CN111467492A - Copper compound-based intelligent nano material, and preparation method and anti-tumor application thereof - Google Patents
Copper compound-based intelligent nano material, and preparation method and anti-tumor application thereof Download PDFInfo
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention discloses an intelligent nano material based on a copper compound, a preparation method and an anti-tumor application thereof, and belongs to the field of nano materials and preparation thereof. The invention firstly synthesizes a copper compound, and the copper compound and the near-infrared fluorescent dye are loaded into the organic phase-change material together to prepare the light-controlled intelligent nano material with uniform dispersion and good photo-thermal efficiency. The nano material targets cell nucleus through light control, causes DNA damage and cell apoptosis, destroys the transfer capacity of tumor cells through inhibiting the EMT process, and is expected to be used for anti-tumor research.
Description
Technical Field
The invention relates to the field of nano materials and preparation thereof, in particular to an intelligent nano material based on a copper compound and a preparation method and anti-tumor application thereof.
Background
High cost, long research time and low success rate greatly limit the clinical application of new drugs. To address these problems, in recent years, there has been much interest in reusing drugs that have been clinically approved for the treatment of other diseases to treat cancer.
In recent years, preclinical studies show that DSF can inhibit the activity of protease, promote apoptosis, deplete tumor stem cells, inhibit epithelial-mesenchymal transition (EMT) and other processes to inhibit tumor occurrence and metastasis.
In molecular mechanism, besides directly inhibiting the activity of A L DH enzyme, the metabolite of DSF and copper (Cu) are2+) The formed complex (CuET), by targeting nuclear localization protein 4(NP L4), causes tumor cell protein aggregation, oxidative stress and apoptosis-related heat shock reaction, and has stronger anticancer effect than DFS.
However, DSF presents a number of problems in the treatment of cancer, such as: (1) the proper Cu ion content is a precondition for forming CuET, but the biological distribution and dynamic balance mechanism of the inherent Cu in vivo are not completely clear, and the anti-tumor effect of DSF can be limited by insufficient Cu ions in the tumor microenvironment; (2) copper is an essential trace element for cells, and based on the mechanism of CuET formation, CuET may form in normal cells and tissues, resulting in unexpected side effects and even toxicity. Therefore, increasing the selective tumor delivery of DSF is critical for therapy; (3) given that, to date, the threshold for regulating copper metabolism between normal and tumor cells is not clear, and that excess copper may cause other carcinogenic effects, additional copper supplementation in patients who are not deficient in copper may present further problems.
To overcome these problems, we developed a novel anti-tumor drug, CuET-based smart nanomaterials (CuET/DIR NPs). Different from previous research reports, the novel nano-drug synthesized by the inventor can realize a large amount of accumulation in cells. Under the irradiation of Near Infrared (NIR) laser, a large amount of CuET is released from the nano-drug, and the DNA damage and apoptosis of tumor cells are caused by effectively targeting cell nucleus. In addition, the CuET can also destroy the metastatic capacity of tumor cells by inhibiting the EMT process, thereby realizing the anti-tumor capacity and the metastatic capacity of the copper compound nano-drug.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provide a preparation method of an intelligent nano-medicament based on a copper compound. The nano-drug has stronger tumor targeting capability, self-tracking capability and controllable drug release capability. The light control is used for targeting cell nucleus to cause cell DNA damage and apoptosis, thereby achieving the purpose of inhibiting tumor growth.
In order to achieve the purpose, the invention adopts the following technical scheme that CuET is synthesized firstly, and is loaded into organic phase change nano materials (PCMs) together with near infrared fluorescent Dye (DIR) in order to improve the controllability and the targeting property of CuET drug release, so that an intelligent light-controlled drug release nano material (CuET/DIR NPs) is obtained, and the tumor killing capacity is enhanced. Different from the previous research report, the synthesized nano material targets cell nucleus through light control to cause DNA damage and cell apoptosis, and in vivo and in vitro experiments prove that the synthesized nano material can effectively inhibit the generation and the metastasis of tumors and is expected to be used for anti-tumor treatment.
The method specifically comprises the following steps:
(1) respectively dissolving water-soluble divalent copper salt and dithiocarbamate with different substituents in deionized water, mixing according to a certain molar ratio, immediately forming a precipitate, centrifugally collecting the precipitate, and dissolving the precipitate in an organic solvent; slowly adding ethanol above the organic solvent, diffusing for one week at room temperature to obtain copper compound crystals, centrifuging and collecting the crystals for later use;
(2) dissolving dodecanoic acid and octadecanoic acid in an organic solvent according to a certain mass ratio to obtain a PCM solution for later use;
(3) dissolving phospholipid and distearoyl fatty acyl ethanolamine-polyethylene glycol in ethanol water solution according to a certain mass ratio to obtain phospholipid solution for later use;
(4) heating the phospholipid solution prepared in the step (3) to about 50 ℃;
(5) weighing a certain mass of copper compound crystal and a near-infrared fluorescent dye, respectively dissolving the copper compound crystal and the near-infrared fluorescent dye in an organic solvent to prepare a solution with the concentration of 1mg/m L-4 mg/m L for later use;
(6) uniformly mixing the PCM solution prepared in the step (2), the copper compound solution obtained in the step (5) and the near-infrared fluorescent dye solution, and then dropwise adding the mixture into the step (4);
(7) transferring the reaction solution obtained in the step (6) into a centrifugal tube, violently whirling for 3min, and placing the centrifugal tube in an ice water bath for cooling for 2 min; then, transferring the turbid solution into a beaker, and stirring at room temperature until the solution temperature is recovered to the room temperature;
(8) and (3) transferring the reaction solution obtained in the step (7) into a centrifuge tube, vortexing for 2min, filtering for 3 times by using a 0.2-micron cellulose acetate filter membrane without a surfactant, centrifugally filtering by using a VIVASPIN6 ultracentrifuge tube to remove uncoated molecules and organic solvents, washing for 3 times by using deionized water, and dispersing the obtained nanoparticles into water to obtain the light-controlled drug release and drug self-tracking nano material.
Preferably, the dithiocarbamate having different substituents in step (1) may be one of sodium dimethyldithiocarbamate, diethyldithiocarbamate, sodium diethyldithiocarbamate, potassium dimethyldithiocarbamate, potassium diethyldithiocarbamate, etc.
Preferably, the dithiocarbamate having different substituents in step (1) is sodium diethyldithiocarbamate (which is a metabolite of disulfiram).
Preferably, in step (1), the molar ratio of the water-soluble divalent copper salt to the sodium diethyldithiocarbamate is 1:2, and the organic disperse phase is chloroform.
Preferably, the mass ratio of the dodecanoic acid to the octadecanoic acid in the step (2) is 4:1, and the organic solvent is methanol.
Preferably, the phospholipid in the step (3) is any one or a mixture of several of egg yolk lecithin, soybean lecithin, dipalmitoyl phosphatidylcholine and dioleoyl phosphatidylcholine, and the distearoyl fatty acyl ethanolamine-polyethylene glycol is distearoyl fatty acyl ethanolamine-polyethylene glycol 2000-5000.
Preferably, in step (3), the phospholipid and distearoylphosphatidylethanolamine-polyethylene glycol are dissolved in a 4% ethanol aqueous solution according to a certain mass ratio.
Preferably, the organic solvent used in step (5) is dimethyl sulfoxide.
The invention also provides application of the copper compound-based intelligent nano material in antitumor drugs.
The invention also provides application of the copper compound-based intelligent nano material in medicines for treating tumors and metastasis thereof. Compared with the prior art, the invention has the beneficial effects that:
1. the intelligent nano material based on the copper compound synthesized by the invention has longer blood circulation time and better tumor selection targeting property, and can effectively target in-vivo tumors.
2. The copper compound-based intelligent nano material synthesized by the invention has intelligent light-operated drug release capacity, and the tumor killing capacity is improved.
3. The copper compound-based intelligent nano material synthesized by the invention is used for targeting cell nucleus by light control to cause DNA damage and apoptosis.
4. The intelligent nano material based on the copper compound, which is synthesized by the invention, destroys the transfer capacity of tumor cells by inhibiting the EMT process.
5. The in vivo and in vitro experiments prove that the intelligent nano material based on the copper compound can effectively inhibit the proliferation and the metastasis of tumor cells.
Drawings
The main features of the present invention are illustrated below by way of examples.
FIG. 1 is a graph of particle size distribution versus Zeta potential for CuET/DIR NPs.
FIG. 2 is a scanning and transmission electron micrograph of CuET/DIR NPs.
FIG. 3 is a graph of photothermal efficiency of CuET/DIR NPs.
FIG. 4 is a graph of controlled drug release of CuET/DIR NPs.
FIG. 5 is a graph of cell co-localization and phagocytosis of CuET/DIR NPs.
FIG. 6 is a DNA damage molecule machine map.
FIG. 7 shows the effect of in situ tumor therapy.
FIG. 8 is a graph of lung tissue bioluminescence signals of lung metastatic tumor mice.
FIG. 9 is a molecular mechanization chart of CuET for inhibiting lung metastasis.
FIG. 10 is a graph showing the evaluation of biological safety of CuET/DIR NPs.
EXAMPLE 1 Synthesis of CuET
Respectively dissolving water-soluble divalent copper salt and sodium diethyldithiocarbamate into deionized water, mixing the metal ion solution and the sodium diethyldithiocarbamate solution according to a molar ratio of 1:2, immediately forming a precipitate, centrifugally collecting the precipitate, and dissolving the precipitate into chloroform again; ethanol was then added slowly over the chloroform solution, diffused at room temperature for one week to give dark brown CuET, and the crystals were collected by centrifugation.
Example 2 Synthesis of CuET/DIR NPs
Dissolving dodecanoic acid and octadecanoic acid (mass ratio of 4:1) in methanol to obtain a PCM solution; dissolving phospholipid and distearoyl fatty acyl ethanolamine-polyethylene glycol in a 4% ethanol water solution according to a certain mass ratio to obtain a phospholipid solution; heating a certain volume of phospholipid solution to about 50 ℃; weighing a certain amount of CuET crystal and a certain amount of DIR dye, and respectively dissolving in an organic solvent; uniformly mixing the PCM solution, the CuET solution and the DIR solution, dropwise adding the mixture into the preheated phospholipid solution for reaction for a certain time, then transferring the reaction solution into a centrifugal tube, violently whirling for 3min, and placing the centrifugal tube in an ice water bath for cooling for 2 min; subsequently, the above turbid solution was transferred to a beaker and stirred at room temperature until the solution temperature returned to room temperature. After the reaction is finished, transferring the solution into a centrifuge tube, whirling for 2min, filtering for 3 times by using a 0.2 mu m cellulose acetate filter membrane without a surfactant, centrifuging and filtering by using a VIVASPIN6 ultracentrifuge tube to remove uncoated molecules and organic solvents, then washing for 3 times by using deionized water, and dispersing the obtained nanoparticles into water to obtain the light-controlled drug release and drug self-tracking nano material (CuET/DIR NPs).
Example 3 particle size distribution and Zeta potential characterization of CuET/DIR NPs
The particle size and the potential of the prepared CuET/DIR NPs are analyzed by a particle size detector, and the result is shown in figures 1A and 1B, wherein the hydrated particle size of the nano material is about 123nm, and the Zeta potential is-20.8 mV.
Example 4 topographical characterization of CuET/DIR NPs
And (3) the prepared CuET/DIR NPs are characterized by scanning and transmission electron microscopy. The results are shown in the scanning electron microscope and transmission electron microscope images (right upper insert) of FIG. 2, the nanoparticles are uniformly distributed, are spherical, and have a particle size of 80-120nm.
Example 5 measurement of photothermal efficiency of CuET/DIR NPs
Irradiating 1m L CuET/DIR NPs aqueous solution (2 μ g/m L DIR) with 808nm laser at different illumination intensities for 10min, recording temperature change every 30s, and showing the result in the photothermal efficiency chart of FIG. 3 when the photothermal intensity is 2W/cm2Meanwhile, the highest temperature of the nano material aqueous solution can reach 51.6 ℃, which shows that the light-operated nano material prepared by the invention can be used for detecting the anti-tumor activity.
Example 6 determination of drug Release efficiency of CuET/DIR NPs
Taking 1m L CuET/DIR NPs aqueous solution, and performing laser treatment at 808nm and 2W/cm2The method comprises the steps of irradiating for 5min under illumination intensity, taking 20 mu L NIR irradiation solution at a specific time point, detecting fluorescence intensity at 432nm in 80 mu L deionized water, and calculating the release amount of CuET, wherein the result is shown in figure 4.
Example 7 laser confocal microscopy localization and phagocytosis of CuET/DIR NPs
Tumor cells 4T 1-L G12 were incubated for 3h with Cy5.5 labeled CuET/DIR NPs (CuET/Cy5.5 NPs) (1 μ M CuET), washed with PBS, followed by addition of Hoechst 33342(1M L, 10 μ G/M L) and L ysotracker Green DND-26(1M L, 250nM) and staining at 37 ℃ for 20min, after 3 washes with PBS, fresh media was supplemented for fluorescence microscopy imaging (DMI6000, L eica). The results are shown in FIG. 5A, and significant co-localization was observed between Cy5.5 fluorescence (red) labeled nanoparticles and L ysotracker labeled nanoparticles, indicating that CuET/DIR NPs are phagocytosed by the lysosomal pathway. in addition, nuclear Cu phagocytosis was detected by inductively coupled plasma mass spectrometry (ICP-MS), as shown in FIG. 5B, after irradiation, the nuclear cells were irradiated at a high nuclear light level 3 times that the nuclear Cu accumulation in the nuclear nuclei of CuET.
EXAMPLE 8 determination of the levels of the DNA Damage markers γ -H2AX and 8-oxodG
Based on the results of cell co-localization and nuclear Cu uptake in example 7, we detected the DNA double-strand break marker gamma-H2 AX by western blotting (Westernbolt). The results are shown in FIG. 6A, and after 4T 1-L G12 cells were incubated by CuET/DIR NPs, the content of gamma-H2 AX was significantly increased, which indicates that the CuET/DIR NPs were optically controlled to target the cell nucleus to cause DNA damage and DNA double-strand break.further, we performed ultra performance liquid chromatography-tandem mass spectrometry (UP L C-MS) on the content of the DNA damage marker 8-oxodG, and the results are shown in FIG. 6B, and after the CuET/DIR cells were treated with CuET/DIR, the content of 8-oxodG was significantly increased, which further indicates that the CuET/DIR NPs synthesized by the present invention can optically control drug nuclear delivery to cause DNA damage and apoptosis, and reveals a new mechanism of CuET-induced cytotoxicity.
Example 9 evaluation of the therapeutic Effect of CuET/DIR NPs on tumor model mice
(1) Establishing mouse in-situ tumor model by culturing 4T 1-L G12 cells in vitro to logarithmic growth phase, injecting tumor cell suspension into right subcutaneous mammary gland fat part of healthy mouse, and allowing the tumor volume to reach 150mm3On the left and right sides, mice with consistent tumor size were screened for grouping experiments.
(2) Establishing a mouse lung metastasis model, namely pre-incubating 4T 1-L G12 cells by CuET and CuET/DIR NPs, injecting a pre-incubated tumor cell suspension into a healthy mouse through tail vein injection, and establishing a mouse in-vivo lung metastasis model.
(3) Research on antitumor effect: after the mice were treated with the in situ tumors in each group (control group, CuET/DIR NPs group, DIR NP + NIR group, and CuET/DIR NPs + NIR group), as shown in fig. 7A, the CuET/DIR NPs + NIR group had significant anti-tumor effects, indicating that NIR played an essential role in chemotherapy for inducing the release of copper complexes. In addition, tumors of each group of mice were selected, as shown in fig. 7B, the CuET/DIR NPs + NIR treatment group significantly inhibited tumor growth, and had a strong anti-tumor effect.
Further, as shown in fig. 8A, the mice in the untreated group were found to have more lung metastasis fluorescence signals by a living animal imaging system, and the CuET/DIR NPs + NIR treatment group showed almost no fluorescence signals. The lung tissues of each group of mice are taken for biological fluorescence imaging, and as shown in fig. 8B, almost no lung metastasis fluorescence signals are generated in the CuET/DIR NPs + NIR treatment group, which indicates that the CuET/DIR NPs + NIR significantly inhibits tumor metastasis.
In order to verify that the cells treated by the CuET inhibit the EMT process, a representative marker in the EMT process is detected, as shown in FIG. 9B, the invasion and migration of tumor cells are well inhibited by the reduction of Viemtin level, the Wnt/B-catenin signal pathway is involved in the expression of an EMT-related transcription activation gene and occludin is used as an epithelial cell marker and is an intact transmembrane protein, the increase of the occludin level can enhance the intercellular cohesiveness, and the results show that CuET significantly destroys the EMT process and inhibits the tumor metastasis.
(4) And (3) evaluating the safety of the CuET/DIR NPs: as shown in fig. 10A, the average body weight of each group of mice was relatively stable throughout the experiment, as seen from the body weight change curve with time. In addition, as shown in fig. 10B, hematoxylin-eosin (H & E) staining was performed on the tissues and organs of the mice of different treatment groups to find that CuET/DIR NPs have no significant biological toxicity, and the results indicate that the synthesized nanomaterial of the present invention has good biological safety.
The experiment proves that: the copper compound-based intelligent nano-drug disclosed by the invention is used for targeting cell nucleus by light control to cause DNA damage and apoptosis and destroying the transfer capacity of tumor cells by inhibiting the EMT process. In vivo and in vitro experiments prove that the nano-drug synthesized by the invention has better biological safety, can effectively treat tumors and metastasis thereof, and is expected to be used for anti-tumor research.
Claims (10)
1. An intelligent nano material based on a copper compound is characterized in that the copper compound obtained by preparation is loaded into organic phase-change nano materials (PCMs) together with near-infrared fluorescent dyes to obtain a light-controlled drug release and drug self-tracking nano material.
2. The method for preparing the copper composite-based intelligent nanomaterial according to claim 1, wherein the method comprises the following steps: firstly, a copper compound is synthesized and loaded into organic phase-change nano materials (PCMs) together with near-infrared fluorescent dyes to prepare the intelligent nano materials.
3. The preparation method of the drug-free nano-tube comprises the steps of (1) respectively dissolving a water-soluble divalent copper salt and dithiocarbamates with different substituents in deionized water, mixing according to a certain molar ratio, immediately forming a precipitate, centrifugally collecting the precipitate, dissolving in an organic solvent, slowly adding ethanol above the organic solvent, diffusing for one week at room temperature to obtain a copper compound crystal, centrifugally collecting the crystal for later use, (2) dissolving dodecanoic acid and octadecanoic acid in the organic solvent according to a certain mass ratio to obtain a PCM solution for later use, (3) dissolving phospholipid and distearoylesterethanolamine-polyethylene glycol in an ethanol water solution according to a certain mass ratio to obtain a phospholipid solution for later use, (4) heating the phospholipid solution prepared in the step (3) to about 50 ℃, (5) weighing a certain amount of the copper compound crystal and a near-infrared fluorescent dye, respectively dissolving in the organic solvent to prepare a solution with a concentration of 1mg/m L-4 mg/m L for later use, (6) dropwise adding the PCM solution prepared in the step (2), transferring the PCM solution obtained in a vigorous reaction solution obtained in a heat-exchange reaction solution, transferring the ultracentrifugation solution to a vacuum filtration reaction chamber to obtain a nano-free nano-filtration solution, and transferring the nano-free nano-cellulose solution to a filtration solution, and transferring the centrifugation process (5) to obtain a nano-free nano-cellulose solution, transferring the centrifugation process for later, transferring the centrifugation process for removing the centrifugation process, transferring the nano-free nano-ion filtration solution, transferring the nano-free nano-filtration solution, transferring the centrifugation process for later, transferring the centrifugation process for removing the nano-tube after the centrifugation process, transferring the centrifugation process (.
4. The method according to claim 3, wherein the dithiocarbamate having different substituents in step (1) is one of sodium dimethyldithiocarbamate, diethyldithiocarbamate, sodium diethyldithiocarbamate, potassium dimethyldithiocarbamate, potassium diethyldithiocarbamate, etc.
5. The dithiocarbamate with different substituents according to claim 4 is further preferably sodium diethyldithiocarbamate (which is a metabolite of disulfiram).
6. The process according to claim 3, wherein the molar ratio of the divalent copper salt to sodium diethyldithiocarbamate in step (1) is 1:2, and the dispersed organic phase is chloroform.
7. The preparation method according to claim 3, wherein the mass ratio of the dodecanoic acid to the octadecanoic acid in the step (2) is 4:1, and the organic solvent is methanol.
8. The preparation method according to claim 3, wherein the phospholipid in the step (3) can be any one or a mixture of egg yolk lecithin, soybean lecithin, dipalmitoylphosphatidylcholine and dioleoylphosphatidylcholine, and the distearoylphosphatidylethanolamine-polyethylene glycol is distearoylphosphatidylethanolamine-polyethylene glycol 2000-5000 which is dissolved in 4% ethanol aqueous solution according to a certain mass ratio.
9. The method according to claim 3, wherein the organic solvent used in the step (5) is dimethyl sulfoxide.
10. Use of the copper complex-based intelligent nanomaterial of claim 1 in the preparation of targeted and self-tracking anti-tumor nano-drugs.
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| CN112022815A (en) * | 2020-08-19 | 2020-12-04 | 四川大学 | Water phase preparation high Cu (DTC)2Method for preparing anti-tumor protein nano medicine with medicine loading capacity |
| CN112999361A (en) * | 2021-03-18 | 2021-06-22 | 南京工业大学 | Selectin-targeting-based CuET @ Fuc nano drug delivery system, preparation method and application of system in antitumor drugs |
| CN116236459A (en) * | 2023-03-06 | 2023-06-09 | 华中科技大学 | Hydroxyethyl starch stabilized CuET nanoparticle, nanoparticle dispersion liquid, preparation method and application thereof |
| CN116236459B (en) * | 2023-03-06 | 2024-05-10 | 华中科技大学 | CuET nanometer particles and nanometer particle dispersion liquid with stable hydroxyethyl starch, and preparation methods and applications thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112022815A (en) * | 2020-08-19 | 2020-12-04 | 四川大学 | Water phase preparation high Cu (DTC)2Method for preparing anti-tumor protein nano medicine with medicine loading capacity |
| CN112022815B (en) * | 2020-08-19 | 2022-05-10 | 四川大学 | Aqueous phase preparation of high Cu content (DTC)2Method for loading anti-tumor protein nano-drug |
| CN112999361A (en) * | 2021-03-18 | 2021-06-22 | 南京工业大学 | Selectin-targeting-based CuET @ Fuc nano drug delivery system, preparation method and application of system in antitumor drugs |
| CN112999361B (en) * | 2021-03-18 | 2022-10-28 | 南京工业大学 | Selectin-targeting CuET @ Fuc nano drug delivery system, preparation method and application thereof in antitumor drugs |
| CN116236459A (en) * | 2023-03-06 | 2023-06-09 | 华中科技大学 | Hydroxyethyl starch stabilized CuET nanoparticle, nanoparticle dispersion liquid, preparation method and application thereof |
| CN116236459B (en) * | 2023-03-06 | 2024-05-10 | 华中科技大学 | CuET nanometer particles and nanometer particle dispersion liquid with stable hydroxyethyl starch, and preparation methods and applications thereof |
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Application publication date: 20200731 |