CN113577101A - Tea polyphenol-metal nanoparticles, drug-loaded nanoparticles, preparation method and application thereof - Google Patents
Tea polyphenol-metal nanoparticles, drug-loaded nanoparticles, preparation method and application thereof Download PDFInfo
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- CN113577101A CN113577101A CN202010365689.3A CN202010365689A CN113577101A CN 113577101 A CN113577101 A CN 113577101A CN 202010365689 A CN202010365689 A CN 202010365689A CN 113577101 A CN113577101 A CN 113577101A
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- nanoparticles
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- tea polyphenol
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Abstract
The invention belongs to the field of medicines, and relates to tea polyphenol-metal nanoparticles, medicine-carrying nanoparticles, a preparation method and application thereof, in particular to application of tea polyphenol in adjusting apoptosis/iron death in the aspect of anti-tumor research by dual response of pH and glutathione. The invention provides a drug delivery system for delivering chemotherapeutic drugs for cancer treatment: tea polyphenols-metal nanoparticles. The tea polyphenol-metal nanoparticles are obtained by dripping metal ion storage liquid into EGCG storage liquid, stirring, centrifuging and collecting precipitates; and (3) dropwise adding the metal ion storage solution and the anti-tumor drug into the EGCG storage solution, stirring, centrifuging, and collecting precipitates to obtain the drug-loaded nanoparticles. The drug-carrying system simultaneously delivers the antitumor drug and the metal element to the tumor tissue and is taken by tumor cells, the tea polyphenol-metal nanoparticle structure is depolymerized under the conditions of weak acidity of the tumor and high-level glutathione, and free metal elements are released, so that the antitumor drug achieves the treatment effect.
Description
Technical Field
The invention belongs to the field of medicines, and relates to tea polyphenol-metal nanoparticles, medicine-carrying nanoparticles, a preparation method and application thereof, in particular to an application of adjusting apoptosis/iron death pathway anti-tumor by dual response of tea polyphenol through pH and glutathione.
Background
With the rapid growth of economy, the deterioration of the surrounding environment is also continuously increased, thereby leading to the increasing cancer incidence. The tumor refers to the condition that the cells are stimulated by some carcinogenic factors such as external and internal factors to cause gene mutation, the growth of the tumor is not regulated, and local lumps are further formed. Tumors are classified as benign and malignant. Benign tumors are generally less harmful to the body, while malignant tumors are life threatening. Scientists continue to explore in the treatment of malignancies. In recent years, many new cancer treatment technologies have emerged, including photothermal therapy, photodynamic therapy, photoacoustic therapy, immunotherapy, and the like. However, in clinical practice, the cancer treatment means is mainly surgical resection, and chemotherapy and radiotherapy are used for assisting to further prolong the survival time of patients and improve the treatment rate of cancer. Many chemotherapeutic drugs mainly play a role by inducing tumor cell apoptosis, but with the long-term use of chemotherapeutic drugs, drug tolerance occurs, and toxic and side effects are generated on normal tissues. Therefore, it is necessary to explore new strategies to provide scientific theoretical basis for the diagnosis and treatment of diseases. The advent of combination therapy has broken this situation.
Epigallocatechin gallate (hereinafter abbreviated as EGCG), which is a main water-soluble component in green tea, is also called tea polyphenol, and has multiple pharmacological activities such as anti-inflammation and anti-oxidation (z.q. liu, Chemical Methods To equivalent Antioxidant activity, Chemical review.2010,110, 5675-5691.). Chinese patent application CN102526022A reports the application of epigallocatechin gallate in preparing antitumor drugs, especially anti-liver cancer drugs, and the drug designed aiming at cell targets is not easy to form drug resistance. EGCG can reduce the risk of cancer, mainly due to its inhibitory effects on enzymatic activity and signal transduction pathways, thereby inhibiting the proliferation of cancer cells and inducing apoptosis. EGCG is an amphiphilic compound, is water-soluble and fat-soluble, and has a plurality of benzene rings in the structure, so that the water solubility of the EGCG is influenced. However, EGCG has poor stability and is deactivated by external factors, including high temperature, high oxygen, alkaline environment and metal ion complexation. In order to improve the stability and keep the pharmacological activity, the EGCG modification solves the problem. Previous studies have shown that simple chemical reactions are sufficient to covalently link polyphenols to hyaluronic acid, thereby preserving EGCG activity (Dixon, s.j.stockwell, b.r., The role of iron and reactive oxygen species in cell death. nature chemical biology.2014,10,9-17.) because Hyaluronic Acid (HA) is a natural polysaccharide that plays a crucial role in regulating The metabolic processes in The human body. Chitosan (CS) is a natural cationic polymer obtained by N-deacetylation of chitin, has good biocompatibility, and is biologically acceptableDegrading; EGCG is modified by hydroxyl radical grafting, which can improve the stability of EGCG and improve the solubility, emulsifying activity and oxidation resistance of chitosan (Curcio, M.; Puoci, F.; Iemma, F.; Parisi, O.I.; Cirilo, G.; Spizzirri, U.G.; Picci, N., compatibility implantation of antibiotic molecules on chitosan by a free radial grafting procedure. journal of agricultural and food chemistry.2009,57,5933-8.). The existence of phenolic hydroxyl in the EGCG structure makes the EGCG easy to generate oxidation reaction and can generate complex reaction with various metal ions, and Fe3+And the complexing self-assembly action between EGCG and PVP is carried out for 24 hours, and the EFPP nano-particle is prepared and used for treating Parkinson disease (Liu Z, Li X, Wu X, Zhu C.A. dual-inhibitor system for the effective infection of Abeta 40peptides by biodegradable EGCG-Fe (iii)/PVP nanoparticles. journal of Materials Chemistry B2019; 7: 1292-9.). Chinese patent application CN107095861A discloses a preparation method of a drug containing EGCG and metal ions, which comprises the steps of adding the drug into dimethylimidazole, polyvinylpyrrolidone and zinc nitrate to form an imidazole skeleton, introducing aqueous solutions of EGCG, metal salts and the like, and finally adding EDTA (ethylene diamine tetraacetic acid) for washing to obtain the drug with double stimulus responses of EGCG and metal ions. The Chinese patent application CN100361655C reports that EGCG-calcium complex is prepared by a series of steps of EGCG, Ca and PVP action, nitrogen protection, homogenization by a high-pressure homogenizer and the like and is used for treating osteoporosis. However, the above methods for preparing EGCG/metal nanoparticles have many steps and take a long time, and some preparation methods require the addition of an organic solvent, which is not favorable for the purification treatment at the later stage, causes environmental pollution and wastes raw materials, and is also not favorable for mass production.
Iron is the fourth highest element in the earth's crust, and iron is one of the trace elements that make up the human body. In the adult human body, there is approximately 4.5g of iron, mainly in the form of hemoglobin. During the human metabolism, iron participates in the transport and storage of oxygen. Hemoglobin, as a carrier for transporting oxygen, is transported to every part of the body by combining with oxygen, participates in respiratory oxidation of the human body, and provides energy required by the body. Mitochondria as the "energy" of the human bodyQuantum factory ", iron element directly mediates the release of energy within mitochondria. In addition, iron can promote the development of the organism and improve the resistance of the organism to diseases. Under normal physiological conditions of the body, the iron content is in dynamic equilibrium, which is a stable state. The iron absorbed by food can supplement iron lost by human body, and can meet the need of development of human body. Iron absorption, transport and storage together regulate the iron homeostasis. However, when the iron intake of the body is too high, it may result in iron overload in the body, further inducing some potential diseases, such as heart and liver diseases. Iron death is a novel cell death pathway defined by Stockwell in 2012 and refers to the iron ion-dependent non-apoptotic cell death pattern (Dixon, s.j.; Lemberg, k.m.; Lamprecht, m.r.; Skouta, r.; Zaitsev, e.m.; Gleason, c.e.; Patel, d.n.; Bauer, a.j.; Cantley, a.m.; Yang, w.s.; Morrison, b.3 rd; Stockwell, b.r., Ferroptosis, an iron-dependendent form of nonapoptotic otcell death.2012, 149-1060.). In the iron death pathway, active oxygen, lipid peroxides, mitochondria become smaller, and mitochondrial membrane density increases are the main features. In the process of iron death, cells are obviously different in morphology, gene and biochemical level and apoptosis. Recent studies have shown that iron death is involved in many physiological and pathological processes, including acute kidney injury, tumorigenesis, central neurodegenerative diseases, and the like. Research shows that various external factors can induce the cell to generate an iron death process. Some activators, inhibitors, and iron chelators may modulate the iron death pathway. Under normal physiological state, the iron content keeps certain dynamic balance in cells; excess iron ions cause "iron overload" and further induce cell death, which is mainly characterized by iron ion accumulation triggering a series of oxidative reactions, including membrane lipid peroxidation and excessive oxidative stress, leading to permselective damage to The plasma membrane, ultimately resulting in cell death (Dixon, s.j.; Stockwell, b.r., The role of iron and reactive oxygen species in cell death. nature chemical biology.2014,10, 9-17.). Research reports that the anti-tumor effect is exerted by depending on the iron ion-induced iron death pathway, and Fe3+、Fe2+By contacting with tumor cellsHigh level of H2O2A fenton reaction occurs to generate reactive oxygen species, which results in inactivation of GPX4 and induction of cellular iron death. (Shen Z, Liu T, Li Y, Lau J, Yang Z, Fan W, et al. Fenton-Reaction-acceptable Magnetic Nanoparticles for ferromagnetic Therapy of organic Brain fibers ACS nano 2018; 12:11355-65.Liu T, Liu W, Zhang M, Yu W, Gao F, Li C, et al. Ferrous-Supply-Regeneration Nanoengineering for Cancer-Cell-Specific ferromagnetic Therapy in Combination with Imaging-bound phenolic Therapy ACS nano 2018; 12:12181-92.), but based on EGCG and Fe3+The nanoparticles formed in the method induce the iron death pathway, and no report is found on the treatment of lung cancer.
Disclosure of Invention
The first technical problem solved by the invention is to provide a drug-carrying system for delivering chemotherapeutic drugs aiming at the treatment of cancer, which comprises the following components: tea polyphenols-metal nanoparticles.
The second technical problem to be solved by the invention is to provide a preparation method of the medicine carrying system tea polyphenol-metal nanoparticles, which comprises the following steps:
A. preparing EGCG stock solution: dissolving EGCG powder in deionized water to obtain EGCG stock solution with concentration of 1-10 mg/mL;
B. preparing a metal ion storage solution: taking FeCl3.6H2O or FeSO4Dissolving in deionized water to obtain ion storage solution with concentration of 1-10 mM;
C. preparing tea polyphenol-metal nanoparticles: and (3) dropwise adding the metal ion storage solution into the EGCG storage solution while stirring, and after stirring for 0.5-4h, centrifuging and collecting precipitates to obtain the tea polyphenol-metal nanoparticles.
In the technical scheme, the concentration of the EGCG stock solution prepared in the step A is preferably 2 mg/mL.
In the above technical scheme, the metal ion storage solution prepared in step B is FeCl3.6H2O or FeSO4Fe as raw material3+And (4) storing the liquid.
In the above technical scheme, the Fe obtained by the preferred preparation in the step B3+The stock solution concentration was 1 mM.
In the above technical scheme, the stirring time in step C is preferably 1 h.
In the above technical scheme, the metal ion storage liquid is Fe3+Storing the solution, in step C, Fe in tea polyphenol-metal nanoparticles3+The volume ratio of the storage liquid to the EGCG storage liquid is 1: 19-1: 199; preferably Fe3+The volume ratio of the storage liquid to the EGCG storage liquid is 1: 99.
The third technical problem solved by the invention is to provide a drug-carrying nanoparticle, which is prepared by taking tea polyphenol-metal nanoparticles as a drug-carrying system and adding active drugs.
The fourth technical problem to be solved by the invention is to provide a preparation method of the drug-loaded nanoparticles, which comprises the following steps:
A. preparing EGCG stock solution: dissolving EGCG powder in deionized water to obtain EGCG stock solution with concentration of 1-10 mg/mL;
B. preparing a metal ion storage solution: taking FeCl3.6H2O or FeSO4Dissolving in deionized water to obtain metal ion storage solution with concentration of 1-10 mM;
C. preparing medicine-carrying nanoparticles: adding the antitumor drug into the EGCG storage solution, then dropwise adding the metal ion storage solution while stirring, after stirring for 0.5-4h, centrifuging to remove the free drug which is not loaded, and collecting the precipitate to obtain the drug-loaded nanoparticles.
In the technical scheme, the concentration of the EGCG stock solution prepared in the step A is preferably 2 mg/mL.
In the above technical solution, the metal ion storage solution preferably prepared in step B is FeCl3.6H2O or FeSO4Fe as raw material3+And (4) storing the liquid.
In the above technical scheme, the Fe obtained by the preferred preparation in the step B3+The stock solution concentration was 1 mM.
In the above technical scheme, the stirring time in step C is preferably 1 h.
In the above technical scheme, the metal ion storage liquid is Fe3+Storing the solution, in step C, Fe in tea polyphenol-metal nanoparticles3+Stock solution and EGCG stock solutionThe volume ratio of (A) to (B) is 1: 19-1: 199; preferably Fe3+The volume ratio of the storage liquid to the EGCG storage liquid is 1: 99.
In the above technical scheme, the water-soluble drug in step C is doxorubicin hydrochloride (hereinafter referred to as DOX); the fat-soluble curcumin (hereinafter referred to as Cur).
The invention utilizes EGCG molecules and metal ions such as Fe3+The interaction between the two forms tea polyphenol-metal nano-particles, and the process is Fe3+/Fe2+And the complexation of Fe. The tea polyphenol-metal nanoparticles prepared by the invention can wrap chemotherapeutic drugs in the nanoparticles to form a nano delivery system for delivering the chemotherapeutic drugs. The drug-loaded nanoparticles can be used as a delivery system to deliver water-soluble chemotherapeutic drug DOX (or fat-soluble drug Cur) and metal element Fe to tumor tissues and be taken up by tumor cells, tea polyphenol-metal nanoparticle structures are depolymerized under the conditions of weak acidity of tumors and high-level glutathione, and free Fe and DOX (or Cur) are released to achieve a therapeutic effect.
The preparation method of the tea polyphenol-metal nanoparticles comprises the following steps: dissolving EGCG in deionized water, dropwise adding a metal ion solution while stirring, immediately changing the solution from colorless to purple when the metal ion solution is added, allowing the color to disappear after a period of time, stirring, centrifuging, and collecting precipitate to obtain the tea polyphenol-metal nanoparticles. The preparation method of the drug-loaded nanoparticles comprises the following steps: before the metal ion storage liquid is dripped into the EGCG storage liquid, adding medicines with different contents, such as DOX and Cur, according to different drug loading rates; the theoretical drug loading ranges from 2% to 12.5%, and the experimental preparation examples have theoretical drug loadings of 2%, 5%, 10%, and 12.5%, respectively. Actual drug loading (%) - (% drug mass/(carrier mass + drug mass) × 100%; encapsulation efficiency (%) — theoretical drug load/actual drug load × 100%; and (3) after fully and uniformly mixing, adding a metal ion solution, stirring, and centrifuging to remove the free drug which is not loaded to obtain the drug-loaded nanoparticles. The tea polyphenol-metal nanoparticles and the drug-loaded nanoparticles obtained by the invention have good re-solubility after freeze-drying.
The fifth technical problem to be solved by the invention is to provide the medical application of the tea polyphenol-metal nanoparticles and the drug-loaded nanoparticles, namely the application of the tea polyphenol-metal nanoparticles and the drug-loaded nanoparticles in the preparation of drugs for treating cancers. In particular to application of the drug-loaded nanoparticles in preparing drugs for treating lung cancer.
Compared with the prior art, the tea polyphenol-metal nanoparticles and the medicine carrying nanoparticles, and the preparation method and the application thereof have the following advantages:
1. the invention is based on the preparation process of tea polyphenol-metal nanoparticles, and the tea polyphenol and metal in the aqueous solution can quickly form the nanoparticles through oxidative coupling and complexation.
2. The preparation process of the tea polyphenol-metal nanoparticles is green and environment-friendly, has mild conditions, does not contain toxic substances such as organic solvents and the like, reduces the pollution to the environment, overcomes the defects of complicated post-treatment process, long period and the like of the nanoparticles, and is beneficial to industrial production.
3. The tea polyphenol-metal nanoparticles are dissolved after freeze-drying, so that good re-solubility is shown; meanwhile, after 7 days of storage, the particle size thereof was free from a mutation phenomenon, exhibiting long-term stability.
4. The tea polyphenol-metal nanoparticles prepared by the invention can be used as a medicament carrier and a bracket for the neighborhood of biological medicines by adjusting the volume ratio of the metal ion storage liquid to the EGCG storage liquid to obtain nanoparticles with controllable sizes ranging from dozens of nanometers to several micrometers.
5. The tea polyphenol-metal nanoparticles can effectively load hydrophilic and hydrophobic antitumor drugs and have potential antitumor effects.
6. When the tea polyphenol-metal nanoparticles are used as tumor drug carriers, tumor cell death can be induced through two ways of iron death and cell apoptosis, and the anti-tumor effect of the tea polyphenol-metal nanoparticles is further exerted.
Drawings
FIG. 1 Transmission Electron micrograph: wherein A represents a transmission electron micrograph of F1; b represents a transmission electron micrograph of F3.
Fig. 2F3 nanoparticle and DF3 nanoparticle redissolution diagram.
FIG. 3F3 is a chart of hemolysis experiments.
Figure 4 stability of different drug loading DF3 nanoparticles.
Figure 5 stability of different drug loading rates of CF3 nanoparticles.
Fig. 6DOX release graph.
FIG. 7LL2 graph of apoptosis.
FIG. 8WB assay protein expression profiles: wherein (1) represents blank control, (2) represents F3, (3) represents DOX, (4) represents ADF3, and (5) represents BDF 3.
FIG. 9 tumor map of tumor-bearing mice.
FIG. 10 tumor growth profile of tumor-bearing mice after treatment.
FIG. 11 is a graph of the change in body weight of tumor-bearing mice after treatment.
Figure 12 in vivo safety experiments.
Detailed Description
The invention provides an anti-tumor research of delivering chemotherapeutic drugs such as adriamycin or curcumin and the like by using tea polyphenol-metal nanoparticles as a carrier.
The special growth form, metabolic pathway and nutrient supply of the tumor tissue promote the tumor tissue microenvironment to be obviously different from that of the normal tissue. Specifically, tumor tissue has a lower pH (5.7-6.8) than that of normal tissue and blood, and the concentration (2-10mM) of glutathione (hereinafter abbreviated as GSH) is significantly higher in cytoplasm than extracellularly (2-10. mu.M). The drug-loaded nanoparticles prepared by the invention can be automatically depolymerized under the acidic condition and high-level GSH (glutathione), so that anticancer drugs and metal ions are released, the anticancer drugs such as DOX (doxylamine) and curcumin enter cell nuclei to induce tumor cell apoptosis, and the metal ions Fe3+Is involved in the iron death of tumor cells.
In the following examples and application examples, epigallocatechin gallate (EGCG), Glutathione (GSH), doxorubicin hydrochloride (DOX), and curcumin (Cur) are used for short.
Example 1
In this embodiment, the preparation process of the tea polyphenol-metal nanoparticles comprises the following steps:
(1) dissolving 20mg of EGCG in 10mL of deionized water, heating for assisting dissolution, and preparing a tea polyphenol water solution with the concentration of 2mg/mL after full dissolution:
(2) 2.7mg FeCl3·6H2Adding O into 10mL of deionized water, fully dissolving to prepare 1mM FeCl3Aqueous solution:
(3) FeCl in the step (2)3Slowly dripping the aqueous solution into the tea polyphenol solution obtained in the step (1) to finally obtain FeCl3The volume ratio of the aqueous solution to the EGCG storage solution is 1:19, stirring is carried out while dripping, after 1h of reaction, the product is collected, centrifuged at 8000rpm and 4 ℃ for 30min, and the precipitate is collected to obtain F1 nanoparticles (the tea polyphenol-metal nanoparticles prepared by the embodiment are called F1 for short). The transmission electron micrograph is shown in FIG. 1A.
Example 2
In this embodiment, the preparation process of the tea polyphenol-metal nanoparticles comprises the following steps:
(1) dissolving 20mg of EGCG powder in 10mL of deionized water, heating for assisting dissolution, and preparing a tea polyphenol water solution with the concentration of 2mg/mL after full dissolution:
(2) 2.7mg FeCl3·6H2Adding O into 10mL of deionized water, fully dissolving to prepare 1mM FeCl3An aqueous solution;
(3) FeCl in the step (2)3Slowly dripping the aqueous solution into the tea polyphenol aqueous solution in the step (1) to finally make FeCl3The volume ratio of the aqueous solution to the EGCG storage solution is 1:99, dropwise adding and stirring, reacting for 1h, collecting the product, centrifuging at 8000rpm and 4 ℃ for 30min, and collecting the precipitate to obtain F3 nanoparticles (the tea polyphenol-metal nanoparticles prepared by the embodiment are referred to as F3). The transmission electron micrograph is shown in FIG. 1B; the picture of the redissolution of the freeze-dried powder is shown in figure 2, and the nanoparticles have good redissolution property as can be seen from figure 2.
Example 3
In this embodiment, the preparation process of the DOX drug-loaded tea polyphenol-metal nanoparticles is as follows in sequence:
(1) precisely weighing 4.000mg of DOX powder, dissolving in 2mL of deionized water, and performing ultrasonic assisted dissolution to obtain the DOX with the final concentration of 2 mg/mL.
(2) The DOX solution from step (1) was slowly added to the preparation of example 2, step (1)To the resulting aqueous solution of tea polyphenols with constant stirring, FeCl prepared in the step (2) of example 2 was added3In an aqueous solution, FeCl3The volume ratio of the aqueous solution to the EGCG storage solution is 1:99, the theoretical drug loading of DOX is 5%, magnetically stirring at room temperature for 1h, collecting the product, centrifuging at 8000rpm and 4 ℃ for 30min, and collecting the precipitate to obtain drug-loaded nanoparticles DF3 nanoparticles (the drug-loaded nanoparticles prepared in this embodiment are abbreviated as DF 3). The particle size of DF3, measured by a Malvern particle sizer, was 110.7. + -. 21.8nm and the potential was 8.50. + -. 0.32 mV. The picture of the redissolution of the DF3 lyophilized powder is shown in figure 2, and the lyophilized powder has good redissolution property as shown in figure 2.
Example 4
In the embodiment, the preparation process of the Cur drug-loaded tea polyphenol-metal nanoparticles sequentially comprises the following steps:
(1) 4.000mg of Cur powder is precisely weighed, dissolved in 2mL of absolute ethyl alcohol and subjected to ultrasonic assisted dissolution, and the final concentration of Cur is 2 mg/mL.
(2) The Cur solution obtained in the step (1) is slowly added into the tea polyphenol water solution obtained in the step (1) of the example 2, the stirring is continuously carried out, and then FeCl obtained in the step (2) of the example 2 is added3In an aqueous solution, FeCl3The volume ratio of the aqueous solution to the EGCG storage solution is 1:99, the theoretical drug-loading rates of Cur are respectively 2%, 5%, 10% and 12.5%, stirring for 1h at room temperature, collecting the product, centrifuging at 8000rpm for 30min at 4 ℃, and collecting the precipitate to obtain drug-loading nanoparticles of Cur, which are referred to as CF3 nanoparticles.
Application example 1
Nanoparticle solutions with different concentrations were prepared according to the method of example 2, mixed with 2% rabbit blood for hemolytic assay analysis, incubated at 37 ℃ for 1h, and then the absorbance of the mixed solution at 540nm was measured with a microplate reader. Wherein: PBS was phosphate buffer (pH 7.4), and the concentrations of F3 were 680. mu.M, 510. mu.M, 340. mu.M, 170. mu.M, 85. mu.M, 42.5. mu.M, and 21.2. mu.M, respectively. Hemolysis assay see fig. 3, from which it was found that no hemolysis occurred when the concentration of F3 reached 340 μ M. The nano-particles of the invention have good biological safety.
Application example 2
The drug loading rates of the nanoparticles of DF3 prepared according to the method of example 3 were 2%, 5%, 10% and 12.5%, respectively. DF3 nanoparticles were centrifuged, the supernatant was collected, and the non-loaded DOX was detected to calculate encapsulation efficiencies of 89.98%, 81.47%, 80.01%, and 79.89%, respectively. The particle size of the nanoparticles was measured at different time points with a Malvern particle sizer, a stability curve was plotted, and the stability of the nanoparticles at different drug loadings DF3 is shown in FIG. 4. The results show that the drug-loaded nanoparticles of the invention have long-term storage stability.
Application example 3
The preparation of CF3 nanoparticles with different drug-loading rates according to the method of example 4, wherein the theoretical drug-loading rates are respectively 2%, 5%, 10% and 12.5%. The nanoparticles were centrifuged, the supernatant was collected, and the unloaded Cur was detected to calculate encapsulation efficiencies of 93.89%, 90.02%, 88.93%, and 87.98%, respectively. The particle size of the nanoparticles was measured at different time points using a malvern particle sizer, a stability curve was plotted, and the stability of the nanoparticles with different drug loading rates CF3 is shown in fig. 5. The results show that the CF3 nanoparticles prepared by the invention have long-term storage stability.
Application example 4
DF3 nanoparticles prepared as in example 3 were transferred into dialysis bags (MWCO ═ 1000Da), immersed in a release medium (pH 5.4/7.4 with or without 10mM GSH), placed in a 37 degree shaker, sampled 1mL at predetermined time points and tested by HPLC for cumulative release of DOX. The DOX release profile is shown in fig. 6, from which it is seen that the release of drug is fairly slow at both pH conditions in the absence of GSH, with no more than 20% cumulative release of DOX at 96 h. The rate of DOX release is significantly increased when GSH is added, especially at pH 5.4. Due to the obvious difference between the tumor microenvironment and the normal physiological condition, the nanoparticles are slowly released under the conditions of pH 7.4 and no GSH, so that the stability of the nanoparticles is favorably kept, and the high release rate under the conditions of pH 5.0 and GSH is favorable for the nanoparticles to quickly release the medicament in the tumor microenvironment, so that the anti-tumor effect is further achieved.
Application example 5
The effects of F3 and DF3, prepared as in example 2 and example 3, and DOX on LL2 lung cancer cell apoptosis were examined. 1mL of a culture medium containing DOX, F3, ADF3 (5% DOX loading), and BDF3 (12.5% DOX loading) was added to LL2 cells, and after 24 hours of culture, the cells were collected by trypsinization and centrifugation. Detecting the apoptosis rate by a cell flow instrument according to the steps of the apoptosis kit. The apoptosis rate of LL2 is shown in FIG. 7, and it can be seen from the figure that the apoptosis rate induced by free doxorubicin is 27.6%, while the apoptosis rate of DF3 is 29.65% and 42.7% respectively according to the drug loading rate. The nanoparticles with high drug loading rate have obvious apoptosis rate, and the experimental results show that the F3 nano-carrier can effectively deliver DOX to tumor cells and play an anti-tumor effect. DF3 nanoparticles loaded with 5% DOX are hereinafter referred to as ADF3, and DF3 nanoparticles loaded with 12.5% DOX are hereinafter referred to as BDF 3.
Application example 6
The culture medium containing blank control group (normal saline NS), DOX, F3, ADF3 (5% DOX loading), BDF3 (12.5% DOX loading) was added to LL2 cells, after 24h of culture, the cells were scraped and collected with a spatula, RIPA lysate was added, lysed on ice for 30min, and the supernatant was collected by centrifugation. The BCA kit detects the total amount of protein, samples are boiled for 10min, and the samples are loaded and electrophoretically detected to express GPX4, xCT and cleared caspase 9. The expression graph of the WB detection protein is shown in FIG. 8, and the result shows that the DF3 nano-group can obviously down-regulate the expression of the iron death-related protein GPX4 and xCT and up-regulate the expression of the apoptosis-related protein clear caspase 9. The DF3 nano-particle can play an anti-tumor effect by inducing two ways of tumor cell apoptosis and iron death.
Application example 7
Nanoparticles prepared according to the method of example 3 were used for in vivo tumor studies. In the application example, LL2 tumor-bearing mice are randomly divided into 6 groups (n is 5), and the tumor volume is grown to 100mm3When the injection is carried out, physiological saline (NS), DOX, F3, ADF3 (5% DOX drug loading amount) and BDF3 (12.5% DOX drug loading amount) are respectively injected into tail vein, and the DOX administration dose is 5 mg/kg. The growth and weight change of the tumor were monitored after three times of administration every other day, as shown in fig. 9-11, and the results showed that the nanoparticles had good antitumor ability, which was stronger as the drug loading was increased.
Application example 8
In the application example, the mouse with the LL2 tumor is takenThe tumor volume is grown to 100mm after the tumor is divided into 6 groups (n is 5)3In the preparation, physiological saline (NS), DOX, F3, ADF3 (5% DOX drug loading amount) and BDF3 (12.5% DOX drug loading amount) were injected into tail vein, and the injections were administered every other day (the DOX dose for each injection was 5 mg/kg). After three administrations, mice were sacrificed, heart, liver, spleen, lung, kidney were removed and sectioned, H&E staining, microscopic observation and picture taking, see figure 12. The results show that the nanoparticles prepared by the invention do not damage main organs, and the nanoparticles prepared by the invention have good in-vivo biological safety.
Claims (10)
1. The preparation method of the tea polyphenol-metal nanoparticles is characterized by comprising the following steps: the method comprises the following steps:
A. preparing an epigallocatechin gallate stock solution: dissolving epigallocatechin gallate powder in deionized water to obtain epigallocatechin gallate stock solution with concentration of 1-10 mg/mL;
B. preparing a metal ion storage solution: taking FeCl3·6H2O or FeSO4Dissolving in deionized water to obtain ion storage solution with concentration of 1-10 mM;
C. preparing tea polyphenol-metal nanoparticles: dropwise adding the metal ion storage solution into the epigallocatechin gallate storage solution while stirring, and centrifuging to collect precipitate after stirring for 0.5-4h to obtain the medicine-carrying nano-tea polyphenol-metal nanoparticles.
2. The method for preparing tea polyphenol-metal nanoparticles according to claim 1, characterized in that: at least one of the following is satisfied:
the concentration of the epigallocatechin gallate storage solution prepared in the step A is 2 mg/mL;
the metal ion storage solution prepared in the step B is Fe3+Storing the liquid;
and C, stirring for 1 h.
3. The method for preparing tea polyphenol-metal nanoparticles according to claim 2, characterized in that: at least one of the following is satisfied:
preparation of Fe in step B3+The storage liquid adopts FeCl as a raw material3·6H2O or FeSO4Preparation of the resulting Fe3+The concentration of the stock solution is 1 mM;
the metal ion storage liquid adopts Fe3+Storing the solution, in step C, Fe in tea polyphenol-metal nanoparticles3+The volume ratio of the stock solution to the epigallocatechin gallate stock solution is 1: 19-1: 199;
preferably, the tea polyphenol-metal nanoparticles Fe in the step C3+The volume ratio of the stock solution to the epigallocatechin gallate stock solution is 1: 99.
4. The tea polyphenol-metal nanoparticles prepared by the preparation method according to any one of claims 1 to 3.
5. Medicine carrying nanoparticles are characterized in that: the tea polyphenol-metal nanoparticles of claim 4 are used as a drug-carrying system, and active drugs are added to prepare the drug-carrying nanoparticles.
6. The preparation method of the drug-loaded nanoparticles of claim 5, which is characterized in that: the method comprises the following steps:
A. preparing an epigallocatechin gallate stock solution: dissolving epigallocatechin gallate powder in deionized water to obtain epigallocatechin gallate stock solution with concentration of 1-10 mg/mL;
B. preparing a metal ion storage solution: taking FeCl3·6H2O or FeSO4Dissolving in deionized water to obtain metal ion storage solution with concentration of 1-10 mM;
C. preparing medicine-carrying nanoparticles: adding the antitumor drug into the epigallocatechin gallate storage solution, then dropwise adding the metal ion storage solution while stirring, stirring for 0.5-4h, centrifuging to remove the free drug which is not loaded, and collecting the precipitate to obtain the drug-loaded nanoparticles.
7. The preparation method of the drug-loaded nanoparticles according to claim 6, which is characterized in that: at least one of the following is satisfied:
the concentration of the epigallocatechin gallate storage solution prepared in the step A is 2 mg/mL;
the metal ion storage solution prepared in the step B is Fe3+Storing the liquid;
and C, stirring for 1 h.
8. The preparation method of the drug-loaded nanoparticles according to claim 7, characterized in that: at least one of the following is satisfied:
preparation of Fe in step B3+The storage liquid adopts FeCl as a raw material3·6H2O or FeSO4Preparation of the resulting Fe3+The concentration of the stock solution is 1 mM;
the metal ion storage liquid adopts Fe3+Stock solution of Fe3+The volume ratio of the stock solution to the epigallocatechin gallate stock solution is 1: 19-1: 199;
preferably, the Fe in the tea polyphenol-metal nanoparticles in the step C3+The volume ratio of the stock solution to the epigallocatechin gallate stock solution is 1: 99.
9. The preparation method of the drug-loaded nanoparticles according to claim 6, which is characterized in that: and C, the anti-tumor drug is adriamycin hydrochloride or curcumin.
10. The use of the tea polyphenol-metal nanoparticles of claim 4, the drug-loaded nanoparticles of claim 5 in the preparation of a medicament for the treatment of cancer;
preferably, in particular to the application of the drug-loaded nanoparticles in the claim 5 in preparing the drugs for treating lung cancer.
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