CN117731631A - Nanocomposite carrier and preparation method and application thereof - Google Patents
Nanocomposite carrier and preparation method and application thereof Download PDFInfo
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- CN117731631A CN117731631A CN202311593865.9A CN202311593865A CN117731631A CN 117731631 A CN117731631 A CN 117731631A CN 202311593865 A CN202311593865 A CN 202311593865A CN 117731631 A CN117731631 A CN 117731631A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
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- 239000002502 liposome Substances 0.000 claims abstract description 83
- 210000001808 exosome Anatomy 0.000 claims abstract description 66
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 40
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims abstract description 36
- 229960002521 artenimol Drugs 0.000 claims abstract description 36
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- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 claims description 2
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a nano-meterA rice composite carrier and a preparation method and application thereof relate to the technical field of biological medicine. The nano-composite comprises a drug-loaded liposome and an exosome, wherein the drug-loaded liposome consists of unsaturated lipid, cholesterol, dihydroartemisinin, a synergist and DSPE-PEG 2000 Is prepared by the method. The nano-composite prepared by the invention does not need to introduce exogenous metal ions, and only increases endogenous Fe 2+ Content, fenton reaction independent lipid peroxidation with carrier material containing unsaturated lipid to induce apoptosis of tumor cells; at the same time Fe 2+ The peroxy bridge of the catalytic dihydroartemisinin is broken to generate active oxygen, so that tumor cells are induced to undergo apoptosis, and sorafenib serving as a synergist can enhance the apoptosis effect of iron by inhibiting reduction of lipid peroxide. The exosomes and the liposome are compounded to be used as carriers, so that the nanocomposite prepared by the invention has excellent targeting property, stability and drug loading capacity.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to a nano-composite carrier and a preparation method and application thereof.
Background
Iron apoptosis is a novel mode of apoptosis caused by the massive accumulation of intracellular iron ions, GSH elimination, or inactivation of glutathione peroxidase 4 (GPX 4). Cells that undergo apoptosis are morphologically characterized by smaller mitochondria, increased membrane density, and reduced or absent mitochondrial peaks. Currently, the novel apoptosis mode of iron apoptosis has many applications in tumor treatment, but most of the apoptosis is induced by introducing exogenous metal ions and by Fenton reaction/Fenton-like reaction. The introduction of a large amount of heavy metals in this approach can cause harm to the human body. And Fenton reaction is limited by the slightly acidic environment of tumors and insufficient hydrogen peroxide, so that the efficiency is lower.
Exosomes are derived from late endosomes, are membranous vesicles released into the extracellular matrix after fusion of cell multivesicles with cell membranes, are the smallest form of extracellular vesicles, and cannot be cleared by the mononuclear phagocyte system due to their smaller size. The exosomes are used as extracellular vesicles, can carry bioactive molecules such as proteins, nucleic acids, saccharides and the like, and are beneficial to information transmission between cells and tissues.
In the prior art, CN106928274A discloses a dihydroartemisinin diploid derivative, a pharmaceutical composition and application thereof, wherein the pharmaceutical composition is liposome nano particles, and comprises the dihydroartemisinin diploid and derivative thereof, sorafenib and liposome. CN105288648B discloses a phospholipid compound of a hydrophilic drug, a pharmaceutical composition and application thereof, and provides a phospholipid compound and liposome of a hydrophilic drug which has better lipophilicity, stronger transmembrane capability, easy cell ingestion and better drug effect, and sorafenib and dihydroartemisinin are also loaded on the drug. However, the above patent only uses liposome as carrier, and is affected by biological barrier obstruction during drug delivery, which affects the effect of the pharmaceutical composition.
Therefore, it is necessary to design a safe and efficient deliverable carrier nanocomposite that can induce apoptosis of tumor cells by Fenton-independent lipid peroxidation without introducing exogenous metal ions.
Disclosure of Invention
The invention aims at providing a nanocomposite carrier, a preparation method and application thereof.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a drug-loaded nanocomposite comprising a drug-loaded liposome and an exosome;
the drug-loaded liposome consists of unsaturated lipid, cholesterol, dihydroartemisinin, a synergist and DSPE-PEG 2000 Is prepared by the steps of;
the exosomes are derived from mesenchymal stem cells, macrophages, 4T1 tumor cells, MCF-7/ADR tumor cells or HepG2 tumor cells;
the synergistic agent is one or more of sorafenib, sulfoximine, RSL3, erastin, ML162, FIN56, FINO2 or sulfasalazine;
the unsaturated liposome is egg yolk lecithin and/or soybean lecithin.
Preferably, the mass ratio of the drug-loaded liposome to the exosome is (1-20): 1.
preferably, the exosome is prepared by the following steps: culturing cells to obtain a cell culture solution, and centrifuging the cell culture solution at 2000g for 10min to obtain a first supernatant; centrifuging the first supernatant at 10000g for 30min to obtain a second supernatant; centrifuging the second supernatant at 100000g for 70min to obtain precipitate; the precipitate was resuspended in PBS to give exosomes.
In a second aspect of the present invention, there is provided a method of preparing a drug-loaded nanocomposite comprising the steps of:
(1) Unsaturated liposome, cholesterol, dihydroartemisinin, synergist and DSPE-PEG 2000 Dissolving in organic solvent, mixing to obtain mixed solution; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; then hydrating the film, and obtaining the drug-loaded liposome after ultrasonic treatment and filtration;
(2) And (3) fusing the drug-loaded liposome with the exosome by adopting a freeze thawing method or an incubation method to prepare the drug-loaded nano-composite.
Preferably, in step (1), the unsaturated liposome, cholesterol, dihydroartemisinin, a potentiator and DSPE-PEG 2000 The mass ratio of (1) to (140): (12-13): (2-12): (1-3): (10-20).
Preferably, in the step (1), the organic solvent is prepared from chloroform and methanol according to the volume ratio (1-3): 1, and mixing.
Preferably, in the step (1), the ultrasonic power is 500-700w, and the ultrasonic time is 3min.
Preferably, in step (1), the filtering operation is: filtration was performed with a 0.22 μm filter.
Preferably, in the step (1), the hydration time is 3-30min.
Preferably, in the step (2), the specific operation of the freeze thawing method is as follows: freezing the drug-loaded liposome and exosome in liquid nitrogen, thawing at 20-25deg.C, and repeating the freezing-thawing process for 3-15 times to obtain the final product.
Preferably, in the step (2), the specific operation of the incubation method is as follows: and (3) uniformly mixing the drug-loaded liposome and the exosome, and incubating for 12-48h at 35-40 ℃ to obtain the drug-loaded nano-composite.
In a third aspect of the invention, there is provided the use of a drug-loaded nanocomposite in the manufacture of a medicament for tumour immunotherapy.
The invention has the beneficial effects that:
1. the nano-composite prepared by the invention does not need to introduce exogenous metal ions and only increases endogenous Fe 2+ The content of the lipid is independent of Fenton reaction with carrier materials containing unsaturated lipid to induce apoptosis of tumor cells. The system permeates into tumor tissues through EPR effect, enters tumor cells through endocytosis, and releases dihydroartemisinin and sorafenib in tumor microenvironment. Dihydroartemisinin can induce autophagy by regulating activity of signal pathway, thereby accelerating degradation of ferritin and increasing endogenous Fe 2+ Content of Fe 2+ The Fenton reaction independent lipid peroxidation reaction with unsaturated lipid is carried out to induce apoptosis of cell-derived iron; meanwhile, fe 2+ The peroxy bridge of the catalytic dihydroartemisinin is broken, and ROS are generated to induce tumor cells to undergo apoptosis. And sorafenib can further enhance the effect of iron apoptosis by inhibiting the reduction of LPO as a potentiator. The liposome and exosome drug-loaded nano-composite loaded with dihydroartemisinin and the synergist, which are prepared by the invention, provide a safer and more efficient treatment mode for treating tumors.
2. The invention adopts exosomes and liposome as composite carriers, wherein the liposome has good drug carrying performance, easy preparation and flexible modification, high biocompatibility of exosomes, targeting capability and contribution to improving the targeting capability of drugs. The invention adopts exosomes and liposome as composite carriers, which not only can ensure that enough drugs can be loaded on the carriers, but also can avoid being cleared by mononuclear macrophages, thereby improving the targeting capability of the nanocomposite. The invention utilizes the complementation of exosomes and liposome functions, and compounds the exosomes and the liposome as a carrier, so that the nanocomposite prepared by the invention has excellent targeting property, stability and drug loading capacity.
Drawings
Fig. 1: particle size diagram of drug-loaded nanocomposite prepared in example 1;
fig. 2: toxicity profile of the different treatment groups on MCF-7 tumor cells in test example 1;
fig. 3: toxicity profile of the different treatment groups in test example 1 on HepG2 tumor cells.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As described in the background, the new apoptosis mode of iron apoptosis has many applications in tumor therapy, but the apoptosis of tumor cells is induced by the Fenton reaction/Fenton-like reaction mostly by introducing exogenous Fenton-type heavy metals. The introduction of a large amount of heavy metals in this approach can cause harm to the human body. And Fenton reaction is limited by the slightly acidic environment of tumors and insufficient hydrogen peroxide, so that the efficiency is lower.
Based on the above, the invention provides a nano-composite for tumor immunotherapy and a preparation method thereof. On one hand, the liposome and exosome are compounded to serve as the carrier of the nano-composite, and the liposome and exosome are compounded to serve as the carrier, so that the targeting of the nano-composite can be improved, the clearance of phagocytes to the nano-composite can be greatly reduced, the iron apoptosis trigger and the like can be loaded, and the iron apoptosis is facilitated to overcome the multi-drug resistance of cells. On the other hand, the invention loads synergistic agent, dihydroartemisinin and DSPE-PEG on the composite carrier composed of exosomes and liposomes 2000 Can induce apoptosis of tumor cells.
The invention adopts the liposome prepared by unsaturated liposome, cholesterol and the like as a carrier, and the dihydroartemisinin is loaded on the liposome to obtain the nano-composite, and the experimental study shows that the liposomeOn the carrier, dihydroartemisinin is loaded, DHA can induce autophagy by regulating the activity of a signal path, so that the degradation of ferritin is accelerated, and endogenous Fe is increased 2+ Content of Fe 2+ Fenton reaction-independent lipid peroxidation with unsaturated lipid to induce apoptosis of cell-induced pig iron, fe 2+ The peroxy bridge of the catalytic dihydroartemisinin is broken, and ROS are generated to induce tumor cells to undergo apoptosis. In order to further enhance the targeting property of the nano-composite, exosomes are added on the basis of the nano-composite with the dihydroartemisinin loaded on the liposome, and the exosomes are fused by adopting an incubation method and the like, so that the targeting capability of the nano-composite is enhanced, and in order to further enhance the action effect of the nano-composite, sorafenib and the like are added on the basis of the nano-composite with the dihydroartemisinin loaded on the liposome to serve as a synergist, so that the action effect of the nano-composite is improved.
In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention are all conventional in the art and are commercially available.
Example 1: preparation method of drug-loaded nano-composite
1. Composition of raw materials
The drug-loaded nano-composite comprises a drug-loaded liposome and an exosome, wherein the mass ratio of the drug-loaded liposome to the exosome is 10:1, and the drug-loaded liposome consists of unsaturated liposome, cholesterol, dihydroartemisinin, a synergist and DSPE-PEG 2000 The preparation method comprises the steps of preparing the unsaturated liposome, wherein the unsaturated liposome is soybean lecithin, the synergist is sorafenib, and the exosome is derived from 4T1 tumor cells.
The preparation method of the exosome comprises the following steps: place 4T1 tumor cells at 5% CO 2 Culturing in a 37 ℃ incubator to obtain a cell culture solution; centrifuging the cell culture solution at 2000g for 10min to obtain a first supernatant; centrifuging the first supernatant at 10000g for 30min to obtain a second supernatant; centrifuging the second supernatant at 100000g for 70min to obtain precipitateA starch; the precipitate was resuspended in PBS to give exosomes.
2. The preparation method comprises the following steps:
(1) Soy lecithin, cholesterol, dihydroartemisinin, sorafenib and DSPE-PEG 2000 According to the mass ratio of 120:12.5:8:3:12, dissolving the mixture in an organic solvent, and uniformly mixing to obtain a mixed solution, wherein the organic solvent is obtained by mixing chloroform and methanol according to a volume ratio of 2:1; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the membrane at room temperature for 16min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
(2) And uniformly mixing the drug-loaded liposome and the exosome, and incubating for 30 hours at 37 ℃ to obtain the drug-loaded nano-composite.
The average particle diameter of the drug-loaded nanocomposite prepared in this example was measured as shown in fig. 1. As can be seen from FIG. 1, the particle size of the prepared drug-loaded nano-composite is between 10 -1 -10 -2 Between nm, it can be seen that the prepared drug-loaded nano-composite has good dimensional stability.
Example 2: preparation of drug-loaded nano-composite
1. Composition of raw materials
The drug-loaded nano-composite comprises a drug-loaded liposome and an exosome, wherein the mass ratio of the drug-loaded liposome to the exosome is 1:1, and the drug-loaded liposome consists of unsaturated liposome, cholesterol, dihydroartemisinin, a synergist and DSPE-PEG 2000 The preparation method comprises the steps of preparing the unsaturated liposome, wherein the unsaturated liposome is soybean lecithin, the synergist is sorafenib, and the exosome is derived from MCF-7 tumor cells.
The preparation method of the exosome comprises the following steps: MCF-7 tumor cells were placed in 5% CO 2 Culturing in a 37 ℃ incubator to obtain a cell culture solution; centrifuging the cell culture solution at 2000g for 10min to obtain a first supernatant; centrifuging the first supernatant at 10000g for 30min to obtain a second supernatant; centrifuging the second supernatant at 100000g for 70min to obtain precipitate; the precipitate was resuspended in PBS to give exosomes.
2. The preparation method comprises the following steps:
(1) Soy lecithin, cholesterol, dihydroartemisinin, sorafenib and DSPE-PEG 2000 According to the mass ratio of 100:12:2:1:10, dissolving the mixture in an organic solvent, and uniformly mixing to obtain a mixed solution, wherein the organic solvent is obtained by mixing chloroform and methanol according to a volume ratio of 1:1; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the membrane at room temperature for 3min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
(2) And uniformly mixing the drug-loaded liposome and the exosome, and incubating for 12 hours at 35 ℃ to obtain the drug-loaded nano-composite.
Example 3: preparation of drug-loaded nano-composite
1. Composition of raw materials
The drug-loaded nano-composite comprises a drug-loaded liposome and an exosome, wherein the mass ratio of the drug-loaded liposome to the exosome is 20:1, and the drug-loaded liposome consists of unsaturated liposome, cholesterol, dihydroartemisinin, a synergist and DSPE-PEG 2000 The preparation method comprises the steps of preparing the unsaturated liposome, wherein the unsaturated liposome is soybean lecithin, the synergist is sorafenib, and the exosome is derived from MCF-7/ADR tumor cells.
The preparation method of the exosome comprises the following steps: MCF-7/ADR tumor cells were placed in 5% CO 2 Culturing in a 37 ℃ incubator to obtain a cell culture solution; centrifuging the cell culture solution at 2000g for 10min to obtain a first supernatant; centrifuging the first supernatant at 10000g for 30min to obtain a second supernatant; centrifuging the second supernatant at 100000g for 70min to obtain precipitate; the precipitate was resuspended in PBS to give exosomes.
2. The preparation method comprises the following steps:
(1) Soy lecithin, cholesterol, dihydroartemisinin, sorafenib and DSPE-PEG 2000 According to the mass ratio of 140:13:12:3:20 in an organic solvent, and uniformly mixing to obtain a mixed solution, wherein the organic solvent is obtained by mixing chloroform and methanol according to a volume ratio of 3:1; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the film at room temperature for 30min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membraneObtaining drug-loaded liposome;
(2) Freezing the liposome and exosome of the drug-loaded drug in liquid nitrogen, thawing at 20-25deg.C, and repeating the freezing-thawing process for 10 times to obtain the drug-loaded nanocomposite.
Comparative example 1: preparation of nanocomposites
1. Composition of raw materials
The nano-composite comprises liposome and exosome, wherein the mass ratio of the liposome to the exosome is 10:1, and the liposome is prepared from soybean lecithin, cholesterol and DSPE-PEG 2000 The exosomes are derived from 4T1 tumor cells, and the exosomes are prepared in the same way as in example 1.
2. The preparation method comprises the following steps:
(1) Soy lecithin, cholesterol and DSPE-PEG 2000 According to the mass ratio of 120:12.5:12, dissolving the mixture in an organic solvent, and uniformly mixing to obtain a mixed solution, wherein the organic solvent is obtained by mixing chloroform and methanol according to a volume ratio of 2:1; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the membrane at room temperature for 16min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membrane to obtain liposome;
(2) And (3) uniformly mixing the liposome and the exosome, and incubating for 30 hours at 37 ℃ to obtain the drug-loaded nano-composite.
Comparative example 2: preparation of drug-loaded nano-composite
1. Composition of raw materials
The drug-loaded nano-composite comprises a drug-loaded liposome and an exosome, wherein the mass ratio of the drug-loaded liposome to the exosome is 10:1, and the drug-loaded liposome is prepared from soybean lecithin, cholesterol, dihydroartemisinin and DSPE-PEG 2000 The exosomes are derived from 4T1 tumor cells, and the exosomes are prepared in the same way as in example 1.
2. The preparation method comprises the following steps:
(1) Soy lecithin, cholesterol, dihydroartemisinin and DSPE-PEG 2000 According to the mass ratio of 120:12.5:8:12 is dissolved in an organic solvent, and is uniformly mixed to obtain a mixed solution, wherein the organic solvent is mixed with chloroform and methanol according to a volume ratio of 2:1And (3) obtaining the product; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the membrane at room temperature for 16min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
(2) And uniformly mixing the drug-loaded liposome and the exosome, and incubating for 30 hours at 37 ℃ to obtain the drug-loaded nano-composite.
Comparative example 3: preparation of drug-loaded nano-composite
1. Composition of raw materials
The drug-loaded nano-composite comprises a drug-loaded liposome and an exosome, wherein the mass ratio of the drug-loaded liposome to the exosome is 10:1, and the drug-loaded liposome is prepared from soybean lecithin, cholesterol, sorafenib and DSPE-PEG 2000 The exosomes are derived from 4T1 tumor cells, and the exosomes are prepared in the same way as in example 1.
2. The preparation method comprises the following steps:
(1) Soy lecithin, cholesterol, sorafenib and DSPE-PEG 2000 According to the mass ratio of 120:12.5:3:12, dissolving the mixture in an organic solvent, and uniformly mixing to obtain a mixed solution, wherein the organic solvent is obtained by mixing chloroform and methanol according to a volume ratio of 2:1; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the membrane at room temperature for 16min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
(2) And uniformly mixing the drug-loaded liposome and the exosome, and incubating for 30 hours at 37 ℃ to obtain the drug-loaded nano-composite.
Test example 1:
the invention selects two tumor cells of MCF-7 tumor cells and HepG2 tumor cells for cytotoxicity test, and the specific test steps are as follows:
(1) Cells in logarithmic growth phase (Density: 1.0X10) 4 Well) was inoculated into 96-well plates, cultured overnight in a cell incubator, and experiments were started until the cells grew to 80-90%;
(2) The test set 6 treatment groups, treatment groups 1-6, respectively:
treatment group 1 employed saturated lipids (DMPC);
unsaturated liposome (Lip) prepared from soybean lecithin in treatment group 2;
treatment group 3 employed free DHA (DHA);
treatment group 4 employed saturated lipid + DHA (dha@dmpc),
the preparation method comprises the following steps: DMPC and dihydroartemisinin are mixed according to the mass ratio of 120:8, dissolving the mixture in an organic solvent, and uniformly mixing to obtain a mixed solution, wherein the organic solvent is obtained by mixing chloroform and methanol according to a volume ratio of 2:1; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the membrane at room temperature for 16min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
the treatment group 5 adopts unsaturated lipid plus DHA (DHA@lip),
the preparation method comprises the following steps: soybean lecithin and dihydroartemisinin are mixed according to the mass ratio of 120:8, dissolving the mixture in an organic solvent, and uniformly mixing to obtain a mixed solution, wherein the organic solvent is obtained by mixing chloroform and methanol according to a volume ratio of 2:1; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; hydrating the membrane at room temperature for 16min, performing ultrasonic treatment under ice bath condition at 600w for 3min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
treatment group 6 (control group): incomplete 1640 medium was used.
(3) Transferring 35.7 mu L of DMPC, lip, DHA, DHA@DMPC and DHA@Lip of the treatment groups 1-5 and a centrifuge tube respectively, adding 964.3 mu L of incomplete 1640 culture medium for dilution to obtain a first diluent, transferring 10 mu L, 100 mu L, 200 mu L and 300 mu L of the first diluent into the centrifuge tube respectively, and adding the incomplete 1640 culture medium to 1mL to obtain a drug-loaded nano-composite diluent;
after 48h of treatment with dihydroartemisinin concentration as standard, 100. Mu.L of incomplete 1640 medium containing 20. Mu.LMTT dye solution (5 mg/mL) is added under dark condition and cultured for 4h in an incubator at 37 ℃, then the culture solution is sucked, 150. Mu.L of DMSO solution is added to each well, incubation is continued in the incubator for 15min, absorbance is measured by an enzyme-labeled instrument at 490nm, and the relative cell viability (OD) is calculated, and the results are shown in FIG. 2 and FIG. 3.
Wherein od= [ OD ] Treatment group /OD Control group ]×100％。
As can be seen from fig. 2 and 3, treatment group 5 has stronger cytotoxicity than treatment group 4, and thus it can be verified that DHA can regulate Fe 2+ And then the content of the unsaturated lipid in the carrier material is subjected to Fenton reaction independent lipid peroxidation to induce the tumor cells to undergo apoptosis.
Test example 2: MTT assay
The drug-loaded nanocomposites prepared in example 1 and comparative examples 1 to 3 were selected as test cells, and MTT assay was performed to detect the survival rate of the cells, specifically as follows:
(1) Cells in logarithmic growth phase (Density: 1.0X10) 4 Well) was inoculated into 96-well plates, cultured overnight in a cell incubator, and experiments were started until the cells grew to 80-90%;
(2) The experimental treatment groups 1-4 are respectively equal volume and same concentration of the drug-carrying nanocomposite diluents 1-4 prepared in the example 1 and the comparative examples 1-3;
the preparation methods of the drug-loaded nanocomposite diluents 1-4 prepared in example 1 and comparative examples 1-3 are as follows: transferring 35.7 mu L of the drug-loaded nano-composite into a centrifuge tube, adding 964.3 mu L of incomplete 1640 culture medium into the centrifuge tube for dilution to obtain a first diluent, transferring 10, 20, 30 and 40 mu L of the first diluent into the centrifuge tube, and adding the incomplete 1640 culture medium into 1mL of the centrifuge tube to obtain the drug-loaded nano-composite diluent with the concentration of 1 mu M, 2 mu M, 3 mu M and 4 mu M of the drug-loaded nano-composite.
(3) After 48 hours of treatment with dihydroartemisinin concentration as a standard, 100. Mu.L of incomplete 1640 medium containing 20. Mu.LMTT dye (5 mg/mL) was added under dark conditions and incubated in an incubator at 37℃for 4 hours, after which the culture was aspirated, 150. Mu.L of DMSO solution was added to each well, incubation was continued in the incubator for 15 minutes, absorbance was measured with an enzyme-labeled instrument at 490nm, and the relative cell viability (OD) was calculated using the group of untreated medium (incomplete 1640 medium) as a control group, and the results are shown in Table 1.
Wherein od= [ OD ] Treatment group /OD Control group ]×100％。
TABLE 1 relative cell viability (%)
As can be seen from Table 1, the drug-loaded nano-composite prepared by the invention adopts liposome and exosome as carriers, and carries dihydroartemisinin and sorafenib, and the relative survival rate of 4T1 cells is far lower than that of comparative example 2 and comparative example 3, namely single-load dihydroartemisinin and single-load sorafenib. From this, it can be seen that the drug-loaded complex prepared by the present invention has cytotoxicity. When the cytotoxicity test is carried out by adopting the equal amount and equal concentration of the drug-loaded nano-composite diluent, the relative survival rate of the 4T1 cells of the drug-loaded nano-composite prepared in the example 1 is far lower than that of the 4T1 cells of the nano-composite prepared in the comparative examples 1-3, so that the invention has better anti-tumor effect by adopting exosomes, unsaturated liposomes, sorafenib and dihydroartemisinin.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the same, but rather, various modifications and variations may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims (9)
1. A drug-loaded nanocomposite, comprising: drug-loaded liposomes and exosomes;
the drug-loaded liposome consists of unsaturated lipid, cholesterol, dihydroartemisinin, a synergist and DSPE-PEG 2000 Is prepared by the steps of; the exosomes are derived from mesenchymal stem cells, macrophages, 4T1 tumor cells,MCF-7 tumor cells, MCF-7/ADR tumor cells or HepG2 tumor cells; the synergist is one or more of sorafenib, sulfoximine, RSL3, erastin, ML162, FIN56, FINO2 or sulfasalazine, and the unsaturated liposome is soybean lecithin and/or egg yolk lecithin;
the mass ratio of the drug-loaded liposome to the exosome is (1-20): 1.
2. the drug-loaded nanocomposite of claim 1, wherein the exosome is prepared by the process of: culturing cells to obtain a cell culture solution, and centrifuging the cell culture solution at 2000g for 10min to obtain a first supernatant; centrifuging the first supernatant at 10000g for 30min to obtain a second supernatant; centrifuging the second supernatant at 100000g for 70min to obtain precipitate; the precipitate was resuspended in PBS to give exosomes.
3. A method for preparing the drug-loaded nanocomposite according to claim 1 or 2, comprising the steps of:
(1) Unsaturated lipid, cholesterol, dihydroartemisinin, synergist and DSPE-PEG 2000 Dissolving in organic solvent, mixing to obtain mixed solution; removing the organic solvent by rotary evaporation of the mixed solution to obtain a film; then hydrating the film, and obtaining the drug-loaded liposome after ultrasonic treatment and filtration;
(2) And (3) fusing the drug-loaded liposome with the exosome by adopting a freeze thawing method or an incubation method to prepare the drug-loaded nano-composite.
4. The method of claim 3, wherein in step (1), the unsaturated lipid, cholesterol, dihydroartemisinin, the synergist and DSPE-PEG are used as the active ingredients 2000 The mass ratio of (1) to (140): (12-13): (2-12): (1-3): (10-20).
5. The method of preparing a drug-loaded nanocomposite according to claim 3, wherein in step (1), the organic solvent is prepared from chloroform and methanol in a volume ratio of (1-3): 1, and mixing.
6. The method of claim 3, wherein in step (1), the hydration time is 3 to 30 minutes.
7. The method of claim 3, wherein in step (2), the freeze thawing method comprises the following specific steps: freezing the drug-loaded liposome and exosome in liquid nitrogen, thawing at 20-25deg.C, and repeating the freezing-thawing process for 3-15 times to obtain the final product.
8. A method for preparing a drug-loaded nanocomposite according to claim 3, wherein in step (2), the incubation method is specifically performed as follows: and (3) uniformly mixing the drug-loaded liposome and the exosome, and incubating for 12-48h at 35-40 ℃ to obtain the drug-loaded nano-composite.
9. Use of a drug-loaded nanocomposite according to claim 1 or 2 for the preparation of a tumor immunotherapeutic agent.
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| CN117965429A (en) * | 2024-03-29 | 2024-05-03 | 四川大学 | Curcumin and miR140 loaded targeted hybridization exosome, preparation method and application |
| CN118402999A (en) * | 2024-06-26 | 2024-07-30 | 天津外泌体科技有限公司 | Extracellular vesicle-artemisinin loading substance as well as preparation method and application thereof |
| CN118402999B (en) * | 2024-06-26 | 2024-09-24 | 天津外泌体科技有限公司 | Extracellular vesicle-artemisinin loading substance as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117965429A (en) * | 2024-03-29 | 2024-05-03 | 四川大学 | Curcumin and miR140 loaded targeted hybridization exosome, preparation method and application |
| CN118402999A (en) * | 2024-06-26 | 2024-07-30 | 天津外泌体科技有限公司 | Extracellular vesicle-artemisinin loading substance as well as preparation method and application thereof |
| CN118402999B (en) * | 2024-06-26 | 2024-09-24 | 天津外泌体科技有限公司 | Extracellular vesicle-artemisinin loading substance as well as preparation method and application thereof |
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