药时设给药组和对照组，对照组每孔加入100μL PBS，给药组每孔加入100μL杨梅素纳米材料制剂(由实施例1制备而成)或杨梅素，使杨梅素纳米材料制剂的最终浓度为1、3、10、30、100、300μg/mL，杨梅素终浓度为1、3、10、30、100、300μM。给药完成后，将96孔板置于37℃，5％CO2培养箱中。48h后在倒置显微镜下观察药物作用并拍照，用移液枪吸出培养液，每孔加入DMEM基础培养液90μL和5mg/mL MTT检测试剂10μL，在培养箱中孵育4小时，离心机转速2000rpm离心时间10min，离心后倒掉上清液，每孔加入150μL DMSO，用多功能酶标仪震荡10min，检测其在570nm波长下的发光值，计算细胞存活率。每组实验重复三次。
4T-1细胞除使用RPMI-1640完全培养基外，其余步骤与上述相同。
2、实验结果
使用MTT法测定本发明的杨梅素纳米材料制剂对MCF-7、MDA-Mb-231、MDA-Mb-231Br、PC-3M-IE8、WM983a、4T-1和4T-1Br细胞活性的影响，通过GraphPad Prism软件计算出IC50值，IC50值分别为174.7，190.0，305.0，202.8，123.1，51.3，69.3μg/mL。说明该纳米材料制剂对以上细胞系均有较好的抑制作用。
实施例3本发明的杨梅素纳米材料制剂对小鼠体内黑色素瘤的抑制作用
1、材料与方法
试验细胞：人黑色素瘤转移细胞(WM983a)；
试验材料：DMEM基础培养基；特级胎牛血清；青-链霉素；磷酸盐缓冲液PBS；胰酶；异氟烷；0.9％氯化钠注射液；杨梅素。
试验方法：
将40只6-8周的NuNu裸鼠随机分为杨梅素纳米材料制剂组(由实施例1制备而成，10mg/kg)、杨梅素组(20mg/kg)和模型组，每组12只，空白组4只，杨梅素纳米材料制剂组、杨梅素组和模型组每只在上肢皮下注射 0.1mL(约1×106个细胞)细胞悬液，空白组注射0.1mL PBS，注射后用医用棉签按住注射孔30s，以免有液体流出。注射细胞7天后开始隔天给药，杨梅素纳米材料制剂组和杨梅素组腹腔注射相应浓度的药品，模型组和空白组腹腔注射生理盐水，实验周期13天。
2、实验结果
体内药效学试验结果表明，与杨梅素单一治疗组相比，本发明的杨梅素纳米材料制剂治疗组的肿瘤质量显著降低，约为其44±5％，存在统计学差异(P<0.05)，显著抑制黑色素瘤生长。
实施例4本发明的杨梅素纳米材料制剂的生物利用度
1、材料与方法
试验动物：SD大鼠。
试验材料：本发明的杨梅素纳米材料制剂(由实施例1制备而来)，肝素钠(250U/mg)，甲醇，水。
试验仪器：安捷伦1100；检测器：VWD；C18色谱柱：250mm×4.6mm×0.5μm；
试验方法：
通过尾静脉注射(15mg/kg)或口服灌胃(50mg/kg)，给药后5min、10min、30min、1h、2h、4h、6h、8h、11h、14h、24h、48h、72h等时间点通过眼眶静脉进行采血。采血后可以视情况给实验大鼠补充相应血量的生理盐水。将血样收集于肝素钠抗凝管中，血样置于离心机中，以15000rpm速离心5min，吸取上清液置于-80℃冰箱中保存待用。取50μL样品至2ml离心管中，加入150μL乙腈，将放入超声机中超声1min，而后放入离心机5000rpm离心15min。取上清液过0.22μm有机系滤膜至1.5mL样品瓶上机进行检测。流动相为甲醇-水(比例：50-50)；检测波长：254nm；柱温：30℃。
2、实验结果
将待测样品与标准杨梅素样品峰做对比，得到各个样品的药物浓度，经计算得出本发明中的杨梅素纳米材料制剂的口服生物利用度约为21.38％，与杨梅素的口服生物利用度相比，提升约11.76％。
实施例5本发明的68Ga-杨梅素-SmIII-CuII纳米材料制剂的制备方法
1、材料与方法
试验材料：杨梅素-SmIII-CuII纳米材料制剂(由实施例1制备而成)，醋酸钠溶液，乙酸铵，乙醇，盐酸等；所用材料均为分析纯或化学纯级别。
试验方法：68Ga-杨梅素-SmIII-CuII纳米材料制剂的制备：将杨梅素-SmIII-CuII纳米材料制剂用1M的醋酸钠溶液制成1mg/mL的混合溶液；取4mL 0.05M HCl对Ge-Ga发生器进行淋洗，淋洗流速为1mL/min，并收集流出溶液；取200μL 68GaCl3溶液(6mCi)加入至前述混合溶液中，并用乙酸铵调节pH，至3.5-4.2，于40℃条件下反应30min；反应结束后待体系降至室温，采用PD-10柱进行分离纯化，流动相为80％乙醇溶液，纯水洗涤，收集液体，获得标记后的产物68Ga-杨梅素-SmIII-CuII纳米材料制剂。
2、实验结果
采用Radio-TLC快速鉴定分析：取5μL反应产物滴至硅胶板下端约1cm位置，并将硅胶板置于展开体系中，展开体系为甲醇与醋酸铵等比例混合溶液，待产物展开至距离下端约10cm时取出，待晾干后进行Radio-TLC分析。放射化学纯度约为57％。
实施例6本发明的68Ga-杨梅素-SmIII-CuII的体内生物分布显像
1、材料与方法
试验材料：68Ga-杨梅素-SmIII-CuII纳米材料制剂(由实施例5制备而成)，裸鼠。
试验方法：取实验用裸鼠3只，由尾静脉注射100μCi 68Ga-杨梅素-SmIII-CuII纳米材料制剂。以体积分数3％的异氟烷-氧气混合气将裸鼠预麻醉，后将其置于小动物micro-PET/CT扫描床上，并以体积分数为1.5％的异氟烷-氧气混合气维持麻醉，同时检测呼吸。分别于注射后30min、60min进行micro-PET/CT静态扫描显像，采集图像。
2、实验结果
结果如图9、图10，光信号清晰可见。且30min、60min后光信号仍清晰可见。
实施例7本发明的64Cu-杨梅素-SmIII-CuII纳米材料制剂的制备方法
1、材料与方法
试验材料：杨梅素-SmIII-CuII纳米材料制剂(由实施例1制备而成)，醋酸钠溶液，乙醇，盐酸等；所用材料均为分析纯或化学纯级别。
试验方法：64Cu-杨梅素-SmIII-CuII纳米材料制剂的制备：将杨梅素-SmIII-CuII纳米材料制剂用1M的醋酸钠溶液制成1mg/mL的混合溶液；将上述溶液与64Cu进行混合，于50℃条件下反应30min；反应结束后待体系降至室温，采用PD-10柱进行分离纯化，流动相为80％乙醇溶液，纯水洗涤，收集液体，获得标记后的产物64Cu-杨梅素-SmIII-CuII纳米材料制剂。
2、实验结果
采用Radio-TLC快速鉴定分析：取5μL反应产物滴至硅胶板下端约1cm位置，并将硅胶板置于展开体系中，展开体系为甲醇与醋酸铵等比例混合溶液，待产物展开至距离下端约10cm时取出，待晾干后进行Radio-TLC分析。放射化学纯度约为33％。
对比例1杨梅素单金属(与单独FeIII)纳米材料制剂的制备
1、材料与方法
试验材料：FeCl3·6H2O，杨梅素，乙醇，PBS缓冲液；
试验方法：将杨梅素溶于75％乙醇，制成0.3mM溶液；将FeCl3·6H2O粉末溶于蒸馏水，制成0.1mM溶液，在室温下将FeIII溶液加到杨梅素溶液中，直至完全反应，将得到的溶液离心，分别用乙醇和蒸馏水洗三次，洗去未反应的杨梅素和FeIII，在显微镜下观察得到的固体。将杨梅素和FeIII溶液分别稀释10倍，100倍，1000倍，在冰浴下反应过夜，涡旋。
2、实验结果
杨梅素溶液为浅黄色，FeIII溶液颜色为淡黄色，将两种溶液混合立即变为黑色浊液。静置一段时间后，离心得到黑色固体。分别用乙醇和蒸馏水清洗后，经显微镜及电镜扫描观察。发现杨梅素与FeIII反应未能得到稳定的纳米制剂。
对比例2杨梅素单金属(与单独SmIII)纳米材料制剂的制备
1、材料与方法
试验材料：Sm(NO3)3·6H2O，杨梅素，乙醇，碳酸钠，DP-聚乙二醇；所 用材料均为分析纯或化学纯级别。
试验方法：杨梅素-SmIII纳米材料的制备：将浓度为8mM的Sm(NO3)3·6H2O量取0.5mL，量取浓度为2mM的杨梅素0.5mL，溶解于乙醇中，使用碳酸钠溶液将混合物pH值调节至7，通过离心收集混合物，然后用去离子水洗涤几次，将杨梅素-SmIII复合物悬浮在1mL去离子水中，将200μL杨梅素-SmIII，200μL DP-聚乙二醇(0.1g/L)和200mL去离子水在60度下超声处理(最高强度)，持续1小时，离心，并用去离子水洗涤几次。
2、实验结果
分别用乙醇和蒸馏水清洗后，经显微镜及电镜扫描观察。发现杨梅素与SmIII反应未能得到稳定的纳米制剂。
对比例3杨梅素单金属(与单独CuII)纳米材料制剂的制备
1、材料与方法
试验材料：氯化铜，杨梅素，乙醇，碳酸钠，DP-聚乙二醇；所用材料均为分析纯或化学纯级别。
试验方法：杨梅素-CuII纳米材料的制备：量取浓度为2mM的杨梅素0.5mL，与10mM的CuCl2溶解于乙醇中，使用碳酸钠溶液将混合物pH值调节至7，通过离心收集混合物，然后用去离子水洗涤几次，将杨梅素-CuII复合物悬浮在1mL去离子水中，将200μL杨梅素-CuII，200μL DP-聚乙二醇(0.1g/L)和200mL去离子水在60度下超声处理(最高强度)，持续1小时，离心，并用去离子水洗涤几次。
2、实验结果
分别用乙醇和蒸馏水清洗后，经显微镜及电镜扫描观察。发现杨梅素与CuII反应未能得到稳定的纳米制剂。
对比例4杨梅素其它双金属(SmIIII、FeIII)纳米材料制剂的制备
1、材料与方法
试验材料：Sm(NO3)3·6H2O，氯化铁，杨梅素，乙醇，碳酸钠，DP-聚乙二醇；所用材料均为分析纯或化学纯级别。
试验方法：杨梅素-SmIIII-FeIII纳米材料的制备：量取浓度为8mM的Sm(NO3)3·6H2O 0.5mL，量取浓度为2mM的杨梅素0.5mL，与10mM的 FeCl3溶解于乙醇中，使用碳酸钠溶液将混合物pH值调节至7，通过离心收集混合物，然后用去离子水洗涤几次，将杨梅素-SmIII-FeIII复合物悬浮在1mL去离子水中，将200μL杨梅素-SmIII-FeIII，200μL DP-聚乙二醇(0.1g/L)和200mL去离子水在60度下超声处理(最高强度)，持续1小时，离心，并用去离子水洗涤几次。
2、实验结果
分别用乙醇和蒸馏水清洗后，经显微镜及电镜扫描观察。发现杨梅素与SmIII和FeIII反应未能得到稳定的纳米制剂。
对比例5杨梅素其它双金属(FeIII、CuII)纳米材料制剂的制备
1、材料与方法
试验材料：氯化铜，氯化铁，杨梅素，乙醇，碳酸钠，DP-聚乙二醇；所用材料均为分析纯或化学纯级别。
试验方法：杨梅素-CuII、-FeIII纳米材料的制备：量取浓度为2mM的杨梅素0.5mL，与10mM的CuCl2、FeCl3溶解于乙醇中，使用碳酸钠溶液将混合物pH值调节至7，通过离心收集混合物，然后用去离子水洗涤几次，将杨梅素-CuII-FeIII复合物悬浮在1mL去离子水中，将200μL杨梅素-CuII-FeIII，200μL DP-聚乙二醇(0.1g/L)和200mL去离子水在60度下超声处理(最高强度)，持续1小时，离心，并用去离子水洗涤几次。
2、实验结果
分别用乙醇和蒸馏水清洗后，经显微镜及电镜扫描观察。发现杨梅素与CuII、FeIII反应未能得到稳定的纳米制剂。

Claims (11)

  1. 一种包含杨梅素纳米材料的显影剂，该显影剂由如下成分制备而成：放射性核素及杨梅素-SmIII-CuII纳米材料制剂。
  2. 根据权利要求1所述的显影剂，其特征在于，所述放射性核素为64Cu或68Ga。
  3. 根据权利要求1或2所述的显影剂，其特征在于，所述杨梅素-SmIII-CuII纳米材料制剂由杨梅素-SmIII-CuII溶液和聚乙二醇水溶液制备而成。
  4. 根据权利要求3所述的显影剂，其特征在于，所述杨梅素-SmIII-CuII溶液由杨梅素与CuII盐和SmIII盐制备而成；
    优选地，所述CuII盐选自金属铜的氯化盐、硝酸盐、醋酸盐、氯化盐水合物、硝酸盐水合物、醋酸盐水合物中的一种或多种；优选地，所述CuII盐选自CuCl2、Cu(NO3)2、(CH3COO)2Cu、CuCl2·2H2O、Cu(NO3)2·3H2O、(CH3COO)2Cu·H2O中的一种或多种；
    优选地，所述SmIII盐选自金属钐的氯化盐、硝酸盐、醋酸盐、氯化盐水合物、硝酸盐水合物、醋酸盐水合物中的一种或多种；优选地，所述SmIII盐选自SmCl3、Sm(NO3)3、(CH3COO)3Sm、SmCl3·6H2O、Sm(NO3)3·H2O、Sm(NO3)3·5H2O、Sm(NO3)3·6H2O、(CH3COO)3Sm·H2O中的一种或多种；
    优选地，所述杨梅素与所述SmIII盐中的金属离子SmIII的摩尔比为1:0.1至1:10，优选为1:2至1:6；
    优选地，所述杨梅素与所述CuII盐中的金属离子CuII的摩尔比为1:0.1至1:20，优选为1:1至1:8。
  5. 根据权利要求1至4中任一项所述的显影剂，其特征在于，所述杨梅素-SmIII-CuII溶液与所述聚乙二醇水溶液的体积比为1:0.1至1:10，优选为1:0.5至1:3。
  6. 根据权利要求1至5中任一项所述的显影剂，其特征在于，所述聚乙二醇水溶液的溶度为0.01-10g/L，优选为0.05-0.5g/L。
  7. 根据权利要求1至6中任一项所述的显影剂，其特征在于，所述杨梅素-SmIII-CuII纳米材料制剂的粒径为5-500nm，优选为50-300nm。
  8. 根据权利要求1至7中任一项所述的显影剂，其特征在于，所述杨梅素-SmIII-CuII纳米材料制剂包括如下步骤：
    (1)制备聚乙二醇水溶液；
    (2)将杨梅素和SmIII盐及CuII盐分别溶解在溶剂中，得到杨梅素-SmIII-CuII溶液；
    (3)将步骤(2)制备得到的杨梅素-SmIII-CuII溶液与步骤(1)制备得到的聚乙二醇水溶液混合反应，得到杨梅素-SmIII-CuII纳米材料制剂；
    优选地，在步骤(1)中，所述聚乙二醇水溶液的溶度为0.01-10g/L，优选为0.05-0.5g/L；
    优选地，在步骤(2)中，所述溶剂包括但不限于水、甲醇、乙醇、丙醇、乙二醇、丙三醇；
    优选地，在步骤(3)中，所述步骤(2)制备得到的杨梅素-SmIII-CuII溶液与所述步骤(1)制备得到的聚乙二醇水溶液的体积比为1:0.1至1:10，优选为1:0.5至1:3。
  9. 一种权利要求1至8中任一项所述的包含杨梅素纳米材料制剂的显影剂的制备方法，该方法包括如下步骤：
    (1)将杨梅素-SmIII-CuII纳米材料制剂用1M的醋酸钠溶液制成1mg/mL的混合溶液；
    (2)将68GaCl3溶液或64CuCl2溶液加入至步骤(1)中制备得到的混合溶液中，并用乙酸铵调节pH，于40℃条件下反应30min；
    (3)将步骤(2)中反应结束后，待体系降至室温，采用固相萃取柱进行分离纯化获得标记后的产物68Ga-杨梅素-SmIII-CuII纳米材料制剂；
    优选地，在步骤(2)中，所述pH为3.5-4.2；
    优选地，在步骤(3)中，所述固相萃取柱为PD-10柱，流动相为80％乙醇溶液，纯水洗涤，收集液体，即得。
  10. 权利要求1至8中任一项所述的包含杨梅素纳米材料制剂的显影剂在制备肿瘤荧光和PET显像试剂、肿瘤光热治疗试剂、肿瘤诊疗一体化试剂、或癌症及转移性癌症放射性诊疗一体化试剂中的应用；
    优选地，所述癌症包括黑色素癌、乳腺癌、前列腺癌；
    优选地，所述转移性癌症包括乳腺癌肺转移癌、乳腺癌脑转移癌。
  11. 一种诊断和治疗癌症及转移性癌症的方法，该方法包括向有需要的受试者给予诊断和治疗有效量的权利要求1至8中任一项所述的包含杨梅素纳米材料制剂的显影剂或权利要求9的制备方法制备得到的包含杨梅素纳米材料制剂的显影剂；
    优选地，所述癌症包括黑色素癌、乳腺癌、前列腺癌；
    优选地，所述转移性癌症包括乳腺癌肺转移癌、乳腺癌脑转移癌。
PCT/CN2023/129857 2022-11-08 2023-11-06 一种包含杨梅素纳米材料的显影剂及其制备方法和用途 WO2024099251A1 (zh)

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